Insulin-like growth factor-I (lGF-l): safety and efficacy.

Science.gov (United States)

Laron, Zvi

2004-11-01

Insulin-like growth factor I (IGF-I) is a peptide synthesized mainly in the liver by stimulation by pituitary growth hormone (GH). It circulates almost entirely bound to its binding proteins. It is the anabolic effector hormone of GH. It is the only treatment in states of GH resistance such as Laron syndrome and blocking antibodies to human GH. As it suppresses insulin and GH secretion it has been used in states of insulin resistance including Type II diabetes mellitus. IGF-I is administered by once or twice daily injections. Adverse effects are mostly caused by overdosage. The usual daily dose in children ranges from 100-200 microg/kg.

Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

International Nuclear Information System (INIS)

Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H.

1990-01-01

To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the α-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor

[Factors associated with insulin resistence in rural populations].

Science.gov (United States)

Mendes, Larissa Loures; Gazzinelli, Andréa; Velásquez-Meléndez, Gustavo

2009-04-01

This study explores the relations of anthropometric, body composition assessments, biochemical and hemodynamic parameters with insulin resistance in two rural communities. Sample was composed by adults aged 18 or older, both sexes. Participants were excluded if pregnant and diabetic. Data collection included demographic lifestyle, hemodynamic, anthropometric and biochemical variables. From the 567 subjects, 50.4% were men and 49.6%, women. Most of the sample was non-white (75.7%), lived with partner (69.3%) and had low educational level. Overweight and obesity prevalences were 17.4% and 5.5%, respectively. Multivariate analysis found risk factors associated to insulin resistance for non-diabetic adults with low income and educational level: overweight, obesity, elevated waist-to-hip ratio, C-reactive protein and skin color.

Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves

International Nuclear Information System (INIS)

Kamal, M.M.; Van Eetvelde, M.; Bogaert, H.; Hostens, M.; Vandaele, L.; Shamsuddin, M.; Opsomer, G.

2016-01-01

Full text: The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves. Birth weight and gestational age of the calves at delivery were determined. On the next day, heart girth, wither height and diagonal length of both the calves and their dams were measured. Parity, body condition score and age at calving were recorded for all dams. For the cows, days open before last gestation, lactation length (LL), lenght of dry period (DP) and calving interval were also calculated. The magnitude and shape of the lactation curve both quantified using the MilkBot model based on monthly milk weights, were used to calculate the amount of milk produced during gestation. Using the same procedure, cumulative milk production from conception to drying off (MGEST) was calculated. A blood sample was collected from all calves (n=481; 169 born to heifers and 312 born to cows) at least 5 h after a milk meal on day 3 of life to measure basal glucose and insulin levels. In addition, an intravenous glucose-stimulated insulin secretion test was performed in a subset of the calves (n=316). After descriptive analysis, generalized linear mixed models were used to identify factors that were significantly associated with the major insulin traits (Insb, basal insulin level; QUICKI, quantitative insulin sensitivity check index; AIR, acute insulin response; DI, disposition index) of the newborn calves. The overall average birth weight of the calves was 42.7 ± 5.92 kg. The insulin traits were significantly associated with MGEST (P=0.076) and longer DP (P=0.034). The QUICKI was estimated to be lower in calves born to the cows having passed a higher MGEST (P=0.030) and longer DP (P=0.058). Moreover, the AIR (P=0.009) and DI (P=0.049) were estimated to be lower in male compared with female calves. Furthermore, the AIR

Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver

DEFF Research Database (Denmark)

Bor, M V; Sørensen, B S; Vinter-Jensen, L

2000-01-01

BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor...... I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth.......8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein transforming growth factor-alpha. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-alpha and epidermal growth factor receptor, as well...

Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor

Energy Technology Data Exchange (ETDEWEB)

Liu, Gang [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Hitomi, Hirofumi, E-mail: hitomi@kms.ac.jp [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Hosomi, Naohisa [Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa (Japan); Lei, Bai; Nakano, Daisuke [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Deguchi, Kazushi; Mori, Hirohito; Masaki, Tsutomu [Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Ma, Hong [Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Griendling, Kathy K. [Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (United States); Nishiyama, Akira [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan)

2011-10-15

Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. -- Highlights: {yields} Mechanical stretch augments insulin-induced VSMC proliferation via IGF-1 receptor. {yields} Src/EGFR-mediated ERK and Akt phosphorylation are augmented in stretched VSMCs. {yields} Similar to in vitro experiment, IGF-1 receptor is increased in hypertensive rats. {yields} Results provide possible mechanisms of vascular remodeling in hypertension with DM.

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

Science.gov (United States)

Wolfe, Andrew; Divall, Sara; Wu, Sheng

2014-10-01

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. Copyright © 2014 Elsevier Inc. All rights reserved.

Insulin-like growth factors: assay methods and their implications

International Nuclear Information System (INIS)

Guyda, H.J.; Posner, B.I.; Schiffrin, A.; Rappaport, R.; Postel-Vinay, M.C.; Corvol, M.T.

1981-01-01

The insulin-like growth factors (IGF's) are small molecular weight peptides (6-10 x 10 3 daltons) that circulate in blood plasma almost entirely bound to macromolecular carrier proteins. The growth-promoting and insulin-like activities of IGF's can be explained by the observed ability of these peptides to interact with the IGF receptor on the one hand and with the insulin receptor on the other. These observations have led to the establishment of radioreceptor assays (RRA's), competitive protein binding assays (CPBA's), and more recently radioimmunoassays (RIA's) for the IGF's that have different specificities. Because of their ease of performance and sensitivity, the radioligand assays have largely supplanted the biological assays originally utilized to identify and characterize these anabolic peptides. In this report the authors' studies are summarised which utilize a slightly acidic IGF which has been purified on the basis of its insulin-like activity in an insulin RRA and which was termed ILAs. They refer to purified insulin-like peptides that have the properties of a somatomedin by the generic term insulin-like growth factor (IGF). Somatomedin (SM) activity will be utilized to connote that activity in plasma or serum determined by bioassay. The competitive dose-response curves for IGF peptides in the insulin RRA as well as those in the ILAs RRA are presented. A combination of bioassays, RRA and RIA were employed to assess somatomedin activity and IGF peptide levels in a number of clinical circumstances. The correlations are discussed. (Auth.)

Vitamin D deficiency and insulin resistance as risk factors for dyslipidemia in obese children.

Science.gov (United States)

Erol, Meltem; Bostan Gayret, Özlem; Hamilçıkan, Şahin; Can, Emrah; Yiğit, Özgu L

2017-04-01

Dyslipidemia is one of the major complications of obesity; vitamin D deficiency and insulin resistance are attending metabolic complications in dyslipidemic obese children. Objective. To determine if vitamin D deficiency and insulin resistance are risk factors for dyslipidemia in obese children. This study was conducted in the Department of Pediatrics at Bagcilar Training and Research Hospital in Istanbul, Turkey between 2014 and 2015. Obese patients whose age range was 8-14 were included in the study. The serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, fasting glucose, insulin, alanine aminotransferase, vitamin D levels were measured; a liver ultrasonography was performed. Homeostatic model assessment (HOMA-IR), was used to calculate insulin resistance. 108 obese children were included; 39 (36.11%) had dyslipidemia. The average fasting blood glucose (88.74 ± 7.58 vs. 95.31 ± 6.82; p= 0.0001), insulin level (14.71 ± 12.44 vs. 24.39 ± 15.02; p= 0.0001) and alanine aminotransferase level (23.45 ± 11.18 vs. 30.4 ± 18.95; p= 0.018) were significantly higher in the children with dyslipidemia. In the dyslipidemic obese children, the average hepatosteatosis rate and HOMA-IR level were higher; 28 (71.9%) had hepatosteatosis, 37 (94.87%) had insulin resistance; the vitamin D levels were dyslipidemia. Obese children in our region exhibit low vitamin D and increased HOMA-IR levels, which are efficient risk factors of dyslipidemia.

Insulin Like Growth Factor System: How Does it Affect Neonatal Anthropometry?

Directory of Open Access Journals (Sweden)

Emine Kacar

2016-09-01

Full Text Available Aim: The present study aims to clarify the role of insulin like growth factor-1 (IGF-1, insulin like growth factor binding protein-3 (IGFBP-3, ghrelin, and insulin in fetal growth. Material and Method: Based on Turkish standards, 14 newborns were defined as small for gestational age (SGA, 33 newborns were described as appropriate for gestational age (AGA, and 13 newborns were identified as large for gestational age (LGA. IGF-1, IGFBP-3, ghrelin, and insulin levels were measured in umbilical cord and maternal serum. Results: The LGA group had significantly higher levels of IGF-1, IGFBP-3, ghrelin, and insulin in umbilical cord and maternal serum than the SGA group. Umbilical cord and maternal serum levels of IGF-1 and IGFBP-3 correlated significantly and positively with body weight, body length, head circumference, and abdominal circumference of the neonates. Discussion: Based on the findings of the present study, it may be postulated that insulin like growth factor system has a role in fetal growth.

Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration.

Science.gov (United States)

Deochand, Chetram; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M

2016-01-01

Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

OpenAIRE

Kong, Kathleen; Kumar, Manish; Taruishi, Midori; Javier, Ronald T.

2015-01-01

The E4-ORF1 protein encoded by human adenovirus stimulates viral replication in human epithelial cells by binding and activating cellular phosphatidylinositol 3-kinase (PI3K) at the plasma membrane and cellular Myc in the nucleus. In this study, we showed that E4-ORF1 hijacks the tyrosine kinase activities of cellular epidermal growth factor receptor (EGFR) and insulin receptor (InsR)/insulin-like growth factor receptor 1 (IGF1R), as well as the lipid kinase activity of PI3K, to mediate const...

Insulin-like growth factors and insulin-like growth factor binding proteins in mammary gland function

International Nuclear Information System (INIS)

Marshman, Emma; Streuli, Charles H

2002-01-01

Insulin-like growth factor (IGF)-mediated proliferation and survival are essential for normal development in the mammary gland during puberty and pregnancy. IGFs interact with IGF-binding proteins and regulate their function. The present review focuses on the role of IGFs and IGF-binding proteins in the mammary gland and describes how modulation of their actions occurs by association with hormones, other growth factors and the extracellular matrix. The review will also highlight the involvement of the IGF axis in breast cancer

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

Science.gov (United States)

Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

2016-02-01

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

Energy Technology Data Exchange (ETDEWEB)

El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

2013-02-21

Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

Application of insulin-like growth factor-I and insulin release test in diabetes mellitus

International Nuclear Information System (INIS)

Chen Dong; Ma Yongxiu; Duan Wenruo

2003-01-01

The purpose of this study was to determine the role of insulin-like growth factor-I (IGF-I) and insulin release test (IRT) in understanding the extent of damage to ability of reducing blood sugar in different types of diabetes mellitus (DM) and in selection of treatment plan and adjustment of using drugs. OGTT, IRT and determination of IGF-I level of 67 normal subjects and 217 DM patients were performed. The result was analyzed comparatively. The level of IGF-I was negatively correlated with the level of fasting blood sugar, and positively correlated with the level of fasting insulin. Our conclusions are: There are two ways of reducing blood sugar: one is by insulin, and the other is by IGF-I. IRT can reflect the former better, and IGF-I the latter. The combination of these two is of significant value in diagnosis and treatment of DM

AZD5363 inhibits inflammatory synergy between interleukin-17 and insulin/insulin-like growth factor 1

Directory of Open Access Journals (Sweden)

Chong eChen

2014-12-01

Full Text Available In the United States, one third of population is affected by obesity and almost 29 million people are suffering from type 2 diabetes. Obese people have elevated serum levels of insulin, insulin-like growth factor 1 (IGF1 and interleukin-17 (IL-17. Insulin and IGF1 are known to enhance IL-17-induced expression of inflammatory cytokines and chemokines, which may contribute to the chronic inflammatory status observed in obese people. We have previously demonstrated that insulin/IGF1 signaling pathway crosstalks with IL-17-activated nuclear factor-kappa B (NF-κB pathway through inhibiting glycogen synthase kinase 3β (GSK3β activity. However, it is unclear whether GSK3α also plays a role and whether this crosstalk can be manipulated by AZD5363, a novel pan-Akt inhibitor that has been shown to increase GSK3 activity through reducing phosphorylation of GSK3α and GSK3β. In this study, we investigated IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1, C-C motif ligand 20 (Ccl20 and interleukin-6 (Il-6 in wild-type, GSK3α-/-, and GSK3β-/- mouse embryonic fibroblast (MEF cells as well as in mouse prostate tissues by real-time quantitative PCR. We examined the proteins involved in the signaling pathways by Western blot analysis. We found that insulin and IGF1 enhanced IL-17- induced expression of Cxcl1, Ccl20 and Il-6, which was associated with increased phosphorylation of GSK3α and GSK3β in the presence of insulin and IGF1. AZD5363 inhibited the synergy between IL-17 and insulin/IGF1 through reducing phosphorylation of GSK3α and GSK3β by inhibiting Akt function. These findings imply that the cooperative crosstalk of IL-17 and insulin/IGF1 in initiating inflammatory responses may be alleviated by AZD5363.

Insulin and insulin-like growth factor-1 increased in preterm neonates following massage therapy.

Science.gov (United States)

Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria; Dieter, John N I; Kumar, Adarsh M; Schanberg, Saul; Kuhn, Cynthia

2008-12-01

To determine if massage therapy increased serum insulin and insulin-like growth factor-1 (IGF-1) in preterm neonates. Forty-two preterm neonates who averaged 34.6 weeks (M = 29.5 wk gestational age; M birth weight = 1237 g) and were in the "grower" (step-down) nursery were randomly assigned to a massage therapy group (body stroking and passive limb movements for three, 15-minute periods per day for 5 days) or a control group that received the standard nursery care without massage therapy. On Days 1 and 5, the serum collected by clinical heelsticks was also assayed for insulin and IGF-1, and weight gain and kilocalories consumed were recorded daily. Despite similar formula intake, the massaged preterm neonates showed greater increases during the 5-day period in (1) weight gain; (2) serum levels of insulin; and (3) IGF-1. Increased weight gain was significantly correlated with insulin and IGF-1. Previous data suggested that preterm infant weight gain following massage therapy related to increased vagal activity, which suggests decreased stress and gastric motility, which may contribute to more efficient food absorption. The data from this study suggest for the first time that weight gain was also related to increased serum insulin and IGF-1 levels following massage therapy. Preterm infants who received massage therapy not only showed greater weight gain but also a greater increase in serum insulin and IGF-1 levels, suggesting that massage therapy might be prescribed for all growing neonates.

Insulin-like growth factor-1 is a negative modulator of glucagon secretion

OpenAIRE

Mancuso, Elettra; Mannino, Gaia C.; Fatta, Concetta Di; Fuoco, Anastasia; Spiga, Rosangela; Andreozzi, Francesco; Sesti, Giorgio

2017-01-01

Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic ?-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of ?-cells glucagon secretion...

Detection of polymorphism of the insulin-like growth factor-I (IGF-I ...

African Journals Online (AJOL)

Molecular genetic selection on individual genes is a promising method to genetically improve economically important traits in chickens. The insulin-like growth factor-I (IGF-I) gene may play important roles in growth of multiple tissues, including muscle cells, cartilage and bone. In the present study, polymorphism of the ...

Delay of insulin initiation in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycemic agents (analysis of patient- and physician-related factors): A prospective observational DIPP-FACTOR study in Korea.

Science.gov (United States)

Kim, Sin Gon; Kim, Nam Hoon; Ku, Bon Jeong; Shon, Ho Sang; Kim, Doo Man; Park, Tae Sun; Kim, Yong-Seong; Kim, In Joo; Choi, Dong Seop

2017-05-01

To assess the time to initiation of insulin therapy, and concurrently investigate both patient- and physician-related factors associated with delaying insulin therapy in Korean patients with type 2 diabetes uncontrolled by oral hypoglycemic agents (OHAs). This prospective, observational disease registry study was carried out across 69 centers in Korea. Type 2 diabetes patients who had received two or more OHAs within the past 5 years, had a glycated hemoglobin ≥8% in the past 6 months and had not received insulin were included. Data recorded on data collection forms during a 12-month period were analyzed. Of 2168 patients enrolled, 1959 were evaluated and classified as the insulin-initiated or insulin-delayed group. Insulin was prescribed for just 20% of the patients during a 1-year follow-up period, and less than half (44.5%) of the patients who were taking two OHAs started insulin after 6 years. Patient-related factors for delay in insulin initiation included older age, shorter duration of diabetes and lower glycated hemoglobin. Physician-related factors included age (~50 to 1000) of patients consulted per month. Patient refusal (33.6%) and physicians' concerns of patient non-compliance (26.5%) were the major physician-reported reasons for delaying insulin therapy. Inconvenience of insulin therapy (51.6%) and fear of injection (48.2%) were the major reasons for patient refusal. Insulin initiation is delayed in patients with type 2 diabetes uncontrolled by two or more OHAs in Korea. Patient- and physician-related factors associated with this delay need to be addressed for better diabetes management. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A

Czech Academy of Sciences Publication Activity Database

Morcavallo, A.; Genua, M.; Palummo, A.; Kletvíková, Emília; Jiráček, Jiří; Brzozowski, A. M.; Lozzo, R. V.; Belfiore, A.; Morrione, A.

2012-01-01

Roč. 287, č. 14 (2012), s. 11422-11436 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z40550506 Keywords : insulin * IGF -II * mitogenic response * IR-A Subject RIV: CE - Biochemistry Impact factor: 4.651, year: 2012

Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

Science.gov (United States)

Govindsamy, Annelene; Naidoo, Strinivasen

2018-01-01

Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology. PMID:29484207

Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women

DEFF Research Database (Denmark)

Grønbæk, Henning; Flyvbjerg, Allan; Mellemkjær, L.

2004-01-01

BACKGROUND: Studies have shown a positive association between serum insulin-like growth factor (IGF)-I and breast cancer risk in premenopausal but not postmenopausal women. IGF-II and estrogen receptor (ER) status has never been investigated. We examined the association between IGF-I, IGF-II, IGF...

Advanced Glycation End-Products affect transcription factors regulating insulin gene expression

International Nuclear Information System (INIS)

Puddu, A.; Storace, D.; Odetti, P.; Viviani, G.L.

2010-01-01

Advanced Glycation End-Products (AGEs) are generated by the covalent interaction of reducing sugars with proteins, lipids or nucleic acids. AGEs are implicated in diabetic complications and pancreatic β-cell dysfunction. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T15 to high concentrations of AGEs leads to a significant decrease of insulin secretion and content. Insulin gene transcription is positively regulated by the beta cell specific transcription factor PDX-1 (Pancreatic and Duodenal Homeobox-1). On the contrary, the forkhead transcription factor FoxO1 inhibits PDX-1 gene transcription. Activity of FoxO1 is regulated by post-translational modifications: phosphorylation deactivates FoxO1, and acetylation prevents FoxO1 ubiquitination. In this work we investigated whether AGEs affect expression and subcellular localization of PDX-1 and FoxO1. HIT-T15 cells were cultured for 5 days in presence of AGEs. Cells were then lysed and processed for subcellular fractionation. We determined intracellular insulin content, then we assessed the expression and subcellular localization of PDX-1, FoxO1, phosphoFoxO1 and acetylFoxO1. As expected intracellular insulin content was lower in HIT-T15 cells cultured with AGEs. The results showed that AGEs decreased expression and nuclear localization of PDX-1, reduced phosphorylation of FoxO1, and increased expression and acetylation of FoxO1. These results suggest that AGEs decrease insulin content unbalancing transcription factors regulating insulin gene expression.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

NARCIS (Netherlands)

Hartog, H.; Boezen, H.M.; Jong, M.M. de; Schaapveld, M.; Wesseling, J.; Graaf, W.T.A. van der

2013-01-01

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer

NARCIS (Netherlands)

Hartog, H; Boezen, H M; de Jong, M M; Schaapveld, M; Wesseling, J; van der Graaf, W T A

2013-01-01

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood

Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

Science.gov (United States)

Jung, Su Yon; Ho, Gloria; Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Papp, Jeanette; Sobel, Eric; Zhang, Zuo-Feng; Crandall, Carolyn

2017-07-01

Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism

OpenAIRE

ÇAKIR, Evrim; TOPALOĞLU, Oya; BOZKURT, Nujen ÇOLAK; BAYRAKTAR, Başak KARBEK

2015-01-01

Hyperinsulinemia and insulin resistance are commonly seen in patients with hirsutism and polycystic ovary syndrome (PCOS), and are associated with cardiovascular disease risk. However, it is not yet known whether insulin-like growth factor I (IGF-I) and alanine transaminase (ALT) produced by the liver play roles in hyperinsulinemia and subclinical atherosclerotic process in patients with PCOS and idiopathic hirsutism (IH). Materials and methods: This was a prospective case-controlled study....

Factors influencing insulin secretion from encapsulated islets

NARCIS (Netherlands)

de Haan, BJ; Faas, MM; de Vos, P

2003-01-01

Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The

Insulin and the Lung

DEFF Research Database (Denmark)

Singh, Suchita; Prakash, Y S; Linneberg, Allan

2013-01-01

, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance.

Science.gov (United States)

Qing, Zhou; Xiao-Hui, Wu; Xi-Mei, Wu; Chao-Chun, Zou

2018-06-15

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo -/- ) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo -/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo -/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

The Role of Insulin, Insulin Growth Factor, and Insulin-Degrading Enzyme in Brain Aging and Alzheimer's Disease

OpenAIRE

Messier, Claude; Teutenberg, Kevin

2005-01-01

Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor-based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity-related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in a...

Frequency and risk factors of severe hypoglycaemia in insulin-treated Type 2 diabetes

DEFF Research Database (Denmark)

Akram, K; Pedersen-Bjergaard, U; Carstensen, B

2006-01-01

AIMS: The reported risk of severe hypoglycaemia in insulin-treated Type 2 diabetes is highly variable and few studies have evaluated the influence of risk factors. We assessed the incidence and the influence of potential risk factors for severe hypoglycaemia in a questionnaire survey in subjects...... with insulin-treated Type 2 diabetes receiving currently recommended multifactorial intervention. METHODS: Consecutive patients with insulin-treated Type 2 diabetes (n = 401) completed a questionnaire about occurrence of hypoglycaemia in the past, hypoglycaemia awareness and socio-demographic factors. A zero...... treatment and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs) were associated with reduced risk. C-peptide concentration and HbA1c were not associated with the risk of severe hypoglycaemia. CONCLUSIONS: In this cohort of insulin-treated Type 2...

Effect of Insulin Infusion on insulin-like growth factor I (IGF-I) during Hemodialysis

DEFF Research Database (Denmark)

Reinhard, Mark; Frystyk, Jan; Bjerre, Mette

2012-01-01

Background: Hemodialysis (HD) is a catabolic procedure probably contributing to the high frequency of protein-energy wasting among patients on maintenance HD. The aim was to investigate the effect of insulin infusion on insulin-like growth factor I (IGF-I) during HD compared with a meal alone...... infusion and followed by the only meal allowed during the study. Results: Data are presented as mean±SD. From baseline to end of HD session we observed an overall increase in both serum bioactive IGF-I (from 0.83±0.27 to 1.01±0.34 µg/L, p... in the change between the groups (p=0.43). Conclusion: A meal at the beginning of a HD session leads to an increase in bioactive IGF-I thereby assumingly counteracting the catabolic effects of HD. However, according to changes in bioactive IGF-I neither glucose nor glucose-insulin infusion during HD appear...

Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism.

Science.gov (United States)

Çakir, Evrim; Topaloğlu, Oya; Çolak Bozkurt, Nujen; Karbek Bayraktar, Başak; Güngüneş, Aşkın; Sayki Arslan, Müyesser; Öztürk Ünsal, İlknur; Tutal, Esra; Uçan, Bekir; Delıbaşi, Tuncay

2014-01-01

Hyperinsulinemia and insulin resistance are commonly seen in patients with hirsutism and polycystic ovary syndrome (PCOS), and are associated with cardiovascular disease risk. However, it is not yet known whether insulin-like growth factor I (IGF-I) and alanine transaminase (ALT) produced by the liver play roles in hyperinsulinemia and subclinical atherosclerotic process in patients with PCOS and idiopathic hirsutism (IH). This was a prospective case-controlled study. The study population consisted of 25 reproductive-age PCOS women, 33 women with IH, and 25 control subjects. Mean IGF-I levels and median ALT levels were higher in patients with IH and PCOS than controls, but these differences were not statistically significant. The participants who had a homeostasis model assessment insulin resistance index (HOMA-IR) greater than 2.7 had significantly higher IGF-1 and ALT levels. ALT levels were positively correlated with body mass index, FG, insulin and HOMA-IR. The study illustrated that IGF-1 and ALT levels were significantly higher in patients with increased insulin resistance. Due to short disease duration in younger participants, we did not observe any correlation between IGF-1 and hyperinsulinemia. These findings suggest that increased hepatic production of IGF-I and ALT might be an early indicator of insulin resistance in hirsutism.

Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells.

Science.gov (United States)

Ververis, J; Ku, L; Delafontaine, P

1994-02-01

Insulin-like growth factor I is an important mitogen for vascular smooth muscle cells, and its effects are regulated by several binding proteins. Western ligand blotting of conditioned medium from rat aortic smooth muscle cells detected a 24 kDa binding protein and a 28 kDa glycosylated variant of this protein, consistent with insulin-like growth factor binding protein-4 by size. Low amounts of a glycosylated 38 to 42 kDa doublet (consistent with binding protein-3) and a 31 kDa non-glycosylated protein also were present. Basic fibroblast growth factor markedly increased secretion of the 24 kDa binding protein and its 28 kDa glycosylated variant. This effect was dose- and time-dependent and was inhibited by co-incubation with cycloheximide. Crosslinking of [125I]-insulin-like growth factor I to cell monolayers revealed no surface-associated binding proteins, either basally or after agonist treatment. Induction of binding protein production by fibroblast growth factor at sites of vascular injury may be important in vascular proliferative responses in vivo.

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

Science.gov (United States)

Ahmed, Muhammad S.; Rainer, Carolyn; Nielsen, Sebastian R.; Quaranta, Valeria; Weyer-Czernilofsky, Ulrike; Engle, Danielle D.; Perez-Mancera, Pedro A.; Coupland, Sarah E.; Taktak, Azzam; Bogenrieder, Thomas; Tuveson, David A.; Campbell, Fiona; Schmid, Michael C.; Mielgo, Ainhoa

2017-01-01

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. PMID:27742686

Human blood-brain barrier insulin-like growth factor receptor

International Nuclear Information System (INIS)

Duffy, K.R.; Pardridge, W.M.; Rosenfeld, R.G.

1988-01-01

Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125 I-IGF-1, 125 I-IGF-2, and 125 I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

Different Effects of Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-2 on Myogenic Differentiation of Human Mesenchymal Stem Cells

Directory of Open Access Journals (Sweden)

Doaa Aboalola

2017-01-01

Full Text Available Insulin-like growth factors (IGFs are critical components of the stem cell niche, as they regulate proliferation and differentiation of stem cells into different lineages, including skeletal muscle. We have previously reported that insulin-like growth factor binding protein-6 (IGFBP-6, which has high affinity for IGF-2, alters the differentiation process of placental mesenchymal stem cells (PMSCs into skeletal muscle. In this study, we determined the roles of IGF-1 and IGF-2 and their interactions with IGFBP-6. We showed that IGF-1 increased IGFBP-6 levels within 24 hours but decreased after 3 days, while IGF-2 maintained higher levels of IGFBP-6 throughout myogenesis. IGF-1 increased IGFBP-6 in the early phase as a requirement for muscle commitment. In contrast, IGF-2 enhanced muscle differentiation as shown by the expression of muscle differentiation markers MyoD, MyoG, and MHC. IGF-1 and IGF-2 had different effects on muscle differentiation with IGF-1 promoting early commitment to muscle and IGF-2 promoting complete muscle differentiation. We also showed that PMSCs acquired increasing capacity to synthesize IGF-2 during muscle differentiation, and the capacity increased as the differentiation progressed suggesting an autocrine and/or paracrine effect. Additionally, we demonstrated that IGFBP-6 could enhance the muscle differentiation process in the absence of IGF-2.

[Concept Analysis for Psychological Insulin Resistance in Korean People with Diabetes].

Science.gov (United States)

Song, Youngshin

2016-06-01

The purpose of this study was to define the concept for psychological insulin resistance in the Korean population with diabetes. The Hybrid model was used to perform the concept analysis of psychological insulin resistance. Results from both the theoretical review with 26 studies and a field study including 19 participants with diabetes were included in final process. The preceding factors of psychological insulin resistance were uncontrolled blood glucose and change in daily life. The concept of psychological insulin resistance was found to have three categories with 8 attributes such as emotional factors (negative feeling), cognitive factors (low awareness and knowledge, low confidence for self-injection) and supportive factors (economic burden, dependency life, embarrassing, feeling about supporters, feeling of trust in, vs mistrust of health care providers). The 8 attributes included 30 indicators. The psychological insulin resistance of population with diabetes in Korea was defined as a complex phenomenon associated with insulin therapy that can be affected by emotional factors, cognitive factors, and supportive relational factors. Based on the results, a tool for measuring psychological insulin resistance of Koreans with diabetes and effective programs for enhancing insulin adherence should be developed in future studies.

Insulin like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation

DEFF Research Database (Denmark)

Zhang, Hongbin; Nøhr, Jane; Jensen, Charlotte Harken

2003-01-01

that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form...... of Pref-1/FA1 in 3T3-L1 or 3T3-F442A cells inhibited adipocyte differentiation when insulin or insulin-like growth factor-1 (IGF-1) was omitted from the differentiation mixture. We demonstrate that the level of the mature form of the IGF-1 receptor is reduced and that IGF-1-dependent activation of p42/p44...... mitogen-activated protein kinases (MAPKs) is compromised in preadipocytes with forced expression of Pref-1. This is accompanied by suppression of clonal expansion and terminal differentiation. Accordingly, supplementation with insulin or IGF-1 rescued p42/p44 MAPK activation, clonal expansion...

Human insulin-like growth factor II leader 2 mediates internal initiation of translation

DEFF Research Database (Denmark)

Pedersen, Susanne; Christiansen, Jan; Hansen, T.O.

2002-01-01

Insulin-like growth factor II (IGF-II) is a fetal growth factor, which belongs to the family of insulin-like peptides. During fetal life, the IGF-II gene generates three mRNAs with different 5' untranslated regions (UTRs), but identical coding regions and 3' UTRs. We have shown previously that IG...

[Insulin-like growth factor-binding protein-1: a new biochemical marker of nonalcoholic fatty liver disease?].

Science.gov (United States)

Graffigna, Mabel Nora; Belli, Susana H; de Larrañaga, Gabriela; Fainboim, Hugo; Estepo, Claudio; Peres, Silvia; García, Natalia; Levalle, Oscar

2009-03-01

to assess the presence of nonalcoholic fatty liver disease in patients with risk factors for this pathology (obesity, dyslipidemia, metabolic syndrome and diabetes type 2) and to determine the role of insulin, HOMA index, insulin-like growth factor-binding protein-1, sex hormone-binding globulin and plasminogen activator inhibitor type 1, as biochemical markers. Ninety-one patients with risk factors for nonalcoholic fatty liver disease were evaluated. Serum transaminases, insulin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 and plasminogen activator inhibitor type 1 were measured. The diagnosis of fatty liver was performed by ultrasonography and liver biopsies were performed to 31 subjects who had steatosis by ultrasonography and high alanine aminotransferase. Nonalcoholic fatty liver disease was present in 65 out of 91 patients (71,4%). Liver biopsy performed to 31 subjects confirmed nonalcoholic steatohepatitis. Twenty-five patients had different degrees of fibrosis. Those individuals with fatty liver had higher waist circumference, serum levels of triglycerides, insulin and HOMA index, and lower serum insulin-like growth factor-binding protein-1 concentration. The degree ofhepatic steatosis by ultrasonography was positively correlated to waist circumference, triglycerides, insulin and HOMA index (p<0,003; p<0,003; p<0,002 and p<0,001, respectively), and was negatively correlated to HDL-cholesterol and insulin-like growth factor-binding protein-1 (p<0,025 and p<0,018, respectively). We found a high prevalence of NAFLD in patients with risk factors, most of them overweight or obese. Although SHBG and PAI-1 have a closely relationship to insulin resistance, they did not show to be markers of NAFLD. Regardless of low IGFBP-1 levels associated with NAFLD, serum IGFBP-1 measure is less accessible than insulin and triglycerides levels, HOMA index and waist circumference. Moreover, it is not a better marker for NAFLD than the above

Insulin-like growth factor II: complexity of biosynthesis and receptor binding

DEFF Research Database (Denmark)

Gammeltoft, S; Christiansen, Jan; Nielsen, F C

1991-01-01

Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line......, Man-6-P induces cellular responses. We have studied rat brain neuronal precursor cells where Man-6-P acted as a mitogen suggesting that phosphomannosylated proteins may act as growth factors via the Man-6-P/IGF-II receptor. In conclusion, the gene expression and mechanism of action of IGF-II is very...

Paediatrics, insulin resistance and the kidney.

Science.gov (United States)

Marlais, Matko; Coward, Richard J

2015-08-01

Systemic insulin resistance is becoming more prevalent in the young due to modern lifestyles predisposing to the metabolic syndrome and obesity. There is also evidence that there are critical insulin-resistant phases for the developing child, including puberty, and that renal disease per se causes systemic insulin resistance. This review considers the factors that render children insulin resistant, as well as the accumulating evidence that the kidney is an insulin-responsive organ and could be affected by insulin resistance.

Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats

Science.gov (United States)

Holl, Katie L.; Oreper, Daniel; Xie, Yuying; Tsaih, Shirng-Wern; Valdar, William

2012-01-01

Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D. PMID:22947656

Expression of human choline kinase in NIH 3T3 fibroblasts increases the mitogenic potential of insulin and insulin-like growth factor I.

Science.gov (United States)

Chung, T; Huang, J S; Mukherjee, J J; Crilly, K S; Kiss, Z

2000-05-01

In mammalian cells, growth factors, oncogenes, and carcinogens stimulate phosphocholine (PCho) synthesis by choline kinase (CK), suggesting that PCho may regulate cell growth. To validate the role of PCho in mitogenesis, we determined the effects of insulin, insulin-like growth factor I (IGF-I), and other growth factors on DNA synthesis in NIH 3T3 fibroblast sublines highly expressing human choline kinase (CK) without increasing phosphatidylcholine synthesis. In serum-starved CK expressor cells, insulin and IGF-I stimulated DNA synthesis, p70 S6 kinase (p70 S6K) activity, phosphatidylinositol 3-kinase (PI3K) activity, and activating phosphorylation of p42/p44 mitogen-activated protein kinases (MAPK) to greater extents than in the corresponding vector control cells. Furthermore, the CK inhibitor hemicholinium-3 (HC-3) inhibited insulin- and IGF-I-induced DNA synthesis in the CK overexpressors, but not in the vector control cells. The results indicate that high cellular levels of PCho potentiate insulin- and IGF-I-induced DNA synthesis by MAPK- and p70 S6K-regulated mechanisms.

Role of growth hormone, insulin-like growth factor-I, and insulin-like growth factor binding proteins in the catabolic response to injury and infection.

Science.gov (United States)

Lang, Charles H; Frost, Robert A

2002-05-01

The erosion of lean body mass resulting from protracted critical illness remains a significant risk factor for increased morbidity and mortality in this patient population. Previous studies have documented the well known impairment in nitrogen balance results from both an increase in muscle protein degradation as well as a decreased rate of both myofibrillar and sacroplasmic protein synthesis. This protein imbalance may be caused by an increased presence or activity of various catabolic agents, such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 or glucocorticoids, or may be mediated via a decreased concentration or responsiveness to various anabolic hormones, such as growth hormone or insulin-like growth factor-I. This review focuses on recent developments pertaining to the importance of alterations in the growth hormone-insulin-like growth factor-I axis as a mechanism for the observed defects in muscle protein balance.

Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

Science.gov (United States)

Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

1998-08-01

We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

Predictive factors of insulin resistance resolution with adjustable gastric band surgery.

Science.gov (United States)

Colsa Gutiérrez, Pablo; Kharazmi Taghavi, Mahgol; Sosa Medina, Rocío; Gutiérrez Cabezas, José Manuel; Ovejero Gómez, Víctor Jacinto; Ruiz, José Luis; Ingelmo Setién, Alfredo

2015-03-01

The aim of the study was to evaluate preoperative factors associated with remission of diabetes and weight loss after laparoscopic gastric band surgery. A retrospective cohort of 95 patients who had an adjustable gastric band placed were included. A preliminary descriptive study of prognostic factors was performed using the logistic regression model with SPSS 17.0. The independent variables were age, sex, body mass index (BMI), diabetes status and degree of obesity; dependent variables were the proportion of weight loss, change in diabetes status score and percent changes in fasting sugar and glycosylated hemoglobin. The variables that were significantly associated with the percentage of changes in fasting blood sugar and glycated hemoglobin were: the degree of obesity in the first year; preoperative and diabetes status respectively. The analysis of the need for antidiabetic treatment using the modified diabetes status score showed preoperative BMI, age and gender as significant predictors. In patients undergoing gastric band surgery, weight loss is the fundamental mechanism by which insulin sensitivity increases. This improvement in glucose metabolism is influenced by factors such as sex, age, insulin treatment, duration of diabetes and degree of preoperative obesity. Copyright © 2014 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

Related Factors of Insulin Resistance in Korean Children: Adiposity and Maternal Insulin Resistance

Directory of Open Access Journals (Sweden)

Kang-Sook Lee

2011-12-01

Full Text Available Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR was calculated using fasting glucose and insulin level as a marker of IR. All children’s adiposity indices (r = 0.309–0.318, all P-value = 0.001 and maternal levels of fasting insulin (r = 0.285, P-value = 0.003 and HOMA-IR (r = 0.290, P-value = 0.002 were positively correlated with children’s HOMA-IR level. There was no statistical difference of children’s HOMA-IR level according to children’s lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children’s HOMA-IR (P-value < 0.001 and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children’s HOMA-IR (P-value = 0.002. This study shows that children’s adiposity and maternal IR are positively associated with children’s IR.

Insulin-like growth factors and pancreas beta cells.

NARCIS (Netherlands)

Haeften, T.W. van; Twickler, M.

2004-01-01

Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

Insulin-like growth factors and pancreas beta cells

NARCIS (Netherlands)

van Haeften, T. W.; Twickler, TB

Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signalling

Insulin-like growth factors and pancreas beta cells

NARCIS (Netherlands)

van Haeften, T. W.; Twickler, Th B.

2004-01-01

Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

Elevated insulin and reduced insulin like growth factor binding protein-3/prostate specific antigen ratio with increase in prostate size in Benign Prostatic Hyperplasia.

Science.gov (United States)

Sreenivasulu, Karli; Nandeesha, Hanumanthappa; Dorairajan, Lalgudi Narayanan; Rajappa, Medha; Vinayagam, Vickneshwaran

2017-06-01

Insulin and insulin like growth factor-1 (IGF-1) have growth promoting effects, while insulin like growth factor binding protein-3 (IGFBP-3) has growth inhibitory effects. The present study was designed to assess the concentrations of insulin, IGF-1, IGFBP-3 and their association with prostate size in patients with BPH. Ninety 90 BPH cases and 90 controls were enrolled in the study. Insulin, IGF-1, IGFBP-3, PSA, testosterone and estradiol were estimated in both the groups. Insulin, IGF-1 and estradiol were increased and IGFBP-3/PSA was decreased in BPH cases when compared with controls. Insulin (r=0.64, p=0.001) and IGF-1 (r=0.22, p=0.03) were positively correlated and IGFBP-3/PSA (r=-0.316, p=0.002) were negatively correlated with prostate size in BPH. Multivariate analysis showed that insulin (p=0.001) and IGFBP-3/PSA (p=0.004) predicts the prostate size in patients with BPH. Insulin was increased and IGFBP-3/PSA was reduced in BPH patients with increased prostate size. At a cutoff concentration of 527.52, IGFBP-3/PSA ratio was found to differentiate benign growth of prostate from normal prostate with 96% sensitivity and 96% specificity. Insulin is elevated and IGFBP-3/PSA is reduced with increase prostate size in BPH cases. Copyright © 2017 Elsevier B.V. All rights reserved.

Insulin-like growth factor (IGF-I and IGF binding proteins axis in diabetes mellitus

Directory of Open Access Journals (Sweden)

Min Sun Kim

2015-06-01

Full Text Available Increasing evidence suggests an important role of the insulin-like growth factor (IGF-IGF binding protein (IGFBP axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM. Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.

Development of a bioassay system for investigating insulin resistance factors of pregnancy

International Nuclear Information System (INIS)

Hausman, D.B.; Singh, R.; Martin, R.J.

1986-01-01

To determine if late-term pregnant serum and/or placenta could induce insulin resistance in normal adipose cells, the authors have developed an insulin sensitive bioassay system. Cells isolated from epididymal fat pads of 250-275 g Sprague Dawley rats are preincubated for 3 hours at 37 0 in media 199 and serum or placental extract. The cells are washed free of serum and tested for metabolic activity in a 2 hour incubation which measures the conversion of U- 14 C-glucose to 14 CO 2 and to 14 C-triglyceride fatty acids under basal and insulin stimulated conditions. Maximal insulin responsiveness (350-450% basal for CO 2 and 1400-1700% basal for fatty acids) is achieved using Worthington Type II collagenase and a 45-60 minute digestion period for cell isolations and Krebs-Ringer bicarbonate buffer containing 0.5 mM glucose, 2% Armour bovine serum albumin (CRG-7), 1000 μU/ml insulin and 110,000 to 120,000 cells in the 2 hour incubations. Using this bioasssay system the authors have found that insulin responsiveness, in terms of glucose conversion to fatty acids, is unchanged when cells are preincubated with 5% control pig serum but reduced following preincubation with late pregnant (110 day) pig serum. In future experiments the authors hope to further characterize the factor(s) in pregnant serum responsible for inducing this metabolic effect

Insulin resistance, insulin response, and obesity as indicators of metabolic risk

DEFF Research Database (Denmark)

Ferrannini, Ele; Balkau, Beverley; Coppack, Simon W

2007-01-01

CONTEXT: Insulin resistance (IR) and obesity, especially abdominal obesity, are regarded as central pathophysiological features of a cluster of cardiovascular risk factors (CVRFs), but their relative roles remain undefined. Moreover, the differential impact of IR viz. insulin response has not been...... evaluated. OBJECTIVE: The objective of this study was to dissect out the impact of obesity, abdominal obesity, and IR/insulin response on CVRF. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at 21 research centers in Europe. SUBJECTS: The study included a cohort of 1308......-cholesterol, and lower high-density lipoprotein-cholesterol, and insulin response to higher heart rate, blood pressure and fasting glucose, and the same dyslipidemic profile as IR (P

A pilot study of factors associated with glycaemic control in adults with Type 1 diabetes mellitus on insulin pump therapy.

Science.gov (United States)

Wen, W; Frampton, R; Wright, K; Fattore, S; Shadbolt, B; Perampalam, S

2016-02-01

To identify the knowledge and management factors associated with glycaemic control among adults with Type 1 diabetes mellitus treated with insulin pump therapy. A cross-sectional study of adults with Type 1 diabetes mellitus on insulin pump therapy for at least 12 months (n = 50, 18-70 years old) was undertaken between December 2013 and May 2014. A new questionnaire was developed to evaluate participants' knowledge and management related to insulin pump therapy, and were correlated with insulin pump data, HbA1c and frequency of hypoglycaemia. Participants who changed their insulin pump settings when indicated had significantly better glycaemic control than those who did not (P = 0.04). Multivariate logistic regression analysis found that better overall insulin pump therapy management was a significant predictor of better glycaemic control (odds ratio 4.45, 95% confidence interval 1.61-12.3; P = 0.004) after adjusting for potential confounders including age, gender, duration of diabetes and insulin pump therapy. However, overall insulin pump therapy knowledge was not a significant predictor of glycaemic control (P = 0.058). There was no significant association between frequency of hypoglycaemia and insulin pump therapy knowledge or management. We identified some key knowledge and management factors associated with glycaemic control in adults with Type 1 diabetes mellitus on insulin pump therapy using a newly designed questionnaire. The pilot study assessed the clinical utility of this evaluation tool, which may facilitate provision of targeted education to insulin pump therapy users to achieve optimal glycaemic control. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

The effects of insulin sensitizers on the cardiovascular risk factors in women with polycystic ovary syndrome.

Science.gov (United States)

Kassi, E; Diamanti-Kandarakis, E

2008-12-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in pre-menopausal women characterized by menstrual cycle disturbances, chronic anovulation, and clinical and/or biochemical hyperandrogenism. Although, the primary etiology of PCOS remains unknown, insulin resistance/hyperinsulinemia plays a pivotal role in the pathogenesis of the syndrome. A growing body of recent data support that women with PCOS have displayed an increased prevelance of cardiovascular disease (CVD) risk factors putting potentially at a hight risk for heart disease. Most of these CVD risk factors are etiologically correlated with insulin resistance/hyperinsulinemia, highlighting the role of insulin sensitizers in the therapeutic quiver for the chronic treatment of PCOS. In this review, we discuss the current literature on the CVD risk factors in PCOS and the influence of insulin sensitizers upon these risk factors.

Insulin/insulin like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms and new blocking strategies

Directory of Open Access Journals (Sweden)

Travis B Salisbury

2015-02-01

Full Text Available The insulin-like growth factor 1 receptor (IGF1R and the insulin receptor (IR are receptor tyrosine kinases (RTKs that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include: anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR and new therapeutic targeting strategies will be discussed.

Explaining psychological insulin resistance in adults with non-insulin-treated type 2 diabetes

DEFF Research Database (Denmark)

Holmes-Truscott, Elizabeth; Skinner, Timothy Chas; Pouwer, F

2016-01-01

to the model. CONCLUSIONS: Psychological insulin resistance may reflect broader distress about diabetes and concerns about its treatment but not general beliefs about medicines, depression or anxiety. Reducing diabetes distress and current treatment concerns may improve attitudes towards insulin as a potential......AIMS: To investigate the contribution of general and diabetes-specific emotional wellbeing and beliefs about medicines in the prediction of insulin therapy appraisals in adults with non-insulin-treated type 2 diabetes. METHODS: The sample included Diabetes MILES-Australia cross-sectional survey...... diabetes medications (BMQ Specific); negative insulin therapy appraisals (ITAS); depression (PHQ-9); anxiety (GAD-7), and diabetes distress (DDS-17). Factors associated with ITAS Negative scores were examined using hierarchical multiple regressions. RESULTS: Twenty-two percent of the variance in ITAS...

Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells.

Science.gov (United States)

Wang, L M; Keegan, A D; Li, W; Lienhard, G E; Pacini, S; Gutkind, J S; Myers, M G; Sun, X J; White, M F; Aaronson, S A

1993-05-01

Interleukin 4 (IL-4), insulin, and insulin-like growth factor I (IGF-I) efficiently induced DNA synthesis in the IL-3-dependent murine myeloid cell lines FDC-P1 and FDC-P2. Although these factors could not individually sustain long-term growth of these lines, a combination of IL-4 with either insulin or IGF-I did support continuous growth. The principal tyrosine-phosphorylated substrate observed in FDC cells stimulated with IL-4, previously designated 4PS, was of the same size (170 kDa) as the major substrate phosphorylated in response to insulin or IGF-I. These substrates had phosphopeptides of the same size when analyzed by digestion with Staphylococcus aureus V8 protease, and each tightly associated with the 85-kDa component of phosphatidylinositol 3-kinase after factor stimulation. IRS-1, the principal substrate phosphorylated in response to insulin or IGF-I stimulation in nonhematopoietic cells, is similar in size to 4PS. However, anti-IRS-1 antibodies failed to efficiently precipitate 4PS, and some phosphopeptides generated by V8 protease digestion of IRS-1 were distinct in size from the phosphopeptides of 4PS. Nevertheless, IL-4, insulin, and IGF-I were capable of stimulating tyrosine phosphorylation of IRS-1 in FDC cells that expressed this substrate as a result of transfection. These findings indicate that (i) IL-4, insulin, and IGF-I use signal transduction pathways in FDC lines that have at least one major feature in common, the rapid tyrosine phosphorylation of 4PS, and (ii) insulin and IGF-I stimulation of hematopoietic cell lines leads to the phosphorylation of a substrate that may be related to but is not identical to IRS-1.

Insulin-Like Growth Factor-1 and Neuroinflammation

OpenAIRE

Labandeira-Garcia, Jose L.; Costa-Besada, Maria A.; Labandeira, Carmen M.; Villar-Cheda, Begoña; Rodríguez-Perez, Ana I.

2017-01-01

Insulin-like growth factor-1 (IGF-1) effects on aging and neurodegeneration is still controversial. However, it is widely admitted that IGF-1 is involved in the neuroinflammatory response. In peripheral tissues, several studies showed that IGF-1 inhibited the expression of inflammatory markers, although other studies concluded that IGF-1 has proinflammatory functions. Furthermore, proinflammatory cytokines such as TNF-α impaired IGF-1 signaling. In the brain, there are controversial results o...

Insulin resistance and associated factors: a cross-sectional study of bank employees.

Science.gov (United States)

Salaroli, Luciane Bresciani; Cattafesta, Monica; Molina, Maria Del Carmen Bisi; Zandonade, Eliana; Bissoli, Nazaré Souza

2017-04-01

Insulin resistance is characterized by the failure of target cells to respond to normal levels of circulating insulin, and this condition is related to cardiovascular disease. This study sought to evaluate the prevalence of insulin resistance and its association with markers of metabolic abnormalities and metabolic syndrome in bank employees. A cross-sectional study was performed on 498 working men and women aged ≥20 years old. The Homeostasis Model Assessment (HOMA-IR) was used to determine the presence of insulin resistance based on cut-off values of ≤2.71 for normal insulin levels and >2.71 for insulin resistance, as established for the adult Brazilian population. It was observed that the 52 (10.4%) overweight individuals with insulin resistance were 4.97 times (95%CI 1.31-18.83) more likely to have high HOMA-IR values than the normal-weight participants; among those who were obese, the likelihood increased to 17.87 (95%CI 4.36-73.21). Individuals with large waist circumferences were 3.27 times (95%CI 1.03-10.38) more likely to develop insulin resistance than those who were within normal parameters. The HOMA-IR values differed between subjects with and without metabolic syndrome, with values of 2.83±2.5 and 1.10±0.81 (p=0.001), respectively. The levels of insulin, ultrasensitive C-reactive protein and uric acid were also associated with insulin resistance. The prevalence of insulin resistance among bank employees is high, and insulin resistance is associated with and serves as a marker of metabolic syndrome. Cardiovascular disease and metabolic syndrome-associated metabolic abnormalities were observed, and insulin resistance may be a risk factor in this group of professionals.

Fibroblast growth factor 21 improves insulin sensitivity and synergizes with insulin in human adipose stem cell-derived (hASC adipocytes.

Directory of Open Access Journals (Sweden)

Darwin V Lee

Full Text Available Fibroblast growth factor 21 (FGF21 has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR, insulin receptor substrate-1 (IRS-1, and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway.

Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease.

Science.gov (United States)

Laatikainen, T; Anttila, L; Suikkari, A M; Ruutiainen, K; Erkkola, R; Seppälä, M

1990-09-01

Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.

Influence of insulin therapy on circulating ghrelin and insulin-like ghrelinowth factor-1(IGF-1) levels in children with type-1 diabetes mellitus

International Nuclear Information System (INIS)

Moawad, A.T.; Nassar, E.M.; Mostafa, A.M.; Mohammed, S.K.

2009-01-01

Diabetes mellitus type 1 (IDDM)is a chronic disease associated with alterations in the growth hormone/insulin -like growth factor (GH-IGF) system and ghrelin level which may lead to changes in metabolic control. This study aimed to evaluate the circulating levels of the gut-derived peptides (ghrelin and insulin-like growth factors (IGF s ) in children with IDDM and to link these two peptides with the glucose level in diabetic children at diagnoses and after insulin therapy. Design and methods: the studied group consisted of 30 newly diagnosed diabetic children (17 females and 13 males) diagnosed in paediatric diabetes unit, children's hospital, Ain shams university. Their age ranged from (6.2-11.8) years with mean of 10.10± 1.74 years. Twenty non diabetic healthy children matching in age and sex served as controls. Serum ghrelin was determined by enzyme linked immuno absorbanet assay (ELISA), while IGF-1 and insulin-like growth factors binding proteins -1 and 3 (IGFBP s ) were assessed by radioimmunoassay(RIA). Results: body mass index (BMI) in patients was significantly decreased in the diabetic group as compared to the healthy group at diagnosis. After insulin therapy BMI was significantly increase as compared to its value at diagnosis (p< 0.05) such increase was not significant on comparing to controls. Regarding blood glucose level there was very highly significant decrease in the level of HBAI (glycolated HB) in diabetic patients after insulin therapy (p<0.0001) than at diagnosis . The mean ghrelin level was highly significantly decreased in diabetic children at diagnosis and after insulin therapy as compared to controls (p<0.0001). No differences were found in the mean ghrelin levels in diabetic children at diagnosis or after insulin therapy.conclusions : the decrease in mean gherlin levels in this study at diagnosis and after therapy could reflect an attempt by the body to decrease the glucose level and thus may prevent hyperglycemia in diabetic patients

Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome

DEFF Research Database (Denmark)

Wikström, Anne M; Bay, Katrine; Hero, Matti

2006-01-01

Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development.......Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development....

Insulin-like growth factor binding protein 3 in inflammatory bowel disease

DEFF Research Database (Denmark)

Kirman, Irena; Whelan, Richard Larry; Jain, Suvinit

2005-01-01

Epithelial cell growth regulation has been reported to be altered in inflammatory bowel disease (IBD) patients. The cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3), may be partly responsible for this phenomenon. So far, IGFBP-3 levels have been assessed...

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

International Nuclear Information System (INIS)

Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

2016-01-01

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates

Circulating growth factors data associated with insulin secretagogue use in women with incident breast cancer

Directory of Open Access Journals (Sweden)

Zachary A.P. Wintrob

2017-04-01

Full Text Available Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.

Insulin-like growth factor-I in growth and metabolism

DEFF Research Database (Denmark)

Backeljauw, P; Bang, P; Dunger, D B

2010-01-01

Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of more...

Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells

DEFF Research Database (Denmark)

Wanscher, Anne Sofie Molsted; Williamson, Michael; Ebersole, Tasja Wainani

2015-01-01

on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins...... and the final protein yields were between 1 and 12mg protein per liter culture media. The recombinant IGFBPs contained PTMs and exhibited high-affinity interactions with their natural ligands IGF-1 and IGF-2.......Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge...

Changes in serum concentrations of growth hormone, insulin, insulin-like growth factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth hormone excretion during the menstrual cycle

DEFF Research Database (Denmark)

Juul, A; Scheike, Thomas Harder; Pedersen, A T

1997-01-01

Few studies exist on the physiological changes in the concentrations of growth hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) within the menstrual cycle, and some controversy remains. We therefore decided to study the impact of endogenous sex steroids on the GH-I...

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.

Science.gov (United States)

Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

2016-12-02

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. Copyright © 2016 Elsevier Inc. All rights reserved.

ROLE OF INSULIN SENSITIZERS ON CARDIOVASCULAR RISK FACTORS IN POLYCYSTIC OVARIAN SYNDROME: A META-ANALYSIS.

Science.gov (United States)

Thethi, Tina K; Katalenich, Bonnie; Nagireddy, Prathima; Chabbra, Pankdeep; Kuhadiya, Nitesh; Fonseca, Vivian

2015-06-01

Polycystic ovarian syndrome (PCOS) is associated with an increase in cardiovascular (CV) risk factors such as insulin resistance, with accompanying hyperinsulinemia and hyperlipidemia, which are predisposing factors for type 2 diabetes mellitus and CV disease. The aim of this meta-analysis is to examine the effect of insulin sensitizers on clinical and biochemical features of PCOS and risk factors for CV disease. A systematic literature review was conducted, and randomized controlled clinical trials were identified by a search of bibliographic databases: Medline database (from 1966 forward), EMBASE (January 1985 forward), and Cochrane Central Register of Controlled Trials. Reviews of reference lists further identified candidate trials. Data was independently abstracted in duplicate by 2 investigators using a standardized data-collection form. Articles without a comparison group and randomization allocation were excluded. Reviewers worked independently and in duplicate to determine the methodological quality of trials, then collected data on patient characteristics, interventions, and outcomes. Of 455 studies, 44 trials were eligible. A random effects model was used. Significant unadjusted results favoring treatment with insulin sensitizers were obtained for body mass index (BMI) (effect size [ES] of 0.58), waist to hip ratio (WHR) (ES of 0.02), low-density-lipoprotein cholesterol (LDL-C) (ES of 0.11), fasting insulin (ES of 2.82), fasting glucose (ES of 0.10), free testosterone (ES of 1.88), and androstenedione level (ES of 0.76). Treatment with insulin sensitizers in women with PCOS results in improvement in CV factors such as BMI, WHR, LDL-C, fasting insulin, glucose, free testosterone, and androstenedione.

Insulin-like growth factor-I, physical activity, and control of cellular anabolism.

Science.gov (United States)

Nindl, Bradley C

2010-01-01

The underlying mechanisms responsible for mediating the beneficial outcomes of exercise undoubtedly are many, but the insulin-like growth factor-I (IGF-I) system is emerging as an important and central hormonal axis that plays a significant role concerning cellular anabolism. This introductory article summarizes the intent and the content for papers presented as part of a 2008 American College of Sports Medicine national symposium entitled "Insulin-like Growth Factor-I, Physical Activity, and Control of Cellular Anabolism." The individual authors and their papers are as follows: Jan Frystyk authoring "The relationship between exercise and the growth hormone/insulin-like growth factor-I axis," Greg Adams authoring "IGF-I signaling in skeletal muscle and the potential for cytokine interactions," and Brad Nindl authoring "Insulin-like growth factor-I as a biomarker of health, fitness, and training status." These papers focus on 1) different assay methodologies for IGF-I within the paradigm of exercise studies, 2) research demonstrating that intracellular signaling components associated with several proinflammatory cytokines have the potential to interact with anabolic signaling processes in skeletal muscle, and 3) an overview of IGF-I as a biomarker related to exercise training, muscle and bone remodeling, body composition, cognition, and cancer. When summed in total, the contribution that these papers will make will undoubtedly involve bringing attention to the vast regulatory complexity of the IGF-I system and will hopefully convince the reader that the IGF-I system warrants further detailed scientific inquiry to resolve many unanswered questions and paradoxical experimental findings. The IGF-I system remains one of the most intriguing and captivating marvels of human physiology that seems central in mediating numerous adaptations from physical activity.

Converting Insulin-like Growth Factors 1 and 2 into High-Affinity Ligands for Insulin Receptor Isoform A by the Introduction of an Evolutionarily Divergent Mutation

Czech Academy of Sciences Publication Activity Database

Macháčková, Kateřina; Chrudinová, Martina; Radosavljević, Jelena; Potalitsyn, Pavlo; Křížková, Květoslava; Fábry, Milan; Selicharová, Irena; Collinsová, Michaela; Brzozowski, A. M.; Žáková, Lenka; Jiráček, Jiří

2018-01-01

Roč. 57, č. 16 (2018), s. 2373-2382 ISSN 0006-2960 R&D Projects: GA ČR GA15-19018S Institutional support: RVO:61388963 ; RVO:68378050 Keywords : insulin-like growth factor * insulin * receptor * analog Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 2.938, year: 2016 https://pubs.acs.org/doi/10.1021/acs.biochem.7b01260

Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women

DEFF Research Database (Denmark)

Grønbaek, Henning; Flyvbjerg, Allan; Mellemkjaer, Lene

2004-01-01

BACKGROUND: Studies have shown a positive association between serum insulin-like growth factor (IGF)-I and breast cancer risk in premenopausal but not postmenopausal women. IGF-II and estrogen receptor (ER) status has never been investigated. We examined the association between IGF-I, IGF-II, IGF......, or IGFBP-3 and risk of ER-negative breast cancer. CONCLUSION: Serum IGFBP-3 and IGF-II levels were positively associated with ER-positive breast cancer risk. This may suggest an important relationship among IGFs, IGFBPs, the ER system, and breast cancer development in postmenopausal women....

Insulin-like growth factor-I and insulin-like growth factor binding proteins in the bovine mammary gland: Receptors, endogenous secretion, and appearance in milk

International Nuclear Information System (INIS)

Campbell, P.G.

1988-01-01

This is the first study to characterize both insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) in bovine milk, to characterize the IGF-I receptor in the dry and lactating mammary gland, and to report de novo synthesis and secretion of IGF-I and IGFBP from normal mammary tissue. Immunoreactive IGF-I was principally associated with 45 kDa IGFBP in milk. Multiparous cows had a higher IGF-I concentration of 307 ng/ml than primiparous cows at 147 ng/ml. IGF-I concentration on day 56 of lactation was 34 ng/ml for combined parity groups. At parturition, IGF-I mass in blood and milk pools was 1.4 and 1.2 mg, respectively. Binding of 125 I-IGF-I was specific for IGF-I with anIC 50 of 2.2 ng which was a 10- and 1273-fold greater affinity than IGF-II and insulin, respectively. Association constants, as determined by Scatchard analysis, were similar for both pregnant and lactating cows at 3.5 and 4.0 L/nM, respectively. In addition, estimated mean receptor concentration was 0.25 and 0.23 pM/mg protein for pregnant and lactating cows, respectively. In a survey of mammary microscomes prepared from 48 cows, 125 I-IGF-I binding declined with progressing lactation and a similar trend was observed during pregnancy

Diagnostic utility of leptin and insulin-like growth factor binding ...

African Journals Online (AJOL)

Serum levels of leptin, insulin growth factor binding protein-2 (IGFBP-2) and alpha fetoprotein (AFP) were measured. ... renewal in response to nutrients. IGF pathway is not only involved in cell growth in tissue culture, but it is also involved in ...

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Petersen, K R; Skouby, S O; Sidelmann, Johannes Jakobsen

1994-01-01

OBJECTIVE: We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. STUDY DESIGN: Twenty-five women with uncomplicated insulin-dependent diabetes m...

Salivary factors in children and adolescents with insulin-dependent diabetes mellitus.

Science.gov (United States)

Karjalainen, K M; Knuuttila, M L; Käär, M L

1996-01-01

To determine whether hyperglycemia in IDDM (insulin-dependent diabetes mellitus) could interfere with salivary secretion rates, salivary glucose levels, and salivary microbial counts, we studied salivary factors in two groups of children and adolescents with IDDM. One study group included 14 children with newly diagnosed IDDM )mean age 11 years, SD +/- 2.4 years). Samples of saliva were collected on admission to hospital and after 2 weeks on insulin treatment. The other study group were 50 IDDM children (mean age 14.4 years, SD +/- 1.7 years, mean duration of diabetes 6.2 years, SD +/- 1.4 years) visiting the outpatient diabetic clinic. Samples of saliva were collected during two visits, approximately 3 months apart. In the newly diagnosed IDDM cases, mean salivary glucose level decreased from 54.1 +/- 31.7 mg/l to 35.2 +/- 29.5 mg/l (P = 0.096) after beginning insulin treatment. During hyperglycemia, salivary glucose levels correlated with mean blood glucose levels for the day concerned (r = 0.65, P salivary glucose levels. Stimulated saliva secretion increased significantly from 5.4 +/- 3.3 ml/5 min to 7.3 +/- 2.6 ml/5 min (P salivary flow rates and salivary glucose levels were not significantly related to the glycosylated hemoglobin (HbA1) values. Salivary glucose levels and salivary secretion rates were inversely correlated (P salivary secretion and high salivary glucose levels. As a consequence, salivary lactobacilli and yeast counts tended to increase.

The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome.

Science.gov (United States)

Ren, Jun; Anversa, Piero

2015-02-15

Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Interaction of insulin-like growth factor I with porcine thyroid cells cultured in monolayer

International Nuclear Information System (INIS)

Saji, M.; Tsushima, T.; Isozaki, O.; Murakami, H.; Ohba, Y.; Sato, K.; Arai, M.; Mariko, A.; Shizume, K.

1987-01-01

The interaction of insulin-like growth factor I (IGF-I) with porcine thyroid cells cultured in monolayer was studied. Specific binding of [ 125 I]iodo-IGF-I to thyroid cells was a reversible process dependent on the time and temperature of incubation. A steady state was achieved in 18 h at 4 C and averaged 14.2 +/- 2% (mean +/- SD)/10(6) cells. Binding of [ 125 I]iodo-IGF-I was inhibited by unlabeled IGF-I; half-maximal inhibition occurred at concentrations of 2-5 ng/ml. Multiplication-stimulating activity (rat IGF-II) and pork insulin had relative potencies of 1:20 and 1:300 compared with IGF-I. Scatchard analysis of binding data revealed a single class of IGF-I receptors with a Ka of 4.3 X 10(10) M-1, 49,000 binding sites were estimated per cell. Affinity cross-linking and autoradiography demonstrated the presence of type I IGF receptors. Thyroid cells also had specific receptors for insulin, but specific binding of [ 125 I]iodoinsulin was much lower than that of [ 125 I]iodo-IGF-I. Preincubation of thyroid cells with IGF-I or insulin caused a concentration-dependent decrease in [ 125 I]iodo-IGF-I binding due to an apparent loss of receptors. Preincubation with epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, or TSH did not alter subsequent binding of [ 125 I]iodo-IGF-I. Low concentrations of IGF-I stimulated DNA synthesis and proliferation of thyroid cells and acted synergistically with epidermal growth factor. Multiplication-stimulating activity and insulin had relative potencies in stimulating DNA synthesis comparable to their abilities to inhibit the binding of [ 125 I]iodo-IGF-I to thyroid cells

Brain pericyte-derived soluble factors enhance insulin sensitivity in GT1-7 hypothalamic neurons.

Science.gov (United States)

Takahashi, Hiroyuki; Takata, Fuyuko; Matsumoto, Junichi; Machida, Takashi; Yamauchi, Atsushi; Dohgu, Shinya; Kataoka, Yasufumi

2015-02-20

Insulin signaling in the hypothalamus plays an important role in food intake and glucose homeostasis. Hypothalamic neuronal functions are modulated by glial cells; these form an extensive network connecting the neurons and cerebral vasculature, known as the neurovascular unit (NVU). Brain pericytes are periendothelial accessory structures of the blood-brain barrier and integral members of the NVU. However, the interaction between pericytes and neurons is largely unexplored. Here, we investigate whether brain pericytes could affect hypothalamic neuronal insulin signaling. Our immunohistochemical observations demonstrated the existence of pericytes in the mouse hypothalamus, exhibiting immunoreactivity of platelet-derived growth factor receptor β (a pericyte marker), and laminin, a basal lamina marker. We then exposed a murine hypothalamic neuronal cell line, GT1-7, to conditioned medium obtained from primary cultures of rat brain pericytes. Pericyte-conditioned medium (PCM), but not astrocyte- or aortic smooth muscle cell-conditioned medium, increased the insulin-stimulated phosphorylation of Akt in GT1-7 cells in a concentration-dependent manner. PCM also enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor β without changing its expression or localization in cytosolic or plasma membrane fractions. These results suggest that pericytes, rather than astrocytes, increase insulin sensitivity in hypothalamic neurons by releasing soluble factors under physiological conditions in the NVU. Copyright © 2015 Elsevier Inc. All rights reserved.

Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3.

Science.gov (United States)

2005-01-01

Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate

Skeletal Muscle Insulin Resistance in Endocrine Disease

Directory of Open Access Journals (Sweden)

Melpomeni Peppa

2010-01-01

Full Text Available We summarize the existing literature data concerning the involvement of skeletal muscle (SM in whole body glucose homeostasis and the contribution of SM insulin resistance (IR to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS, adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Insulin-like growth factors act synergistically with basic fibroblast growth factor and nerve growth factor to promote chromaffin cell proliferation

DEFF Research Database (Denmark)

Frödin, M; Gammeltoft, S

1994-01-01

We have investigated the effects of insulin-like growth factors (IGFs), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF) on DNA synthesis in cultured chromaffin cells from fetal, neonatal, and adult rats by using 5-bromo-2'-deoxyuridine (BrdUrd) pulse labeling for 24 or 48 h...... implications for improving the survival of chromaffin cell implants in diseased human brain....

Insulin-like growth factor family and combined antisense approach in therapy of lung carcinoma.

OpenAIRE

Pavelić, Jasminka; Pavelić, Ljubomir; Karadza, Jerolim; Krizanac, Simun; Unesić, Josip; Spaventi, Sime; Pavelić, Kresimir

2002-01-01

BACKGROUND: Perturbation in a level of any peptide from insulin-like growth factor (IGF) family (ligands, receptors, and binding proteins) seems to be implicated in lung cancer formation; IGF ligands and IGF-I receptor through their mitogenic and anti-apoptotic action, and the mannose 6-phosphate/insulin-like growth factor II receptor (M6-P/IGF-IIR) possibly as a tumor suppressor. MATERIALS AND METHODS: To determine the identity, role, and mutual relationship of IGFs in lung cancer growth and...

Exercise, Insulin Absorption Rates, and Artificial Pancreas Control

Science.gov (United States)

Frank, Spencer; Hinshaw, Ling; Basu, Rita; Basu, Ananda; Szeri, Andrew J.

2016-11-01

Type 1 Diabetes is characterized by an inability of a person to endogenously produce the hormone insulin. Because of this, insulin must be injected - usually subcutaneously. The size of the injected dose and the rate at which the dose reaches the circulatory system have a profound effect on the ability to control glucose excursions, and therefore control of diabetes. However, insulin absorption rates via subcutaneous injection are variable and depend on a number of factors including tissue perfusion, physical activity (vasodilation, increased capillary throughput), and other tissue geometric and physical properties. Exercise may also have a sizeable effect on the rate of insulin absorption, which can potentially lead to dangerous glucose levels. Insulin-dosing algorithms, as implemented in an artificial pancreas controller, should account accurately for absorption rate variability and exercise effects on insulin absorption. The aforementioned factors affecting insulin absorption will be discussed within the context of both fluid mechanics and data driven modeling approaches.

Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors

DEFF Research Database (Denmark)

Kveiborg, Marie; Flyvbjerg, Allan; Eriksen, E F

2001-01-01

While transforming growth factor-beta1 (TGF-beta1) regulates proliferation and differentiation of human osteoblast precursor cells, the mechanisms underlying these effects are not known. Several hormones and locally acting growth factors regulate osteoblast functions through changes in the insulin......-like growth factors (IGFs) and IGF-binding proteins (IGFBPs). Thus, we studied the effects of TGF-beta1 on IGFs and IGFBPs in human marrow stromal (hMS) osteoblast precursor cells. TGF-beta1 increased the steady-state mRNA level of IGF-I up to 8.5+/-0.6-fold (P...

Molecular Mechanisms of Insulin Secretion and Insulin Action.

Science.gov (United States)

Flatt, Peter R.; Bailey, Clifford J.

1991-01-01

Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

Characterization of insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function

International Nuclear Information System (INIS)

Penhoat, A.; Chatelain, P.G.; Jaillard, C.; Saez, J.M.

1988-01-01

We have characterized insulin-like growth factor I (IGF-I) and insulin receptors in cultured bovine adrenal cells by binding and cross-linking affinity experiments. At equilibrium the dissociation constant and the number of binding sites per cell for IGF-I were 1.4 +/- (SE) 0.3 x 10(-9) M and 19,200 +/- 2,100, respectively. Under reduction conditions, disuccinimidyl suberate cross-linked [ 125 I]iodo-IGF-I to one receptor complex with an Mr of 125,000. Adrenal cells also contain specific insulin receptors with an apparent dissociation constant (Kd) of 10(-9) M. Under reduction conditions [ 125 I]iodo-insulin binds to one band with an approximate Mr of 125,000. IGF-I and insulin at micromolar concentrations, but not at nanomolar concentrations, slightly stimulated DNA synthesis, but markedly potentiated the mitogenic action of fibroblast growth factor. Adrenal cells cultured in a serum-free medium containing transferrin, ascorbic acid, and insulin (5 micrograms/ml) maintained fairly constant angiotensin-II (A-II) receptor concentration per cell and increased cAMP release on response to ACTH and their steroidogenic response to both ACTH and A-II. When the cells were cultured in the same medium without insulin, the number of A-II receptors significantly decreased to 65% and the increased responsiveness was blunted. Treatment of such cells for 3 days with increasing concentrations of IGF-I (1-100 ng/ml) produced a 2- to 3-fold increase in A-II receptors and enhanced the cAMP response (3- to 4-fold) to ACTH and the steroidogenic response (4- to 6-fold) to ACTH and A-II. These effects were time and dose dependent (ED50 approximately equal to 10(-9) M). Insulin at micromolar concentrations produced an effect similar to that of IGF-I, but at nanomolar concentrations the effect was far less

Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism

NARCIS (Netherlands)

J.M.A. Emmen (Judith); A. McLuskey; I.M. Adham; W. Engel; M. Verhoef-Post (Miriam); A.P.N. Themmen (Axel); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

2000-01-01

textabstractRecently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an

Overfeeding Dairy Cattle During Late-Pregnancy Alters Hepatic PPARα-Regulated Pathways Including Hepatokines: Impact on Metabolism and Peripheral Insulin Sensitivity

Science.gov (United States)

Khan, M Jawad; Jacometo, Carolina B; Graugnard, Daniel E; Corrêa, Marcio N; Schmitt, Eduardo; Cardoso, Felipe; Loor, Juan J

2014-01-01

Hepatic metabolic gene networks were studied in dairy cattle fed control (CON, 1.34 Mcal/kg) or higher energy (overfed (OVE), 1.62 Mcal/kg) diets during the last 45 days of pregnancy. A total of 57 target genes encompassing PPARα-targets/co-regulators, hepatokines, growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, lipogenesis, and lipoprotein metabolism were evaluated on −14, 7, 14, and 30 days around parturition. OVE versus CON cows were in more negative energy balance (NEB) postpartum and had greater serum non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), and liver triacylglycerol (TAG) concentrations. Milk synthesis rate did not differ. Liver from OVE cows responded to postpartal NEB by up-regulating expression of PPARα-targets in the fatty acid oxidation and ketogenesis pathways, along with gluconeogenic genes. Hepatokines (fibroblast growth factor 21 (FGF21), angiopoietin-like 4 (ANGPTL4)) and apolipoprotein A-V (APOA5) were up-regulated postpartum to a greater extent in OVE than CON. OVE led to greater blood insulin prepartum, lower NEFA:insulin, and greater lipogenic gene expression suggesting insulin sensitivity was not impaired. A lack of change in APOB, MTTP, and PNPLA3 coupled with upregulation of PLIN2 postpartum in cows fed OVE contributed to TAG accumulation. Postpartal responses in NEFA and FGF21 with OVE support a role of this hepatokine in diminishing adipose insulin sensitivity. PMID:24737933

Skin Tags and Acanthosis Nigricans in Patients with Hepatitis C Infection in Relation to Insulin Resistance and Insulin Like Growth Factor-1 Levels

Science.gov (United States)

El Safoury, Omar Soliman; Shaker, Olfat G; Fawzy, May Mohsen

2012-01-01

Background: Skin tags (ST) are papillomas commonly found in the neck, axillae of middle-aged and elderly people Aim: Insulin and insulin-like growth factor (IGF-1) levels are affected by hepatitis C virus (HCV) infection and both of them may be implicated in the etiopathogenesis of ST and acanthosis nigricans (AN) through their proliferative and differentiating properties. So, the aim of this work was to evaluate the impact of HCV infection on ST and AN through the estimation of insulin resistance and IGF-1. Materials and Methods: Participants were arranged into four groups: (ST +ve / HCV +ve) 23 subjects, (ST+ / HCV -ve) 19 subjects, (HCV -ve / ST-ve) 20 subjects and (ST-ve /HCV +ve) 22 subjects. Age, ST size, color, number, AN, fasting glucose, fasting insulin, insulin resistance, IGF-1, HCV-antibodies (Ab) were recorded. Results: The mean number of ST in Group 1 was half the number of ST in Group 2 (11.0±9.3 / 22.3±14.0) (P=0.005). The difference in insulin resistance between the same groups was non-significant (13.1±10.6 / 9.0±5.5) (P=0.441) while the difference in IGF-1 was statistically significant (218.6±46.2 /285.4±32.8) (P=0.002). The multivariate logistic regression for the variables revealed that insulin resistance is the only factor affecting the occurrence of ST (OR=1.096, P=0.023). Multivariate regression analysis for the variables showed that HCV was borderline but not a significant factor affecting the number of ST (Beta=-0.409, P=0.053). The number of patients with AN was doubled in Group 2 in comparison to Group 1 but this was non significant 3(13%) / 6(32%) (P=0.2800). Conclusion: HCV is associated with a significant decrease in the ST number and in the serum level of IGF-1 together with an obvious decrease in the occurrence of AN. Our results may point to the entrant effect of insulin resistance and IGF-1 in ST and AN development. The current study suggests the evaluation of IGF-1-lowering agents in the control of ST and AN especially in

Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance.

Science.gov (United States)

Huntington, M O; Krell, K E; Armour , W E; Liljenquist, J E

2001-06-01

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor. We report here a remarkable degree of insulin resistance in a patient with adult respiratory distress syndrome and myelodysplasia.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

Science.gov (United States)

Hartog, H; Boezen, H M; de Jong, M M; Schaapveld, M; Wesseling, J; van der Graaf, W T A

2013-12-01

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival. Copyright © 2013 Elsevier Ltd. All rights reserved.

Lipid droplets hypertrophy: a crucial determining factor in insulin regulation by adipocytes

Science.gov (United States)

Sanjabi, Bahram; Dashty, Monireh; Özcan, Behiye; Akbarkhanzadeh, Vishtaseb; Rahimi, Mehran; Vinciguerra, Manlio; van Rooij, Felix; Al-Lahham, Saad; Sheedfar, Fareeba; van Kooten, Theo G.; Spek, C. Arnold; Rowshani, Ajda T.; van der Want, Johannes; Klaassen, Rene; Sijbrands, Eric; Peppelenbosch, Maikel P.; Rezaee, Farhad

2015-03-01

Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically functional. Insulin concentrations and release are fat mass- and LDs-dependent respectively. Fat reduction mediated by bariatric surgery repairs obesity-associated T2D. The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD38 and NNAT, involved in insulin regulation/release were differentially expressed in pancreas and adipose tissue (AT). INS (insulin) and GCG expression reduced in human AT-T2D as compared to AT-control, but remained unchanged in pancreas in either state. Insulin levels (mRNA/protein) were higher in AT derived from prediabetes BB rats with destructed pancreatic β-cells and controls than pancreas derived from the same rats respectively. Insulin expression in 10 human primary cell types including adipocytes and macrophages is an evidence for extrapancreatic insulin-producing cells. The data suggest a crosstalk between AT and pancreas to fine-tune energy metabolic system or may minimize the metabolic damage during diabetes. This study opens new avenues towards T2D therapy with a great impact on public health.

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

DEFF Research Database (Denmark)

Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj

2003-01-01

BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow....... Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (Palpha...

Basal insulin persistence, associated factors, and outcomes after treatment initiation among people with type 2 diabetes mellitus in the US.

Science.gov (United States)

Perez-Nieves, Magaly; Kabul, Samaneh; Desai, Urvi; Ivanova, Jasmina I; Kirson, Noam Y; Cummings, Alice Kate; Birnbaum, Howard G; Duan, Ran; Cao, Dachuang; Hadjiyianni, Irene

2016-01-01

To assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in the US. People aged ≥18 years diagnosed with T2DM initiating basal insulin between April 2006 and March 2012 (index date), no prior insulin use, and continuous insurance coverage for 6 months before (baseline) and 24 months after index date (follow-up period) were selected using de-identified administrative claims data in the US. Based on whether there were ≥30 day gaps in basal insulin use in the first year post-index, patients were classified as continuers (no gap), interrupters (≥1 prescription after gap), and discontinuers (no prescription after gap). Factors associated with persistence - assessed using multinomial logistic regression model; annual healthcare resource use and costs during follow-up period - compared separately between continuers and interrupters, and continuers and discontinuers. Of the 19,110 people included in the sample (mean age: 59 years, ∼60% male), 20% continued to use basal insulin, 62% had ≥1 interruption, and 18% discontinued therapy in the year after initiation. Older age, multiple antihyperglycemic drug use, and injectable antihyperglycemic use during baseline were associated with significantly higher likelihoods of continuing basal insulin. Relative to interrupters and discontinuers, continuers had fewer emergency department visits, shorter hospital stays, and lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers: $13,021), but higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers: $4857) in the first year post-index (p US. In addition, persistence patterns were assessed using administrative claims as opposed to actual medication-taking behavior and did not account for measures of glycemic control. Further research is needed to understand the reasons behind basal insulin persistence and the implications thereof, to help

Association between Insulin Like Growth Factor-1 (IGF-1) gene ...

African Journals Online (AJOL)

The insulin-like growth factor-1 (IGF1) is a key regulator of muscle development and metabolism in birds and other vertebrate. Our objective was to determine the association between IGF1 gene polymorphism and carcass traits in FUNAAB Alpha chicken. Genomic DNA was extracted from the blood of 50 normal feathered ...

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

OpenAIRE

Yu, Yue; Sun, Ying; He, Shengqi; Yan, Cheng; Rui, Liangyou; Li, Wenjun; Liu, Yong

2012-01-01

The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-lik...

Gender differences in factors influencing insulin resistance in elderly hyperlipemic non-diabetic subjects

Directory of Open Access Journals (Sweden)

Hrebícek Jirí

2002-10-01

Full Text Available Abstract Background The increase in the prevalence of insulin resistance-related metabolic syndrome, a disorder that greatly increases the risk of diabetes, heart attack and stroke, is alarming. One of the most frequent and early symptoms of metabolic syndrome is hypertriglyceridemia. We examined the gender differences between various metabolic factors related to insulin resistance in elderly non-diabetic men and postmenopausal women of comparable age suffering from hypertriglyceridemia, and compared them with healthy subjects of equal age. Results The indexes of insulin resistance HOMA IR and QUICKI were significantly higher in both hyperlipemic men and women than in controls; 95% confidence limits of hyperlipemic subjects did not overlap with controls. In both normolipemic and hyperlipemic men and women serum leptin correlated significantly with insulin resistance, while HDL-cholesterol correlated inversely with HOMA-IR only in women (both normo- and hyperlipemic, and serum tumor necrosis factor α (TNFα only in hyperlipemic women. According to results of multiple regression analysis with HOMA-IR as a dependent variable, leptin played a significant role in determining insulin resistance in both genders, but – aside from leptin – triglycerides, TNFα and decreased HDL-cholesterol were significant determinants in women, while body mass index and decreased HDL-cholesterol were significant determinants in men. The coefficient of determination (R2 of HOMA IR by above mentioned metabolic variables was in women above 60%, in men only about 40%. Conclusion The significant role of serum leptin in determination of insulin resistance in both elderly men and postmenopausal women of equal age was confirmed. However, the study also revealed significant gender differences : in women a strong influence of triglycerides, TNFα and decreased HDL-cholesterol, in men only a mild role of BMI and decreased HDL-cholesterol.

Induction of insulin and islet amyloid polypeptide production in pancreatic islet glucagonoma cells by insulin promoter factor 1

DEFF Research Database (Denmark)

Serup, P; Jensen, J; Andersen, F G

1996-01-01

Insulin promoter factor 1 (IPF1), a member of the homeodomain protein family, serves an early role in pancreas formation, as evidenced by the lack of pancreas formation in mice carrying a targeted disruption of the IPF1 gene [Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. (1994) Nature (London...

Insulin receptors

International Nuclear Information System (INIS)

Kahn, C.R.; Harrison, L.C.

1988-01-01

This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4 ...

African Journals Online (AJOL)

Tropical Journal of Pharmaceutical Research July 2015; 14 (7): 1191-1197 ... Abstract. Purpose: To evaluate the receptor-mediated neuroprotective effect of insulin-like growth factor-II (IGF- ... catecholamines, reduces levels of dopamine and.

Changes in serum concentrations of growth hormone, insulin, insulin-like growth factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth hormone excretion during the menstrual cycle

DEFF Research Database (Denmark)

Juul, A; Scheike, Thomas Harder; Pedersen, A T

1997-01-01

Few studies exist on the physiological changes in the concentrations of growth hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) within the menstrual cycle, and some controversy remains. We therefore decided to study the impact of endogenous sex steroids on the GH......-IGF-IGFBP axis during the ovulatory menstrual cycle in 10 healthy women (aged 18-40 years). Blood sampling and urinary collection was performed every morning at 0800 h for 32 consecutive days. Every second day the subjects were fasted overnight before blood sampling. Follicle stimulating hormone, luteinizing...... hormone (LH), oestradiol, progesterone, IGF-I, IGFBP-3, sex hormone-binding globulin, dihydroepiandrosterone sulphate and GH were determined in all samples, whereas insulin and IGFBP-1 were determined in fasted samples only. Serum IGF-I concentrations showed some fluctuation during the menstrual cycle...

Growth factors II: insuline-like growth binging proteins (GFBPs Factores de crecimiento II: factores insulinoides de crecimiento

Directory of Open Access Journals (Sweden)

Hilda Norha Jaramillo Londoño

1996-03-01

Full Text Available This review summarizes recent knowledge concerning Insulin.like growth factors I and II, with emphasis on their biochemical structure, concentrations, binding proteins, receptors, mechanisms of action, biological effects, and alterations of their concentrations in biological fluids. Se revisan los Factores Insulinoides de Crecimiento, también denominados ";Factores de Crecimiento Similares a la Insulina";, sobre los cuales se dispone de abundante información. Se sintetizan conocimientos recientes sobre dichos factores con énfasis en los siguientes aspectos: estructura bioquímica, concentraciones y sus cambios en los líquidos biológicos, proteínas fijadoras, receptores, mecanismos de acción y efectos biológicos.

Insulin transport into the brain and cerebrospinal fluid.

Science.gov (United States)

Begg, Denovan P

2015-01-01

The pancreatic hormone insulin plays a well-described role in the periphery, based principally on its ability to lower circulating glucose levels via activation of glucose transporters. However, insulin also acts within the central nervous system (CNS) to alter a number of physiological outcomes ranging from energy balance and glucose homeostasis to cognitive performance. Insulin is transported into the CNS by a saturable receptor-mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is dependent on numerous factors including diet, glycemia, a diabetic state and notably, obesity. Obesity leads to a marked decrease in insulin transport from the periphery into the CNS and the biological basis of this reduction of transport remains unresolved. Despite decades of research into the effects of central insulin on a wide range of physiological functions and its transport from the periphery to the CNS, numerous questions remain unanswered including which receptor is responsible for transport and the precise mechanisms of action of insulin within the brain. © 2015 Elsevier Inc. All rights reserved.

Gene expression of tumour necrosis factor and insulin signalling-related factors in subcutaneous adipose tissue during the dry period and in early lactation in dairy cows.

Science.gov (United States)

Sadri, H; Bruckmaier, R M; Rahmani, H R; Ghorbani, G R; Morel, I; van Dorland, H A

2010-10-01

Gene expression of adipose factors, which may be part of the mechanisms that underlie insulin sensitivity, were studied in dairy cows around parturition. Subcutaneous fat biopsies and blood samples were taken from 27 dairy cows in week 8 antepartum (a.p.), on day 1 postpartum (p.p.) and in week 5 p.p. In the adipose tissue samples, mRNA was quantified by real-time reverse transcription polymerase chain reaction for tumour necrosis factor alpha (TNFα), insulin-independent glucose transporter (GLUT1), insulin-responsive glucose transporter (GLUT4), insulin receptor, insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), regulatory subunit of phosphatidylinositol-3 kinase (p85) and catalytic subunit of phosphatidylinositol-3 kinase. Blood plasma was assayed for concentrations of glucose, β-hydroxybutyric acid, non-esterified fatty acids (NEFA) and insulin. Plasma parameters followed a pattern typically observed in dairy cows. Gene expression changes were observed, but there were no changes in TNFα concentrations, which may indicate its local involvement in catabolic adaptation of adipose tissue. Changes in GLUT4 and GLUT1 mRNA abundance may reflect their involvement in reduced insulin sensitivity and in sparing glucose for milk synthesis in early lactation. Unchanged gene expression of IRS1, IRS2 and p85 over time may imply a lack of their involvement in terms of insulin sensitivity dynamics. Alternatively, it may indicate that post-transcriptional modifications of these factors came into play and may have concealed an involvement. © 2010 Blackwell Verlag GmbH.

Development of receptors for insulin and insulin-like growth factor-I in head and brain of chick embryos: Autoradiographic localization

International Nuclear Information System (INIS)

Bassas, L.; Girbau, M.; Lesniak, M.A.; Roth, J.; de Pablo, F.

1989-01-01

In whole brain of chick embryos insulin receptors are highest at the end of embryonic development, while insulin-like growth factor-I (IGF-I) receptors dominate in the early stages. These studies provided evidence for developmental regulation of both types of receptors, but they did not provide information on possible differences between brain regions at each developmental stage or within one region at different embryonic ages. We have now localized the specific binding of [125I]insulin and [125I]IGF-I in sections of head and brain using autoradiography and computer-assisted densitometric analysis. Embryos have been studied from the latter part of organogenesis (days 6 and 12) through late development (day 18, i.e. 3 days before hatching), and the binding patterns have been compared with those in the adult brain. At all ages the binding of both ligands was to discrete anatomical regions. Interestingly, while in late embryos and adult brain the patterns of [125I]insulin and [125I] IGF-I binding were quite distinct, in young embryos both ligands showed very similar localization of binding. In young embryos the retina and lateral wall of the growing encephalic vesicles had the highest binding of both [125I]insulin and [125I]IGF-I. In older embryos, as in the adult brain, insulin binding was high in the paleostriatum augmentatum and molecular layer of the cerebellum, while IGF-I binding was prominent in the hippocampus and neostriatum. The mapping of receptors in a vertebrate embryo model from early prenatal development until adulthood predicts great overlap in any possible function of insulin and IGF-I in brain development, while it anticipates differential localized actions of the peptides in the mature brain

Insulin-like growth factor receptor inhibitors: baby or the bathwater?

Science.gov (United States)

Yee, Douglas

2012-07-03

The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response, larger randomized phase III trials have not shown clear clinical benefit of targeting this pathway in combination with conventional strategies. These disappointing results have resulted in the discontinuation of several anti-IGF1R programs. However, the conduct of these trials has brought to the forefront several important factors that need to be considered in the conduct of future clinical trials. The need to develop biomarkers, a clearer understanding of insulin receptor function, and defining rational combination regimens all require further consideration. In this commentary, the current state of IGF1R inhibitors in cancer therapy is reviewed.

Insulin resistance and maximal oxygen uptake

DEFF Research Database (Denmark)

Seibaek, Marie; Vestergaard, Henrik; Burchardt, Hans

2003-01-01

BACKGROUND: Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown. HYPOTHESIS: This study was undertaken to determine the relationship between insulin resistance, maximal oxygen uptake......, and the presence of either diabetes or ischemic heart disease. METHODS: The study population comprised 33 patients with and without diabetes and ischemic heart disease. Insulin resistance was measured by a hyperinsulinemic euglycemic clamp; maximal oxygen uptake was measured during a bicycle exercise test. RESULTS......: There was a strong correlation between maximal oxygen uptake and insulin-stimulated glucose uptake (r = 0.7, p = 0.001), and maximal oxygen uptake was the only factor of importance for determining insulin sensitivity in a model, which also included the presence of diabetes and ischemic heart disease. CONCLUSION...

Insulin-like growth factor-1 signaling in renal cell carcinoma

International Nuclear Information System (INIS)

Tracz, Adam F.; Szczylik, Cezary; Porta, Camillo; Czarnecka, Anna M.

2016-01-01

Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells

Insulinaemia and insulin resistance in Caucasian general paediatric population aged 2 to 10 years: Associated risk factors.

Science.gov (United States)

Alías-Hernández, Irene; Galera-Martínez, Rafael; García-García, Emilio; Muñoz-Vico, Francisco Javier; Vázquez Lopez, María Ángeles; Olvera-Porcel, María Carmen; Bonillo Perales, Antonio

2018-02-01

The aim of this study is to determine values of insulinaemia, homeostasis model assessment (HOMA) index and quantitative insulin sensitivity check index (QUICKI) among a population of prepubertal Caucasian children, to analyse factors associated with insulin resistance (IR), and to study its association with cardiovascular risk factors. Population-based study conducted on a randomly selected sample of prepubescent Caucasian subjects aged 2.00 to 9.99 years old. Anthropometric measurements, blood pressure, and fasting blood samples were obtained, including fasting glucose, triglycerides, High Density Lipoprotein (HDL)-cholesterol, and insulin. In addition, QUICKI and HOMA indices were calculated. Generalised additive models for location, scale and shape (GAMLSS) was used to calculate centiles curves and multivariate logistic regression analysis to assess factors associated with IR. A total of 654 subjects were included. Mean values obtained for insulinaemia, HOMA index, and QUICKI were 3.74 μIU/mL, 0.73, and 0.44, respectively, in the overall population and 3.32 μIU/mL, 0.64 and 0.46, respectively, in normal weight subjects. The main factor associated with IR was abdominal obesity (odds ratio [OR] 3.38 [95% CI 1.44-7.94] in the subgroup aged 2.00-5.99 years and OR 9.14 [3.42-24.41] for those aged 6.00-9.99 years). An increased risk of hyperglycaemia (P = 0.043), hypertriglyceridaemia (P < .001), and HDL < p10 (P = 0.021) was described among children aged 2.00 to 5.99 years with IR, and among those aged 6.00 to 9.99 years, IR was associated with an increased risk of hypertriglyceridaemia (P < .001). Abdominal obesity was the main factor associated with IR. Metabolic changes associated with IR seem to be present from early stages of life, which highlights the importance of the prevention, early diagnosis and treatment of obesity. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hyperglycemia in critical patients: Determinants of insulin dose choice

Directory of Open Access Journals (Sweden)

Aline Klitzke Paliosa

Full Text Available Summary Objective: To identify factors that can determine the choice of intermittent subcutaneous regular insulin dose in critically ill patients with hyperglycemia. Method: Cross-sectional study in a general adult ICU with 26 beds, data collected between September and October 2014. The variables analyzed were: sex, age, previous diagnosis of diabetes mellitus, use of corticosteroids, use of lactulose, sepsis, fasting, enteral nutrition, use of dextrose 5% in water, NPH insulin prescription and blood glucose level. Patients with one or more episodes of hyperglycemia (blood glucose greater than 180 mg/dL were included as a convenience sample, not consecutively. Those with continuous insulin prescription were excluded from analysis. Results: We included 64 records of hyperglycemia observed in 22 patients who had at least one episode of hyperglycemia. The median administered subcutaneous regular human insulin was 6 IU and among the factors evaluated only blood glucose levels were associated with the choice of insulin dose administered. Conclusion: Clinical characteristics such as diet, medications and diagnosis of diabetes mellitus are clearly ignored in the decision-making regarding insulin dose to be administered for glucose control in critically ill patients with hyperglycemia.

FACTORS AFFECTING THE DEPOSITION OF AEROSOLIZED INSULIN

Science.gov (United States)

AbstractBackground The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their...

Daily chocolate consumption is inversely associated with insulin resistance and liver enzymes in the Observation of Cardiovascular Risk Factors in Luxembourg study.

Science.gov (United States)

Alkerwi, Ala'a; Sauvageot, Nicolas; Crichton, Georgina E; Elias, Merrill F; Stranges, Saverio

2016-05-01

This study examined the association of chocolate consumption with insulin resistance and serum liver enzymes in a national sample of adults in Luxembourg. A random sample of 1153 individuals, aged 18-69 years, was recruited to participate in the cross-sectional Observation of Cardiovascular Risk Factors in Luxembourg study. Chocolate consumption (g/d) was obtained from a semi-quantitative FFQ. Blood glucose and insulin levels were used for the homoeostasis model assessment of insulin resistance (HOMA-IR). Hepatic biomarkers such as serum γ-glutamyl-transpeptidase (γ-GT), serum aspartate transaminase and serum alanine transaminase (ALT) (mg/l) were assessed using standard laboratory assays. Chocolate consumers (81·8 %) were more likely to be younger, physically active, affluent people with higher education levels and fewer chronic co-morbidities. After excluding subjects taking antidiabetic medications, higher chocolate consumption was associated with lower HOMA-IR (β=-0·16, P=0·004), serum insulin levels (β=-0·16, P=0·003) and γ-GT (β=-0·12, P=0·009) and ALT (β=-0·09, P=0·004), after adjustment for age, sex, education, lifestyle and dietary confounding factors, including intakes of fruits and vegetables, alcohol, polyphenol-rich coffee and tea. This study reports an independent inverse relationship between daily chocolate consumption and levels of insulin, HOMA-IR and liver enzymes in adults, suggesting that chocolate consumption may improve liver enzymes and protect against insulin resistance, a well-established risk factor for cardiometabolic disorders. Further observational prospective research and well-designed randomised-controlled studies are needed to confirm this cross-sectional relationship and to comprehend the role and mechanisms that different types of chocolate may play in insulin resistance and cardiometabolic disorders.

Failure to initiate early insulin therapy - A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35).

Science.gov (United States)

Gupta, Aditi; Delhiwala, Kushal S; Raman, Rajiv P G; Sharma, Tarun; Srinivasan, Sangeetha; Kulothungan, Vaitheeswaran

2016-06-01

Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. Insulin users had more incidence of DR (52.9% vs. 16.3%, P 1) and sight threatening DR (19.1% vs. 2.4%, P 1) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00-1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02-1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (≥5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub-optimal glycemic control (glycosylated hemoglobin insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control.

Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors.

Science.gov (United States)

Bortvedt, Sarah F; Lund, P Kay

2012-03-01

To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.

Determination of free insulin-like growth factor-I in human serum

DEFF Research Database (Denmark)

Frystyk, J.; Skjærbæk, C.; Ivarsen, P.

2001-01-01

Two fundamentally different methods are currently used for the determination of free insulin-like growth factor-I (IGF-I): ultrafiltration by centrifugation (UF) and direct immunoradiometric assay (IRMA). The aim was to evaluate a commercial IRMA (DSL, Webster, TX, USA) and to compare it with UF....

Diminished concentrations of insulin-like growth factor I in cystic fibrosis

DEFF Research Database (Denmark)

Laursen, Erik; Juul, A; Lanng, S

1995-01-01

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data...

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging.

Science.gov (United States)

Ratajczak, Mariusz Z; Bartke, Andrzej; Darzynkiewicz, Zbigniew

2017-08-01

The dream of slowing down the aging process has always inspired mankind. Since stem cells are responsible for tissue and organ rejuvenation, it is logical that we should search for encoded mechanisms affecting life span in these cells. However, in adult life the hierarchy within the stem cell compartment is still not very well defined, and evidence has accumulated that adult tissues contain rare stem cells that possess a broad trans-germ layer differentiation potential. These most-primitive stem cells-those endowed with pluripotent or multipotent differentiation ability and that give rise to other cells more restricted in differentiation, known as tissue-committed stem cells (TCSCs) - are of particular interest. In this review we present the concept supported by accumulating evidence that a population of so-called very small embryonic-like stem cells (VSELs) residing in adult tissues positively impacts the overall survival of mammals, including humans. These unique cells are prevented in vertebrates from premature depletion by decreased sensitivity to growth hormone (GH), insulin (INS), and insulin-like growth factor (IGF) signaling, due to epigenetic changes in paternally imprinted genes that regulate their resistance to these factors. In this context, we can envision nutrient response GH/INS/IGF signaling pathway as a lethal factor for these most primitive stem cells and an important culprit in aging.

Insulin-like growth factor I and anthropometric parameters in a Danish population

DEFF Research Database (Denmark)

Friedrich, N; Jørgensen, Torben; Juul, A

2012-01-01

study was to analyse the associations between anthropometric measures and IGF-I levels in a population-based sample. From the Danish cross-sectional Health2006 study 3,328 subjects (1,835 women; 1,493 men) aged 19-72 years were included in the analyses. Serum IGF-I levels were determined...... consumption, smoking and physical activity. Our large cross-sectional study suggests that IGF-I may serve as the link between obesity and mortality although any causal relation cannot be inferred and longitudinal analyses are needed to clarify the causal relation.......During the last decade several studies indicated that low insulin-like growth factor (IGF) I levels are related to higher risk of cardiovascular disease and mortality. Obesity represents one further main cardiovascular risk factor which might also be related to IGF-I. The objective of the present...

Insulin sensitivity and clustering of coronary heart disease risk factors in young adults. The Northern Ireland Young Hearts Study

DEFF Research Database (Denmark)

Andersen, Lars Bo; Boreham, Colin A.G.; Young, Ian S.

2006-01-01

risk factor. Subjects with clustered risk were defined as those displaying four or more risk factors. Blood glucose and insulin were measured in the fasting state and 2 h after ingestion of a 75 g glucose load. Results. Fasting insulin and the homeostasis model assessment insulin resistance score (HOMA......) were strong, graded predictors of clustered risk. The odds ratio (OR) for having clustered risk was 10.8 (95% CI: 3.6-32.4) for the upper quartile of fasting insulin compared to the lowest quartile, and the corresponding OR for HOMA was 23.2 (95% CI: 5.3-101.6). Conclusion. HOMA score predicts...

The study of Insulin Resistance in the Off Springs of Diabetics and Non Diabetic Patients

Directory of Open Access Journals (Sweden)

Ganesh Manoorkar

2017-12-01

Full Text Available Introduction: Insulin resistance is one of the main cause in the pathogenesis of the development of type- 2 diabetes mellitus. Elevated insulin levels and insulin resistance may be present several years prior to the development of hyperglycaemia. Hence the diagnosis of insulin resistance at the initial stages in risk group people could be used as an effective measure to prevent type 2 diabetes mellitus and its outcome, including reduction in morbidity and mortality. Though type 2 diabetes mellitus has multifactorial aetiology, genetic factor plays an important role in the development of diabetes mellitus. So we have tried to establish relation between genetic factor and insulin resistance by studying the insulin resistance in off springs of diabetics and non diabetics patients. Aims and objectives: Estimation of insulin levels in the off springs (non diabetics of diabetics and non diabetics patients. Comparision of insulin resistance in the off springs (non diabetics of diabetics and non diabetics. To find the relation between insulin resistance and genetic factor. Material and method: This study was carried out in the department of Biochemistry Grant Government Medical College Mumbai. Total 100 non diabetic people were included in the study of age above 30 years. These are divided into two groups as- Group-I includes 50 off springs (Ist degree relatives of non diabetic people. Group-II includes 50 off springs (Ist degree relatives of diabetic people. The fasting plasma glucose and serum insulin levels are estimated in the above two groups. The insulin resistance was calculated by using HOMA-IR model. Result: Fasting plasma glucose, serum insulin level and insulin resistance is significantly increased in group-II people as compared to group-I people. Conclusion: There is a strong relation between genetic factor and insulin resistance which exist prior to the development of diabetes mellitus. The people of group-II are susceptible for the

Adipokines and Hepatic Insulin Resistance

Science.gov (United States)

Hassan, Waseem

2013-01-01

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it. PMID:23762871

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

International Nuclear Information System (INIS)

Naidoo, C.

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

Energy Technology Data Exchange (ETDEWEB)

Naidoo, C

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, /sup 125/I-insulin binding to the solubilized erythrocyte membrane receptor and /sup 125/I-insulin binding to fibroblasts in culture.

Activity of insulin growth factors and shrimp neurosecretory organ extracts on a lepidopteran cell line.

Science.gov (United States)

Hatt, P J; Liebon, C; Morinière, M; Oberlander, H; Porcheron, P

1997-01-01

Ecdysteroids, or molting hormones, have been proven to be key differentiation regulators for epidermal cells in the postembryonic development of arthropods. Regulators of cell proliferation, however, remain largely unknown. To date, no diffusible insect peptidic growth factors have been characterized. Molecules structurally related to insulin have been discovered in insects, as in other eucaryotes. We developed in vitro tests for the preliminary characterization of potential growth factors in arthropods by adapting the procedures designed to detect such factors in vertebrates to an insect cell line (IAL-PID2) established from imaginal discs of the Indian meal moth. We verified the ability of these tests to measure the proliferation of IAL-PID2 cells. We tested mammalian insulin and insulin-like growth factors (IGF-I, IGF-II). Following an arrest of cell proliferation by serum deprivation, IGF-I and IGF-II caused partial resumption of the cell cycle, evidenced by DNA synthesis. In contrast, the addition of 20-hydroxyecdysone arrested the proliferation of the IAL-PID2 cells. The cell line was then used in a test for functional characterization of potential growth factors originating from the penaeid shrimp, Penaeus vannamei. Crude extracts of neurosecretory and nervous tissues, eyestalks, and ventral neural chain compensated for serum deprivation and stimulated completion of mitosis. Arch.

Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action.

Science.gov (United States)

Deng, Youping; Bhattacharya, Sujoy; Swamy, O Rama; Tandon, Ruchi; Wang, Yong; Janda, Robert; Riedel, Heimo

2003-10-10

The regulation of the metabolic insulin response by mouse growth factor receptor-binding protein 10 (Grb10) has been addressed in this report. We find mouse Grb10 to be a critical component of the insulin receptor (IR) signaling complex that provides a functional link between IR and p85 phosphatidylinositol (PI) 3-kinase and regulates PI 3-kinase activity. This regulatory mechanism parallels the established link between IR and p85 via insulin receptor substrate (IRS) proteins. A direct association was demonstrated between Grb10 and p85 but was not observed between Grb10 and IRS proteins. In addition, no effect of mouse Grb10 was observed on the association between IRS-1 and p85, on IRS-1-associated PI 3-kinase activity, or on insulin-mediated activation of IR or IRS proteins. A critical role of mouse Grb10 was observed in the regulation of PI 3-kinase activity and the resulting metabolic insulin response. Dominant-negative Grb10 domains, in particular the SH2 domain, eliminated the metabolic response to insulin in differentiated 3T3-L1 adipocytes. This was consistently observed for glycogen synthesis, glucose and amino acid transport, and lipogenesis. In parallel, the same metabolic responses were substantially elevated by increased levels of Grb10. A similar role of Grb10 was confirmed in mouse L6 cells. In addition to the SH2 domain, the Pro-rich amino-terminal region of Grb10 was implicated in the regulation of PI 3-kinase catalytic activity. These regulatory roles of Grb10 were extended to specific insulin mediators downstream of PI 3-kinase including PKB/Akt, glycogen synthase kinase, and glycogen synthase. In contrast, a regulatory role of Grb10 in parallel insulin response pathways including p70 S6 kinase, ubiquitin ligase Cbl, or mitogen-activated protein kinase p38 was not observed. The dissection of the interaction of mouse Grb10 with p85 and the resulting regulation of PI 3-kinase activity should help elucidate the complexity of the IR signaling

Insulin in human milk and the use of hormones in infant formulas.

Science.gov (United States)

Shamir, Raanan; Shehadeh, Naim

2013-01-01

Human milk contains a substantial number of hormones and growth factors. Studies in animal models show that some of these peptides (e.g. insulin, insulin-like growth factor 1, IGF-1, epidermal growth factors) have an effect on the small intestine after orogastric administration. Recently, two efforts were made to incorporate growth factors into infant formulas. One of these efforts included the incorporation of IGF-1, and the second is an ongoing effort to evaluate the safety and efficacy of incorporating insulin into infant formulas. The rational and current evidence for adding insulin to infant formulas (presence in human milk, effects of orally administrated insulin on gut maturation, intestinal permeability, systemic effects and preliminary encouraging results of supplementing insulin to a preterm infant formula) is detailed in this review. If the addition of insulin to preterm infant formulas indeed results in better growth and accelerated intestinal maturation, future studies will need to address the supplementation of insulin in term infants and assess the efficacy of such supplementation in enhancing gut maturation and prevention of later noncommunicable diseases such as allergy, autoimmune diseases and obesity. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients.

Science.gov (United States)

Fava, Antonietta; Plastino, Massimiliano; Cristiano, Dario; Spanò, Antonio; Cristofaro, Stefano; Opipari, Carlo; Chillà, Antonio; Casalinuovo, Fatima; Colica, Carmen; De Bartolo, Matteo; Pirritano, Domenico; Bosco, Domenico

2013-12-01

To evaluate glucose metabolism and/or insulin resistance (IR) in 96 patients with Fibromyalgia (FM), associated or not to cognitive impairment. We investigated glucose metabolism in 96 FM patients. Enrolled patients were divided into two groups: 48 patients with memory deficit (group A) and 48 without memory deficit (control group). We evaluated glucose and insulin levels after a 2 h-Oral-Glucose-Tolerance-Test (2 h-OGTT) and insulin resistance (IR) by the homeostasis model assessment formula (HOMA). Body Mass Index (BMI), waist-to-hip-ratio (WHR), anxiety level, fasting plasma insulin and Non-Steroidal Anti-Inflammatory agents use were higher in patients with FM with memory impairment; while age, sex, waist circumference, education level, fasting plasma glucose, glycate hemoglobin, triglycerides, blood lipid profile, C- Reactivity-Protein (CRP), blood pressure and smoking habits were similar in both groups. Following OGTT the prevalence of glucose metabolism abnormalities was significantly higher in group A. IR was present in 79% patients, of whom 23% had also impaired glucose tolerance, 4% newly diagnosed diabetes mellitus and 52% IR only. Obesity and overweight prevailed in group A. IR, but not BMI or WHR was associated to an increased risk of memory impairment (OR = 2,6; 95% CI: 1,22-3,7). The results of this study suggest that IR may represent a risk factor for memory impairment in fibromialgic patients.

Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease

DEFF Research Database (Denmark)

Juul, Anders; Scheike, Thomas Harder; Davidsen, Michael

2002-01-01

Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD).......Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD)....

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions.

Science.gov (United States)

Heni, M; Kullmann, S; Ketterer, C; Guthoff, M; Linder, K; Wagner, R; Stingl, K T; Veit, R; Staiger, H; Häring, H-U; Preissl, H; Fritsche, A

2012-06-01

Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.

Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling

Science.gov (United States)

Wang, Linlin; Schulz, Thomas C.; Sherrer, Eric S.; Dauphin, Derek S.; Shin, Soojung; Nelson, Angelique M.; Ware, Carol B.; Zhan, Mei; Song, Chao-Zhong; Chen, Xiaoji; Brimble, Sandii N.; McLean, Amanda; Galeano, Maria J.; Uhl, Elizabeth W.; D'Amour, Kevin A.; Chesnut, Jonathan D.; Rao, Mahendra S.

2007-01-01

Despite progress in developing defined conditions for human embryonic stem cell (hESC) cultures, little is known about the cell-surface receptors that are activated under conditions supportive of hESC self-renewal. A simultaneous interrogation of 42 receptor tyrosine kinases (RTKs) in hESCs following stimulation with mouse embryonic fibroblast (MEF) conditioned medium (CM) revealed rapid and prominent tyrosine phosphorylation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R); less prominent tyrosine phosphorylation of epidermal growth factor receptor (EGFR) family members, including ERBB2 and ERBB3; and trace phosphorylation of fibroblast growth factor receptors. Intense IGF1R and IR phosphorylation occurred in the absence of MEF conditioning (NCM) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSR). Inhibition of IGF1R using a blocking antibody or lentivirus-delivered shRNA reduced hESC self-renewal and promoted differentiation, while disruption of ERBB2 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis. A simple defined medium containing an IGF1 analog, heregulin-1β (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines. These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs. PMID:17761519

Leptin, insulin like growth factor-1 and thyroid profile in a studied ...

African Journals Online (AJOL)

Howida Hosny El Gebali

2014-02-26

Feb 26, 2014 ... roid stimulating hormone (TSH) and free thyroxin (FT4) in a prepubertal Egyptian sample of chil- dren with DS ... serum levels of leptin, IGF-I (insulin like growth factor-I), ..... a deficit in receptor synthesis in DS. They also ...

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

Science.gov (United States)

Hu, Xiaolei; Chen, Fengling

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

The insulin-like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

DEFF Research Database (Denmark)

Wolthers, O D; Juul, A; Hansen, M

1995-01-01

Serum concentrations of growth hormone-dependent insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) and ...... the calculations (p reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 micrograms period was excluded from the calculations (p = 0.05; z = -1.9). No other statistically significant variations were seen....

Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer.

Science.gov (United States)

Greenall, Sameer A; Bentley, John D; Pearce, Lesley A; Scoble, Judith A; Sparrow, Lindsay G; Bartone, Nicola A; Xiao, Xiaowen; Baxter, Robert C; Cosgrove, Leah J; Adams, Timothy E

2013-01-04

Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.

Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

Science.gov (United States)

Greenall, Sameer A.; Bentley, John D.; Pearce, Lesley A.; Scoble, Judith A.; Sparrow, Lindsay G.; Bartone, Nicola A.; Xiao, Xiaowen; Baxter, Robert C.; Cosgrove, Leah J.; Adams, Timothy E.

2013-01-01

Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed “pro” and “big” IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling. PMID:23166326

Insulin-like growth factor-I and the liver

DEFF Research Database (Denmark)

Bonefeld, Karen; Møller, Søren

2011-01-01

Insulin-like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction...... consequences in cirrhosis are only partly understood. Disruption of the growth hormone (GH)-IGF-I axis seems to be closely associated with the development of liver disease, and treatment with recombinant human IGF (rhIGF)-I has been shown to halt, and even reverse, the fibrotic degeneration. IGF-I in itself...

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

Science.gov (United States)

Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

2017-12-01

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Age-related changes in Serum Growth Hormone, Insulin-like Growth Factor-1 and Somatostatin in System Lupus Erythematosus

Directory of Open Access Journals (Sweden)

Malemud Charles J

2004-10-01

Full Text Available Abstract Background Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus patients to a group of normal female subjects. Methods Basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels were measured by standard radioimmunoassay. Results Serum growth hormone levels failed to correlate with age (r2 = 3.03 in the entire group of normal subjects (i.e. 20 – 80 years. In contrast, serum insulin-like growth factor-1 levels were inversely correlated with age (adjusted r2 = 0.092. Of note, serum growth hormone was positively correlated with age (adjusted r2 = 0.269 in the 20 – 46 year range which overlapped with the age range of patients in the systemic lupus erythematosus group. In that regard, serum growth hormone levels were not significantly higher compared to either the entire group of normal subjects (20 – 80 yrs or to normal subjects age-matched to the systemic lupus erythematosus patients. Serum insulin-like growth factor-1 levels were significantly elevated (p 55 yrs systemic lupus erythematosus patients. Conclusions These results indicated that systemic lupus erythematosus was not characterized by a modulation of the growth hormone/insulin-like growth factor-1 paracrine axis when serum samples from systemic lupus erythematosus patients were compared to age- matched normal female subjects. These results in systemic lupus erythematosus differ from those previously reported in other musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, fibromyalgia, diffuse idiopathic skeletal

Regulation of the pituitary tumor transforming gene by insulin-like-growth factor-I and insulin differs between malignant and non-neoplastic astrocytes

International Nuclear Information System (INIS)

Chamaon, Kathrin; Kirches, Elmar; Kanakis, Dimitrios; Braeuninger, Stefan; Dietzmann, Knut; Mawrin, Christian

2005-01-01

The reasons for overexpression of the oncogene pituitary tumor transforming gene (PTTG) in tumors are still not fully understood. A possible influence of the insulin-like growth factor I (Igf-I) may be of interest, since enhanced Igf-I signalling was reported in various human tumors. We examined the influence of Igf-I and insulin on PTTG expression in human astrocytoma cells in comparison to proliferating non-neoplastic rat embryonal astrocytes. PTTG mRNA expression and protein levels were increased in malignant astrocytes treated with Igf-I or insulin, whereas in rat embryonic astrocytes PTTG expression and protein levels increased only when cells were exposed to Igf-I. Enhanced transcription did not occur after treatment with inhibitors of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), blocking the two basic signalling pathways of Igf-I and insulin. In addition to this transcriptional regulation, both kinases directly bind to PTTG, suggesting a second regulatory route by phosphorylation. However, the interaction of endogenous PTTG with MAPK and PI3K, as well as PTTG phosphorylation were independent from Igf-I or insulin. The latter results were also found in human testis, which contains high PTTG levels as well as in nonneoplastic astrocytes. This suggest, that PI3K and MAPK signalling is involved in PTTG regulation not only in malignant astrocytomas but also in non-tumorous cells

The insulin-like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

DEFF Research Database (Denmark)

Wolthers, O D; Juul, A; Hansen, M

1995-01-01

Serum concentrations of growth hormone-dependent insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP......) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double-blind treatment periods (200 and 800 micrograms) and one open...

Extrinsic Factors Involved in the Differentiation of Stem Cells into Insulin-Producing Cells: An Overview

Directory of Open Access Journals (Sweden)

Rebecca S. Y. Wong

2011-01-01

Full Text Available Diabetes mellitus is a chronic disease with many debilitating complications. Treatment of diabetes mellitus mainly revolves around conventional oral hypoglycaemic agents and insulin replacement therapy. Recently, scientists have turned their attention to the generation of insulin-producing cells (IPCs from stem cells of various sources. To date, many types of stem cells of human and animal origins have been successfully turned into IPCs in vitro and have been shown to exert glucose-lowering effect in vivo. However, scientists are still faced with the challenge of producing a sufficient number of IPCs that can in turn produce sufficient insulin for clinical use. A careful choice of stem cells, methods, and extrinsic factors for induction may all be contributing factors to successful production of functional beta-islet like IPCs. It is also important that the mechanism of differentiation and mechanism by which IPCs correct hyperglycaemia are carefully studied before they are used in human subjects.

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

Directory of Open Access Journals (Sweden)

Nicole M. Templeman

2017-07-01

Full Text Available The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1 signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan.

Science.gov (United States)

Templeman, Nicole M; Flibotte, Stephane; Chik, Jenny H L; Sinha, Sunita; Lim, Gareth E; Foster, Leonard J; Nislow, Corey; Johnson, James D

2017-07-11

The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 +/- mice to Ins2 +/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 +/- mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type 2 insulin-like growth factor receptor

International Nuclear Information System (INIS)

Bayne, M.L.; Applebaum, J.; Chicchi, G.G.; Hayes, N.S.; Green, B.G.; Cascieri, M.A.

1988-01-01

Four structural analogs of human insulin-like growth factor I (hIGF-I) have been prepared by site-directed mutagenesis of a synthetic IGF-I gene and subsequent expression and purification of the mutant protein from the conditioned media of transformed yeast. [Phe -1 , Val 1 , Asn 2 , Gln 3 , His 4 , Ser 8 , His 9 , Glu 12 , Tyr 15 , Leu 16 ]IGF-I (B-chain mutant), in which the first 16 amino acids of hIGF-I were replaced with the first 17 amino acids of the B-chain of insulin, has >1000-, 100-, and 2-fold reduced potency for human serum binding proteins, the rat liver type 2 IGF receptor, and the human placental type 1 IGF receptor, respectively. The B-chain mutant also has 4-fold increased affinity for the human placental insulin receptor. [Gln 3 , Ala 4 ] IGF-I has 4-fold reduced affinity for human serum binding proteins, but is equipotent to hIGF-I at the types 1 and 2 IGF and insulin receptors. [Tyr 15 , Leu 16 ] IGH-I has 4-fold reduced affinity for human serum binding proteins and 10-fold increased affinity for the insulin receptor. The peptide in which these four-point mutations are combined, [Gln 3 , Ala 4 , Tyr 15 ,Leu 16 ]IGF-I, has 600-fold reduced affinity for the serum binding proteins. All four of these mutants stimulate DNA synthesis in the rat vascular smooth muscle cell line A10 with potencies reflecting their potency at the type 1 IGF receptor. These studies identify some of the domains of hIGF-I which are responsible for maintaining high affinity binding with the serum binding protein and the type 2 IGF receptor. In addition, These peptides will be useful in defining the role of the type 2 IGF receptor and serum binding proteins in the physiological actions of hIGF-I

Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome.

Science.gov (United States)

Belli, Susana H; Graffigna, Mabel N; Oneto, Adriana; Otero, Patricia; Schurman, Leon; Levalle, Oscar A

2004-03-01

To evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS). Prospective study. Women with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. Twenty-four insulin-resistant women with PCOS. Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily. Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated. A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone-binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month. Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS.

Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans

Directory of Open Access Journals (Sweden)

Wang Xiaoqin

2005-10-01

Full Text Available Abstract Background Defective insulin secretion is a key defect in the pathogenesis of type 2 diabetes (T2DM. The β-cell specific transcription factor, insulin promoter factor 1 gene (IPF1, is essential to pancreatic development and the maintenance of β-cell mass. We hypothesized that regulatory or coding variants in IPF1 contribute to defective insulin secretion and thus T2DM. Methods We screened 71 Caucasian and 69 African American individuals for genetic variants in the promoter region, three highly conserved upstream regulatory sequences (PH1, PH2 and PH3, the human β-cell specific enhancer, and the two exons with adjacent introns. We tested for an association of each variant with T2DM Caucasians (192 cases and 192 controls and African Americans (341 cases and 186 controls. Results We identified 8 variants in the two populations, including a 3 bp insertion in exon 2 (InsCCG243 in African Americans that resulted in an in-frame proline insertion in the transactivation domain. No variant was associated with T2DM in Caucasians, but polymorphisms at -3766 in the human β-cell enhancer, at -2877 bp in the PH1 domain, and at -108 bp in the promoter region were associated with T2DM in African American subjects (p Conculsion The common alleles of regulatory variants in the 5' enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions. In contrast, IPF1 is not a cause of type 2 diabetes in Caucasians. A previously described InsCCG243 variant may contribute to diabetes susceptibility in African American individuals, but is of low penetrance.

Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune Children's Study.

Science.gov (United States)

Yajnik, Chittaranjan S; Katre, Prachi A; Joshi, Suyog M; Kumaran, Kalyanaraman; Bhat, Dattatray S; Lubree, Himangi G; Memane, Nilam; Kinare, Arun S; Pandit, Anand N; Bhave, Sheila A; Bavdekar, Ashish; Fall, Caroline H D

2015-07-01

The Pune Children's Study aimed to test whether glucose and insulin measurements in childhood predict cardiovascular risk factors in young adulthood. We followed up 357 participants (75% follow-up) at 21 years of age who had undergone detailed measurements at 8 years of age (glucose, insulin, HOMA-IR and other indices). Oral glucose tolerance, anthropometry, plasma lipids, BP, carotid intima-media thickness (IMT) and arterial pulse wave velocity (PWV) were measured at 21 years. Higher fasting glucose, insulin and HOMA-IR at 8 years predicted higher glucose, insulin, HOMA-IR, BP, lipids and IMT at 21 years. A 1 SD change in 8 year variables was associated with a 0.10-0.27 SD change at 21 years independently of obesity/adiposity at 8 years of age. A greater rise in glucose-insulin variables between 8 and 21 years was associated with higher cardiovascular risk factors, including PWV. Participants whose HOMA-IR measurement remained in the highest quartile (n = 31) had a more adverse cardiovascular risk profile compared with those whose HOMA-IR measurement remained in the lowest quartile (n = 28). Prepubertal glucose-insulin metabolism is associated with adult cardiovascular risk and markers of atherosclerosis. Our results support interventions to improve glucose-insulin metabolism in childhood to reduce cardiovascular risk in later life.

The insulin-like growth factor axis and collagen turnover during prednisolone treatment

DEFF Research Database (Denmark)

Wolthers, O D; Juul, A; Hansen, M

1994-01-01

Serum concentrations of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), the carboxyterminal propeptide of type I collagen (PICP), the carboxyterminal pyridinoline crosslinked telopeptide of type I collagen (ICTP), and the aminoterminal propeptide...... of type III procollagen (PIIINP) were studied in 10 prepubertal children with asthma (mean age 9.0 years). The children were treated with 2.5 and 5.0 mg/day prednisolone in a randomised double blind crossover trial with run in, treatment, and washout periods of two weeks. No statistically significant...... effects on serum concentrations of IGF-I and IGFBP-3 were found. Dose related reductions of PICP, ICTP, and PIIINP were observed: the mean (SEM) reduction in PICP was 33.4 (26.3) and 68.4 (20.6) micrograms/l, in ICTP 2.5 (0.5) and 2.9 (0.6) micrograms/l, and in PIIINP 2.1 (0.7) and 3.1 (1.8) micrograms...

Exogenous insulin antibody syndrome (EIAS: a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients

Directory of Open Access Journals (Sweden)

Xiaolei Hu

2018-01-01

Full Text Available Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs. IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS. The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS.

The Insulin-like Growth Factor System in Cancer Prevention: Potential of Dietary intervention Strategies

NARCIS (Netherlands)

Voskuil, D.W.; Vrieling, A.; Veer, van 't L.J.; Kampman, E.; Rookus, M.A.

2005-01-01

The insulin-like growth factor (IGF) system is related to proliferation and tumor growth, and high levels of circulating IGF-I are thought to be a risk factor for several types of cancer. This review summarizes the epidemiologic evidence for an association between circulating IGF-I and cancer risk

The insulin-like growth factor system in cancer prevention: potential of dietary intervention strategies.

NARCIS (Netherlands)

Voskuil, D.W.; Vrieling, A.; Veer, L.J. van 't; Kampman, E.; Rookus, M.A.

2005-01-01

The insulin-like growth factor (IGF) system is related to proliferation and tumor growth, and high levels of circulating IGF-I are thought to be a risk factor for several types of cancer. This review summarizes the epidemiologic evidence for an association between circulating IGF-I and cancer risk

Acceptance of insulin therapy: a long shot? Psychological insulin resistance in primary care

NARCIS (Netherlands)

Woudenberg, Y. J. C.; Lucas, C.; Latour, C.; Scholte Op Reimer, W. J. M.

2012-01-01

Diabet. Med. 29, 796802 (2012) Abstract Aim To explore which factors are associated with psychological insulin resistance in insulin-naive patients with Type 2 diabetes in primary care. Methods A sample of 101 insulin-naive patients with Type 2 diabetes completed self-administered questionnaires

Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk.

Directory of Open Access Journals (Sweden)

Su Yon Jung

Full Text Available Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E, influencing postmenopausal colorectal cancer (CRC risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs in genes related to insulin-like growth factor-I (IGF-I/ insulin resistance (IR traits and signaling pathways, using data from 704 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment-insulin resistance on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway-related genetic variants had different associations with CRC risk between strata, and the proportion of the SNP-cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

Evaluation of Posttransplantation Diabetes Mellitus After Liver Transplantation: Assessment of Insulin Administration as a Risk Factor.

Science.gov (United States)

Linder, Kristin E; Baker, William L; Rochon, Caroline; May, Scott T; Sheiner, Patricia A; Martin, Spencer T

2016-05-01

Impaired glucose regulation posttransplantation can affect allograft survival and may lead to the development of posttransplant diabetes mellitus (PTDM). The primary purpose of this study is to assess the difference in insulin burden between liver transplant patients who develop PTDM and patients who do not. This was a single-center, retrospective study. Adult liver transplant recipients transplanted between January 1, 2005, and August 1, 2013, were included. PTDM was defined as: (1) use of an oral antihyperglycemic agent for ≥30 consecutive days after transplant, (2) use of insulin ≥30 consecutive days after transplant, or (3) hemoglobin A1C≥6.5 any time after transplant. Of the 114 patients included, 48 (42%) developed PTDM. The average 24-hour insulin requirement on the medical floors was 17.2 ± 14.5 units in the PTDM group and 11.3 ± 12.2 units in the PTDM-free group;P= 0.02. The average blood glucose level on the medical floor was 184.7 ± 31.5 mg/dL in the PTDM group and 169.3 ± 31.4 mg/dL in the PTDM-free group;P= 0.013. Multivariate analysis revealed that experiencing rejection was positively associated with the development of PTDM: adjusted odds ratio (AOR) = 3.237; 95% CI = 1.214-8.633. Basiliximab was negatively associated with the development of PTDM: AOR = 0.182; 95% CI = 0.040-0.836. Univariate analyses suggest that insulin burden is a positive risk factor for the development of PTDM; this association is lost in multivariate analyses. Rejection was a positive predictor, and use of basiliximab was a negative predictor for the development of PTDM. © The Author(s) 2016.

Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4 ...

African Journals Online (AJOL)

Purpose: To evaluate the receptor-mediated neuroprotective effect of insulin-like growth factor-II (IGFII) on 1-methyl-4-phenyl pyridinium (MPP) induced oxidative damage in adult cortical neuronal cultures. Methods: Adult rats were randomly divided into 5 groups. Cortical neurons were prepared from rats. The cells were ...

Cell-Cell Adhesion and Insulin-Like Growth Factor I Receptor in Breast Cancer

National Research Council Canada - National Science Library

Bartucci, Monica

2001-01-01

.... Our goal was to study the role of the insulin-like growth factor I receptor (IGF-IR) in breast cancer. The IGF-IR is a multifunctional tyrosine kinase that has been recently implicated in breast tumor development and progression...

Homeostatic model assessment for insulin resistance (homa-ir): a better marker for evaluating insulin resistance than fasting insulin in women with polycystic ovarian syndrome

International Nuclear Information System (INIS)

Majid, H.; Khan, A.H.; Masood, Q.

2017-01-01

To assess the utility of HOMA-IR in assessing insulin resistance in patients with polycystic ovary syndrome (PCOS) and compare it with fasting insulin for assessing insulin resistance (IR). Study Design: Observational study. Place and Duration of Study: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2009 to September 2012. Methodology: Medical chart review of all women diagnosed with PCOS was performed. Of the 400 PCOS women reviewed, 91 met the inclusion criteria. Insulin resistance was assessed by calculating HOMA-IR using the formula (fasting glucose x fasting insulin)/405, taking normal value =12 micro IU/ml. Results: A total of 91 premenopausal women diagnosed with PCOS were included. Mean age was 30 +-5.5 years. Mean HOMA-IR of women was 3.1 +-1.7, respectively with IR in 69% (n=63) women, while hyperinsulinemia was present in 60% (n=55) women (fasting Insulin 18.5 +-5.8 micro IU/ml). Hyperandrogenism was present in 53.8% (n=49), whereas 38.5% (n=35) women had primary infertility or subfertility, while 65.9% (n=60) had menstrual irregularities; and higher frequencies were observed in women with IR. Eight subjects with IR and endocrine abnormalities were missed by fasting insulin. Conclusion: Insulin resistance is common in PCOS and it is likely a pathogenic factor for development of PCOS. HOMA-IR model performed better than hyperinsulinemia alone for diagnosing IR. (author)

Rebelling against the (Insulin Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds

Directory of Open Access Journals (Sweden)

Jaime L. Clark

2018-03-01

Full Text Available Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance.

Alteration in insulin action

DEFF Research Database (Denmark)

Tanti, J F; Gual, P; Grémeaux, T

2004-01-01

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

Update on insulin treatment for dogs and cats: insulin dosing pens and more

Directory of Open Access Journals (Sweden)

Thompson A

2015-04-01

Full Text Available Ann Thompson,1 Patty Lathan,2 Linda Fleeman3 1School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia; 2College of Veterinary Medicine Mississippi State University, Starkville, MS, USA; 3Animal Diabetes Australia, Melbourne, VIC, Australia Abstract: Insulin therapy is still the primary therapy for all diabetic dogs and cats. Several insulin options are available for each species, including veterinary registered products and human insulin preparations. The insulin chosen depends on the individual patient's requirements. Intermediate-acting insulin is usually the first choice for dogs, and longer-acting insulin is the first choice for cats. Once the insulin type is chosen, the best method of insulin administration should be considered. Traditionally, insulin vials and syringes have been used, but insulin pen devices have recently entered the veterinary market. Pens have different handling requirements when compared with standard insulin vials including: storage out of the refrigerator for some insulin preparations once pen cartridges are in use; priming of the pen to ensure a full dose of insulin is administered; and holding the pen device in place for several seconds during the injection. Many different types of pen devices are available, with features such as half-unit dosing, large dials for visually impaired people, and memory that can display the last time and dose of insulin administered. Insulin pens come in both reusable and disposable options. Pens have several benefits over syringes, including improved dose accuracy, especially for low insulin doses. Keywords: diabetes, mellitus, canine, feline, NPH, glargine, porcine lente

Endonucleolysis in the turnover of insulin-like growth factor II mRNA

DEFF Research Database (Denmark)

Nielsen, F C; Christiansen, Jan

1992-01-01

The overlapping transcription units constituting the rat insulin-like growth factor II (IGF-II) locus generate multiple mRNAs by using different promoters. Three promoters have been identified, giving rise to 4.6-, 3.8-, and 3.6-kilobase mRNAs. The latter, originating from promoter P3, is the most...

H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein

DEFF Research Database (Denmark)

Runge, Steffen; Nielsen, Finn Cilius; Nielsen, Jacob

2000-01-01

H19 RNA is a major oncofetal 2.5-kilobase untranslated RNA of unknown function. The maternally expressed H19 gene is located 90 kilobase pairs downstream from the paternally expressed insulin-like growth factor II (IGF-II) gene on human chromosome 11 and mouse chromosome 7; and due to their recip......H19 RNA is a major oncofetal 2.5-kilobase untranslated RNA of unknown function. The maternally expressed H19 gene is located 90 kilobase pairs downstream from the paternally expressed insulin-like growth factor II (IGF-II) gene on human chromosome 11 and mouse chromosome 7; and due...

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

Science.gov (United States)

Yu, Yue; Sun, Ying; He, Shengqi; Yan, Cheng; Rui, Liangyou; Li, Wenjun

2012-01-01

The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat β-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in β cells. PMID:22778134

Factors associated to adherence to blood glucose self-monitoring in patients with diabetes treated with insulin. The dapa study.

Science.gov (United States)

Vidal Florc, Mercè; Jansà Morató, Margarita; Galindo Rubio, Mercedes; Penalba Martínez, Maite

2018-02-01

To assess adherence to self-monitoring of blood glucose and the main factors associated with it, particularly those related to self-perception of glycemia, in patients with diabetes on insulin therapy. An epidemiological, observational, prospective, multicenter study conducted in standard clinical practice in primary care, outpatient centers, and hospitals from different Spanish regions. Sociodemographic, clinical and treatment data were collected. Patients were considered adherent to self-monitoring if they performed the minimum number of controls recommended by the Spanish Society of Diabetes (SED). Adherence was shown in 61.6% of patients. Factors associated to adherence included treatment with less than three insulin injections daily (OR 2.678; 95% CI 2.048- 3.5029; p <0.001), presence of peripheral vascular disease (OR 1.529; 95% CI 1.077 - 2.171; p=0.018), alcohol abstinence (OR 1.442; 95% CI 1.118 - 1.858; p=0.005), and collection of the glucose test strips from the pharmacy (OR 1.275; 95% CI 1.026 - 1.584; p=0.028). Adequate self-perception of glycemia was found in 21.4% of patients. Our results show a suboptimal adherence to the recommended protocol for blood glucose self-monitoring in patients with diabetes on insulin therapy. Independent variables associated to good adherence were treatment with less than three insulin injections dailyu, presence of peripheral vascular disease, alcohol abstinence, and collection of glucose test strips from the pharmacy. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Repopulation of the atrophied thymus in diabetic rats by insulin-like growth factor I

International Nuclear Information System (INIS)

Binz, K.; Joller, P.; Froesch, P.; Binz, H.; Zapf, J.; Froesch, E.R.

1990-01-01

Atrophy of the thymus is one of the consequences of severe insulin deficiency. The authors describe here that the weight and the architecture of the thymus of diabetic rats is restored towards normal not only by insulin but also by insulin-like growth factor I (IGF-I) treatment. In contrast to insulin, this effect of IGF-I occurs despite persisting hyperglycemia and adrenal hyperplasia. They also investigated the in vivo effect of IGF-I on replication and differentiation of thymocytes from streptozotocin-induced diabetic rats. Thymocytes from diabetic rats incorporated less [ 3 H]thymidine than did thymocytes from healthy rats. Insulin, as well as IGF-I treatment of diabetic rats increased [ 3 H]thymidine incorporation by thymocytes. Flow cytometry of thymocytes labeled with monoclonal antibodies revealed a decreased expression of the Thy-1 antigen in diabetic rats compared with control rats. In addition, a major deficiency of thymocytes expressing simultaneously the W3/25 and the Ox8 antigens was observed. These changes were restored towards normal by insulin as well as by IGF-I treatment. The antibody response to a T cell-dependent antigen (bovine serum albumin) was comparable in normal and diabetic rats. They conclude that IGF-I has important effects on the thymocyte number and the presence of CD4 + /CD8 + immature cells in the thymus of diabetic rats despite persisting hyperglycemia. However, helper T-cell function for antibody production appears to be preserved even in the severely diabetic state

Effect of fat supplementation on leptin, insulin-like growth factor I, growth hormone, and insulin in cattle.

Science.gov (United States)

Becú-Villalobos, Damasia; García-Tornadú, Isabel; Shroeder, Guillermo; Salado, Eloy E; Gagliostro, Gerardo; Delavaud, Carole; Chilliard, Yves; Lacau-Mengido, Isabel M

2007-07-01

We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models.

Leptin, insulin like growth factor-1 and thyroid profile in a studied ...

African Journals Online (AJOL)

Background: Several mechanisms have been suggested for obesity in Down syndrome. Aim of the study: Assessment of serum levels of leptin, insulin like growth factor-I (IGF-I), thyroid stimulating hormone (TSH) and free thyroxin (FT4) in a prepubertal Egyptian sample of children with DS compared to their age and sex ...

Evaluation of insulin-like growth factor-1 and insulin like growth factor binding protein-3 in diagnosis of growth hormone deficiency in short-stature children

International Nuclear Information System (INIS)

Ali, A.; Hashim, R.; Khan, F.A.; Sattar, A.; Ijaz, A.; Manzoor, S.M.; Younas, M.

2009-01-01

Growth Hormone Deficiency (GHD) is conventionally diagnosed and confirmed by diminished peak Growth Hormone (GH) levels to provocative testing. Serum Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are under the influence of GH and reflect the spontaneous endogenous GH secretion. Owing to the absence of a circadian rhythm, it is possible to take individual measurements of IGF-1 and IGFBP-3 at any time of the day for evaluation of GH status instead of subjecting the individual to cumbersome provocative tests. Objectives of this study were to compare IGF-1 and IGFBP-3 assays with Exercise and L-Dopa stimulation tests in the diagnosis of growth hormone deficiency in short stature children using ITT as gold standard. Methods: This validation study was conducted at Department of Chemical Pathology and Endocrinology, AFIP, Rawalpindi, from November 2005 to October 2006. Fifty-two short stature children were included in the study. Basal samples for GH levels and simultaneous IGF-1 and IGFBP-3 measurements were obtained and afterwards all children were subjected to sequential exercise and LDopa stimulation tests. Insulin Tolerance Test (ITT) was performed one week later with all the necessary precautionary measures. On the basis of ITT results, children were divided into two groups, i.e., 31 growth hormone deficient and 21 Normal Variant Short Stature (NVSS). Results: The diagnostic value of exercise stimulation test remained highest with sensitivity 90.3%, specificity 76.0%, Positive Predictive Value (PPV) 84.84%, Negative Predictive Value (NPV) 84.2% and accuracy 84.6%. The conventional L-Dopa stimulation had sensitivity 96.7%, specificity 38.0%, PPV 69.7%, NPV 88.8 % and accuracy 73.0%. The serum IGF-1 and IGFBP-3 levels were positively correlated with post ITT peak GH levels (r= 0.527, r=0.464 respectively, both p<0.001). The diagnostic value of IGF-1 had sensitivity 83.87%, specificity 76.2%, PPV 83.87%, NPV 76.2% and

Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

LENUS (Irish Health Repository)

Cooley, Sharon M

2010-07-01

To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET).

Urinary catecholamines, plasma insulin and environmental factors in relation to body fat distribution.

Science.gov (United States)

Leonetti, D L; Bergstrom, R W; Shuman, W P; Wahl, P W; Jenner, D A; Harrison, G A; Fujimoto, W Y

1991-05-01

The relationship of body fat distribution to insulin and the catecholamines, hormones that affect lipolysis differentially by fat site, was examined within an environmental context, including factors of medication use, physical activity, dietary intake, educational attainment, and age. Four cross-sectional body fat areas (cm2) were determined by three computed tomography (CT) scans (subcutaneous chest fat at the level of the nipples, subcutaneous and intra-abdominal fat at the level of the umbilicus, and subcutaneous left mid-thigh fat) in 191 second-generation Japanese-American men aged 45-74 years. The site-specific fat measurements were first examined in relation to use of beta-adrenergic antagonists, then to fasting plasma insulin and C-peptide levels and to urinary epinephrine and norepinephrine levels from a 24-h urine collection made during usual daily activities. Greater fat stores in the intra-abdominal area, even after adjustment for body mass index (BMI, weight/height2) and presence of coronary heart disease, were found to be related to use of beta-adrenergic antagonists. In men taking no adrenergic antagonists (n = 157), after adjustment for BMI, truncal fat measurements of the chest (partial r = -0.16, P less than 0.05) and intra-abdominal area (partial r = -0.21, P less than 0.05) were found to be inversely related to epinephrine, and intra-abdominal fat (partial r = 0.25, P less than 0.01) alone was directly related to fasting plasma insulin. With respect to other environmental variables, the significant inverse relationship of intra-abdominal fat (adjusted for BMI) with physical activity (partial r = -0.17, P less than 0.05) and the significant difference in intra-abdominal fat by educational attainment (college 102.3 +/- 5.7 vs no college 115.7 +/- 6.1 cm2, P = 0.03) became non-significant with adjustment, using multiple regression analysis, for insulin in the case of physical activity and epinephrine in the case of educational attainment. Thus

The effect of dietary fiber and other factors on insulin response: role in obesity.

Science.gov (United States)

Ullrich, I H; Albrink, M J

1985-07-01

Epidemiologic evidence favors the hypothesis that obesity may result from the fiber-depleted diet of industrialized societies. Since hyperinsulinemia is a universal characteristic and perhaps causal of obesity, the possibility is considered that dietary factors causing excess insulin secretion might lead to obesity. Dietary glucose causes a slightly greater insulin rise than cooked starch containing an equal amount of carbohydrate, and high fiber starchy foods cause a much lesser insulin response than does glucose in solution. Doubling the dose of carbohydrate in a meal causes only a small increase in glucose response but a large increase in insulin response. Dietary fiber could act by displacing some of the carbohydrate that would normally be absorbable in the small intestine, or could translocate the carbohydrate to a point lower in the intestinal tract where less effect on insulin secretion would be observed. Evidence is presented that a higher fiber diet is associated with a higher concentration of fasting circulating free fatty acids, a lesser post-cibal decrease in circulating free fatty acids and triglycerides and less chronic increase in fasting triglycerides than a low fiber diet. These differences are associated with a lesser insulin response to high fiber meals. The extreme fluctuations between the fed and fasted states seen with low fiber diets are thus dampened by high fiber diets. The less complete inhibition of lipolysis during the fed state, and more intense lipolysis during fasting, suggested by the above data, might tend to prevent obesity. The mechanisms of the lesser insulin response to high rather than low fiber meals are not known, but the possibility that dietary fiber decreases the GIP response is considered.

Insulin-Like Growth Factor (IGF System in Liver Diseases

Directory of Open Access Journals (Sweden)

Agnieszka Adamek

2018-04-01

Full Text Available Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2 act in response to growth hormone (GH. Other IGF family components include at least six binding proteins (IGFBP1 to 6, manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R. The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth, and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD, lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

Barbados Insulin Matters (BIM) study: Perceptions on insulin initiation by primary care doctors in the Caribbean island of Barbados.

Science.gov (United States)

Taylor, Charles Grafton; Taylor, Gordon; Atherley, Anique; Hambleton, Ian; Unwin, Nigel; Adams, Oswald Peter

2017-04-01

With regards to insulin initiation in Barbados we explored primary care doctor (PCD) perception, healthcare system factors and predictors of PCD reluctance to initiate insulin. PCDs completed a questionnaire based on the theory of planned behaviour (TPB) and a reluctance to initiate insulin scale. Using linear regression, we explored the association between TPB domains and the reluctance to initiate insulin scale. Of 161 PCDs, 70% responded (75 private and 37 public sector). The majority felt initiating insulin was uncomplicated (68%) and there was benefit if used before complications developed (68%), but would not use it until absolutely necessary (58%). More private than public sector PCDs (p<0.05) thought that the healthcare system allowed enough flexibility of time for education (68 vs 38%) and initiating insulin was easy (63 vs 35%), but less thought system changes would help initiating insulin (42 vs 70%). Reasons for reluctance to initiate insulin included patient nonadherence (83%) and reluctance (63%). Only the attitudes and belief domain of the TPB was associated with the reluctance to initiate insulin scale (p<0.001). Interventions focusing on PCD attitudes and beliefs and restructuring services inclusive of the use of diabetes specialist nurses are required. Copyright © 2016 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

DEFF Research Database (Denmark)

Bot, M; Pouwer, F; De Jonge, P

2013-01-01

Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin......AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin...... sensitivity (OGIS) index. Insulin secretion was estimated using three model-based parameters of insulin secretion (beta-cell glucose sensitivity, the potentiation factor ratio, and beta-cell rate sensitivity). RESULTS: A total of 162 out of 1027 participants (16%) had significant depressive symptoms. Having...

A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

Science.gov (United States)

Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

1997-04-01

The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

Protein kinase C is differentially regulated by thrombin, insulin, and epidermal growth factor in human mammary tumor cells

Energy Technology Data Exchange (ETDEWEB)

Gomez, M.L.; Tellez-Inon, M.T. (Instituto de Ingenieria Genetica y Biologia Molecular, Buenos Aires (Argentina)); Medrano, E.E.; Cafferatta, E.G.A. (Instituto de Investigaciones Bioquimicas Fundacion Campomar, Buenos Aires (Argentina))

1988-03-01

The exposure of serum-deprived mammary tumor cells MCF-7 and T-47D to insulin, thrombin, and epidermal growth factor (EGF) resulted in dramatic modifications in the activity and in the translocation capacity of protein kinase C from cytosol to membrane fractions. Insulin induces a 600% activation of the enzyme after 5 h of exposure to the hormone in MCF-7 cells; thrombin either activates (200% in MCF-7) or down-regulates (in T-47D), and EGF exerts only a moderate effect. Thus, the growth factors studied modulate differentially the protein kinase C activity in human mammary tumor cells. The physiological significance of the results obtained are discussed in terms of the growth response elicited by insulin, thrombin, and EGF.

Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells.

Science.gov (United States)

Wanscher, Anne Sofie Molsted; Williamson, Michael; Ebersole, Tasja Wainani; Streicher, Werner; Wikström, Mats; Cazzamali, Giuseppe

2015-04-01

Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins such as full-length human IGFBPs, still remains a challenge. Here we present a mammalian HEK293 expression method suitable for over-expression of secretory full-length human IGFBP-1 to -7. Protein purification of full-length human IGFBP-1, -2, -3 and -5 was conducted using a two-step chromatography procedure and the final protein yields were between 1 and 12mg protein per liter culture media. The recombinant IGFBPs contained PTMs and exhibited high-affinity interactions with their natural ligands IGF-1 and IGF-2. Copyright © 2014 Elsevier Inc. All rights reserved.

Relationship between increased serum tumor necrosis factor levels and insulin resistance in patients with essential hypertension

International Nuclear Information System (INIS)

Wang Weimin; Li Jinliang; Huang Yongqiang

2010-01-01

Objective: To investigate the relationship between serum tumor necrosis factor-α (TNF-α) levels and insulin resistance (IR) in patients with essential by pertension. Methods: Serum TNF-α and free insulin (fINS)levels were measured with RIA in 41 patients with essential hypertension and 38 controls. Insulin resistance was calculated with insulin resistance index (HOMA-IR). Results: The serum TNF-α levels were significantly higher in patients with essential hypertension than those in the controls (P<0.001). The HOMA-IR was also significantly higher in hypertension group than that in controls (P<0.001). Serum TNF-α levels was positively correlated with BMI, HOMA-IR and SBP both in hypertension group and control group (P<0.05). Conclusion: Serum TNF-α level was increased in hypertensive patients and positively correlated with obesity and IR. (authors)

The interplay between noncoding RNAs and insulin in diabetes.

Science.gov (United States)

Tian, Yan; Xu, Jia; Du, Xiao; Fu, Xianghui

2018-04-10

Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, regulate various biological processes and are involved in the initiation and progression of human diseases. Insulin, a predominant hormone secreted from pancreatic β cells, is an essential factor in regulation of systemic metabolism through multifunctional insulin signaling. Insulin production and action are tightly controlled. Dysregulations of insulin production and action can impair metabolic homeostasis, and eventually lead to the development of multiple metabolic diseases, especially diabetes. Accumulating data indicates that ncRNAs modulate β cell mass, insulin synthesis, secretion and signaling, and their role in diabetes is dramatically emerging. This review summarizes our current knowledge of ncRNAs as regulators of insulin, with particular emphasis on the implications of this interplay in the development of diabetes. We outline the role of ncRNAs in pancreatic β cell mass and function, which is critical for insulin production and secretion. We also highlight the involvement of ncRNAs in insulin signaling in peripheral tissues including liver, muscle and adipose, and discuss ncRNA-mediated inter-organ crosstalk under diabetic conditions. A more in-depth understanding of the interplay between ncRNAs and insulin may afford valuable insights and novel therapeutic strategies for treatment of diabetes, as well as other human diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Fasting glucose, fasting insulin, and insulin resistance in the prediction of myocardial infarction and mortality at long-term follow-up

DEFF Research Database (Denmark)

Nielsen, M. L.; Pareek, M.; Leosdottir, M.

2015-01-01

Objective: To assess the additional prognostic value of fasting blood glucose (FBG), fasting plasma insulin (FPI), and homeostasis model assessment derived insulin resistance (HOMA-IR) for predicting incident myocardial infarction (MI) and all-cause mortality, independently of traditional...... measured at baseline. Subsequently, HOMA-IR was derived using the computerized HOMA calculator and ranked into quartiles due to the non-normal distribution and presumably non-linear biological effect of insulin resistance. Prognostic values of FBG, FPI, HOMA-IR, and traditional risk factors were tested.......1-48.3] years, whereas median [IQR] HOMA-IR was 0.9 [0.4-1.4]. Over a median follow-up time of 20 years, 1448 events occurred (11.3 per 1000 person-years). The simple prediction model, i.e. the model with traditional CV risk factors only, included age, gender, body mass index, systolic blood pressure, total...

Low-fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women.

Science.gov (United States)

Young, Lindsay R; Kurzer, Mindy S; Thomas, William; Redmon, J Bruce; Raatz, Susan K

2013-07-01

The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in healthy individuals are not well defined. Three test diets-high-fat diet (40% energy as fat), low-fat diet (LF; 20% energy as fat), and a diet with low fat and high omega-3 fatty acid (LFn3; 23% energy as fat)--were tested in a randomized crossover designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGF binding protein-3 (IGFBP-3), insulin, glucose, and ratio of IGF-I/IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance We hypothesized that IGF-I, insulin, and glucose concentrations would decrease and IGFBP-3 concentration would increase in response to the low-fat diets. Eight weeks of the LFn3 diet increased circulating IGF-I (P diet increased IGFBP-3 (P = .04), resulting in trends toward an increased IGF-I/IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I/IGFBP-3 ratio with the LF diet (P = .13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-1, IGFBP-3, or the ratio of IGF-1/IGFBP-3. Insulin, glucose, and the homeostatic model assessment of insulin resistance were not altered by the interventions. Low-fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals. Published by Elsevier Inc.

Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis

Science.gov (United States)

Kim, Hyo Jung; Cha, Jiyoung Y.; Seok, Jo Woon; Choi, Yoonjeong; Yoon, Bo Kyung; Choi, Hyeonjin; Yu, Jung Hwan; Song, Su Jin; Kim, Ara; Lee, Hyemin; Kim, Daeun; Han, Ji Yoon; Kim, Jae-woo

2016-01-01

Glucocorticoids are associated with obesity, but the underlying mechanism by which they function remains poorly understood. Previously, we showed that small G protein Dexras1 is expressed by glucocorticoids and leads to adipocyte differentiation. In this study, we explored the mechanism by which Dexras1 mediates adipogenesis and show a link to the insulin-like growth factor-1 (IGF-1) signaling pathway. Without Dexras1, the activation of MAPK and subsequent phosphorylation of CCAAT/enhancer binding protein β (C/EBPβ) is abolished, thereby inhibiting mitotic clonal expansion and further adipocyte differentiation. Dexras1 translocates to the plasma membrane upon insulin or IGF-1 treatment, for which the unique C-terminal domain (amino acids 223–276) is essential. Dexras1-dependent MAPK activation is selectively involved in the IGF-1 signaling, because another Ras protein, H-ras localized to the plasma membrane independently of insulin treatment. Moreover, neither epidermal growth factor nor other cell types shows Dexras1-dependent MAPK activation, indicating the importance of Dexras1 in IGF-1 signaling in adipogenesis. Dexras1 interacts with Shc and Raf, indicating that Dexras1-induced activation of MAPK is largely dependent on the Shc-Grb2-Raf complex. These results suggest that Dexras1 is a critical mediator of the IGF-1 signal to activate MAPK, linking glucocorticoid signaling to IGF-1 signaling in adipogenesis. PMID:27345868

Insulin Resistance in Alzheimer's Disease

Science.gov (United States)

Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

2014-01-01

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

Early Stress History Alters Serum Insulin-Like Growth Factor-1 and Impairs Muscle Mitochondrial Function in Adult Male Rats.

Science.gov (United States)

Ghosh, S; Banerjee, K K; Vaidya, V A; Kolthur-Seetharam, U

2016-09-01

Early-life adversity is associated with an enhanced risk for adult psychopathology. Psychiatric disorders such as depression exhibit comorbidity for metabolic dysfunction, including obesity and diabetes. However, it is poorly understood whether, besides altering anxiety and depression-like behaviour, early stress also evokes dysregulation of metabolic pathways and enhances vulnerability for metabolic disorders. We used the rodent model of the early stress of maternal separation (ES) to examine the effects of early stress on serum metabolites, insulin-like growth factor (IGF)-1 signalling, and muscle mitochondrial content. Adult ES animals exhibited dyslipidaemia, decreased serum IGF1 levels, increased expression of liver IGF binding proteins, and a decline in the expression of specific metabolic genes in the liver and muscle, including Pck1, Lpl, Pdk4 and Hmox1. These changes occurred in the absence of alterations in body weight, food intake, glucose tolerance, insulin tolerance or insulin levels. ES animals also exhibited a decline in markers of muscle mitochondrial content, such as mitochondrial DNA levels and expression of TFAM (transcription factor A, mitochondrial). Furthermore, the expression of several genes involved in mitochondrial function, such as Ppargc1a, Nrf1, Tfam, Cat, Sesn3 and Ucp3, was reduced in skeletal muscle. Adult-onset chronic unpredictable stress resulted in overlapping and distinct consequences from ES, including increased circulating triglyceride levels, and a decline in the expression of specific metabolic genes in the liver and muscle, with no change in the expression of genes involved in muscle mitochondrial function. Taken together, our results indicate that a history of early adversity can evoke persistent changes in circulating IGF-1 and muscle mitochondrial function and content, which could serve to enhance predisposition for metabolic dysfunction in adulthood. © 2016 British Society for Neuroendocrinology.

Monoclonal antibodies directed to human insulin-like growth factor I (IGF I)

International Nuclear Information System (INIS)

Laubli, U.K.; Baier, W.; Celio, M.R.; Binz, H.; Humbel, R.E.

1982-01-01

Mouse hybridomas secreting antibodies to human insulin-like growth factor I (IGF I) were produced by fusion of spleen cells of hyperimmunised mice with FO mouse-myeloma cells. Eight clones producing antibodies against human IGF I have been isolated, two of which have been characterised. One was used in a radioimmunoassay, the other for immunopurification of IGF. (Auth.)

Insulin-like Growth Factor Receptor Inhibitors: Baby or the Bathwater?

OpenAIRE

Yee, Douglas

2012-01-01

The success of targeted therapies for cancer is undisputed; strong preclinical evidence has resulted in the approval of several new agents for cancer treatment. The type I insulin-like growth factor receptor (IGF1R) appeared to be one of these promising new targets. Substantial population and preclinical data have all pointed toward this pathway as an important regulator of tumor cell biology. Although early results from clinical trials that targeted the IGF1R showed some evidence of response...

Role of the Insulin-Like Growth Factor Type 1 Receptor in the Pathogenesis of Diabetic Encephalopathy

Directory of Open Access Journals (Sweden)

Duo Zhang

2015-01-01

Full Text Available Defective cognitive function is common in patients with diabetes, suggesting that insulin normally exerts anabolic actions in neuron, namely, diabetic encephalopathy. However, because insulin can cross-activate the insulin-like growth factor type 1 receptor (IGF-1R, which also functions in most of tissues, such as muscle and bone, it has been difficult to establish the direct (IGF-1-independent actions of insulin in the pathogenesis of diabetic encephalopathy. To overcome this problem, we examined insulin signaling and action in primary PC-12 cells engineered for conditional disruption of the IGF-1 receptor (ΔIGF-1R. The results showed that the lower glucose metabolism and high expression of IGF-1R occurred in the brain of the DE rat model. The results also showed the defect of IGF-1R could significantly improve the ability of glucose consumption and enhance sensitivity to insulin-induced IR and Akt phosphorylation in PC12 cells. And meanwhile, IGF-1R allele gene knockout (IGF-1Rneo mice treated with HFD/STZ had better cognitive abilities than those of wild mice. Those results indicate that insulin exerts direct anabolic actions in neuron-like cells by activation of its cognate receptor and prove that IGF-1R plays an important role in the pathogenesis of diabetic encephalopathy.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

Science.gov (United States)

Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome

NARCIS (Netherlands)

H.J. Thierry van Dessel; P.D.K. Lee (Philip); G. Faessen; B.C.J.M. Fauser (Bart); L.C. Giudice

1999-01-01

textabstractPolycystic ovary syndrome (PCOS) is the most common cause of anovulation in women. Previous studies suggest that the pathogenesis of PCOS may involve interrelated abnormalities of the insulin-like growth factor (IGF) and ovarian steroidogenesis systems. We

Insulin sensitizers in adolescents with polycystic ovary syndrome.

Science.gov (United States)

LE, Trang N; Wickham, Edmond P; Nestler, John E

2017-10-01

Polycystic ovary syndrome (PCOS) is the most common disorder of androgen excess in women of reproductive age. The diagnosis of PCOS can be more challenging in adolescents than in adult women given significant overlap between normal puberty and the signs of PCOS, including acne, menstrual irregularity, and polycystic ovarian morphology. Optimal treatments for adult women with PCOS vary depending on patient risk factors and reproductive goals, but mainly include hormonal contraception and insulin sensitizers. There is continued interest in targeting the intrinsic insulin resistance that contributes to metabolic and hormonal derangements associated with PCOS. The vast majority of published data on insulin sensitizing PCOS treatments are reported in adult women; these have included weight loss, metformin, thiazolidinediones, and the inositols. Furthermore, there is also a small but growing body of evidence in support of the use of insulin sensitizers in adolescents, with or without oral contraceptives. Discussion of the available treatments, including benefits, potential side effects, and incorporation of patient and family preferences is critical in developing a plan of care aimed at achieving patient-important improvements in PCOS signs and symptoms while addressing the longer-term cardiometabolic risks associated with the syndrome.

Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

Science.gov (United States)

Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

1993-01-01

Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

Insulin-like growth factor-I, insulin-like growth factor binding protein-3 and the risk of fibrocystic breast conditions among Chinese women.

Science.gov (United States)

Chen, Chu; Doherty, Jennifer A; Lewis, S Kay; Ray, Roberta M; Gao, Dao Li; Stalsberg, Helge; Feng, Ziding; Thomas, David B

2006-05-01

We investigated whether circulating insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels are associated with the risk of fibrocystic breast conditions (FBC), in a case-control study nested within a randomized trial of breast self-examination conducted in Shanghai, China. Participants were enrolled during 1989-1991 and were followed over 10 years for the development of breast diseases. Controls (n = 897) were frequency-matched by age to cases (n = 451), who were diagnosed with FBC between 1995 and 2000. Circulating IGF-I and IGFBP-3 levels and their molar ratio were positively associated with risk of FBC. The odds ratios (ORs) and 95% confidence intervals (CI) for the upper fourth of the distribution compared to the lowest fourth for IGF-I, IGFBP3 and their molar ratio were 3.02 (2.02-4.52), 1.92 (1.37-2.71) and 2.26 (1.52-3.36), respectively. The strength of the association between IGF-I levels and FBC was attenuated after adjustment for IGFBP-3 and that for IGFBP-3 was largely eliminated after adjustment for IGF-I. Increasing levels of IGF-I were particularly associated with increasing risk of FBC with proliferative elements (ORs and 95% CIs for the 2nd, 3rd and upper fourth of the distribution of IGF-I: 3.13 (1.50-6.53), 4.57 (2.22-9.39) and 6.30 (3.08-12.89), compared with the lowest fourth. Our results suggest that elevated levels of IGF-I may contribute to the development of FBC. 2005 Wiley-Liss, Inc.

Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

Science.gov (United States)

Zeng, Yi; Zhang, Le; Hu, Zhiping

2016-01-01

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Economic benefits of improved insulin stability in insulin pumps.

Science.gov (United States)

Weiss, Richard C; van Amerongen, Derek; Bazalo, Gary; Aagren, Mark; Bouchard, Jonathan R

2011-05-01

Insulin pump users discard unused medication and infusion sets according to labeling and manufacturer's instructions. The stability labeling for insulin aspart (rDNA origin] (Novolog) was increased from two days to six. The associated savings was modeled from the perspective of a hypothetical one-million member health plan and the total United States population. The discarded insulin volume and the number of infusion sets used under a two-day stability scenario versus six were modeled. A mix of insulin pumps of various reservoir capacities with a range of daily insulin dosages was used. Average daily insulin dose was 65 units ranging from 10 to 150 units. Costs of discarded insulin aspart [rDNA origin] were calculated using WAC (Average Wholesale Price minus 16.67%). The cost of pump supplies was computed for the two-day scenario assuming a complete infusion set change, including reservoirs, every two days. Under the six-day scenario complete infusion sets were discarded every six days while cannulas at the insertion site were changed midway between complete changes. AWP of least expensive supplies was used to compute their costs. For the hypothetical health plan (1,182 pump users) the annual reduction in discarded insulin volume between scenarios was 19.8 million units. The corresponding cost reduction for the plan due to drug and supply savings was $3.4 million. From the U.S. population perspective, savings of over $1 billion were estimated. Using insulin that is stable for six days in pump reservoirs can yield substantial savings to health plans and other payers, including patients.

Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3

DEFF Research Database (Denmark)

Juul, A; Skakkebaek, N E

1997-01-01

Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) reflect the secretion of endogenous growth hormone (GH) in healthy children and exhibit little diurnal variation, which makes them potential candidates for screening of GH deficiency (GHD......). We evaluated serum IGF-I and IGFBP-3 levels in relation to the outcome of GH provocative testing in 203 children and adolescents (111 boys and 92 girls) in whom GHD was suspected. A total of 1030 children served as control subjects. In children less than 10 years of age, IGF-I levels were below...... with a normal GH response (specificity 97.9%). Consequently the predictive value of a positive test result in prepubertal children was 88.8% for IGF-I and 90% for IGFBP-3. In children and adolescents between 10 and 20 years of age, IGF-I levels were below the cutoff limit in 34 of 46 children with GHD...

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

Science.gov (United States)

Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

2014-01-01

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

Science.gov (United States)

Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

2013-08-01

"Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

Relationship between Inflammation markers, Coagulation Activation and Impaired Insulin Sensitivity in Obese Healthy Women

International Nuclear Information System (INIS)

Soliman, S.Et; Shousha, M.A.

2011-01-01

Obesity, insulin resistance syndrome, and atherosclerosis are closely linked phenomena, often connected with a chronic low grade inflammatory state and pro thrombotic hypo fibrinolytic condition. This study investigated the relationship between impaired insulin sensitivity and selected markers of inflammation and thrombin generation in obese healthy women. The study included 36 healthy obese women (body mass index ≥ 30), with normal insulin sensitivity (NIS, n = 18) or impaired insulin sensitivity (IIS, n 18), and 10 non obese women (body mass index < 25).Impaired insulin sensitivity patients had significantly higher levels of high sensitivity C-reactive protein (hs-CRP), transforming growth factor -β1(TGF-β1), plasminogen activator inhibitor-1 (PAI-1), activated factor VII (VIIa), and prothrombin fragments 1 + 2 (F1 + 2) compared with either control subjects or normal insulin sensitivity patients. On the other hand, NIS patients had higher hs-CRP, TGF-β1, PAI-1, and factor VIIa, but not F1 + 2, levels than controls. Significant inverse correlations were observed between the insulin sensitivity index and TGF-β1, hs-CRP, PAI-1; factor VIIa, and F1 + 2 levels. Moreover, significant direct correlations were noted between TGF-β1 and CRP, PAI-1, factor VIIa, and F1 + 2 concentrations. Finally, multiple regressions revealed that TGF-β1 and the insulin sensitivity index were independently related to F1 + 2. These results document an in vivo relationship between insulin sensitivity and coagulation activation in obesity. Here we report that obesity is associated with higher TGF-β, PAI-1, prothrombin fragments 1 and 2 (F1 + 2), and activated factor VII (VIIa) plasma levels, and that insulin resistance exacerbates these alterations. The elevated TGF-β1 levels detected in the obese population may provide a biochemical link between insulin resistance and an increased risk for cardiovascular disease

Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes.

Science.gov (United States)

Patel, Tushar P; Rawal, Komal; Bagchi, Ashim K; Akolkar, Gauri; Bernardes, Nathalia; Dias, Danielle da Silva; Gupta, Sarita; Singal, Pawan K

2016-01-01

Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here.

Insulin in the brain: there and back again.

Science.gov (United States)

Banks, William A; Owen, Joshua B; Erickson, Michelle A

2012-10-01

Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain. Published by Elsevier Inc.

Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs

Czech Academy of Sciences Publication Activity Database

Jiráček, Jiří; Žáková, Lenka

2017-01-01

Roč. 8, Jul 27 (2017), č. článku 167. ISSN 1664-2392 R&D Projects: GA ČR GA15-19018S Institutional support: RVO:61388963 Keywords : insulin receptor * insulin binding * analog * diabetes * glucose Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 3.675, year: 2016 http://journal.frontiersin.org/article/10.3389/fendo.2017.00167/full

Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

DEFF Research Database (Denmark)

Tørring, N; Vinter-Jensen, L; Pedersen, S B

1997-01-01

PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate.MA...

Constraints and challenges in access to insulin: a global perspective.

Science.gov (United States)

Beran, David; Ewen, Margaret; Laing, Richard

2016-03-01

Substantial attention has been given to the issue of access to medicines for communicable diseases; however, access to essential medicines for diabetes, especially insulin, has had insufficient focus. Although insulin was discovered in 1921, the drug is unattainable to many globally, and this Review aims to highlight the range and complexity of factors that contribute to this unattainability. Manufacturers' selling prices of various insulin formulations and presentations, duties, taxes, mark-ups, and other supply chain costs affect the price of insulin and hence the drug's affordability to health systems and individuals. Unlike drugs for HIV and AIDS, the production of generic or biosimilar insulin has not had an effect on the overall market. Other factors contributing to poor availability of insulin include its quantification at the national level, in-country distribution, and determination of needs at lower levels of the health system. Although insulin is essential for the survival of people with type 1 diabetes and is needed for improved management of diabetes for some people with type 2 diabetes, very little has been done globally to address the issue of access, despite the UN's political commitment to address non-communicable diseases and ensure universal access to drugs for these disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Insulin internalization in isolated rat hepatocytes

International Nuclear Information System (INIS)

Galan, J.; Trankina, M.; Noel, R.; Ward, W.

1990-01-01

This project was designed to determine whether neomycin, an aminoglycoside antibiotic, has a significant effect upon the pathways of ligand endocytosis in isolated rat hepatocytes. The pathways studied include receptor-mediated endocytosis and fluid-phase endocytosis. Neomycin causes a dose-dependent acceleration of 125 I-insulin internalization. Since fluid-phase endocytosis can also be a significant factor in 125 I-insulin internalization, lucifer yellow (LY), a marker for fluid-phase endocytosis, was incorporated into an assay similar to the 125 I-insulin internalization procedure. In the presence of 5 mM neomycin, a significant increase in LY uptake was evident at 0.2 and 0.4 mg/ml of LY. At 0.8 mg/ml, a decrease in LY uptake was observed. The increased rate of 125 I-insulin internalization in the presence of neomycin was intriguing. Since one action of neomycin is to inhibit phosphoinositidase C, it suggests that the phosphotidylinositol cycle may be involved in ligand internalization by hepatocytes. At low insulin concentrations, receptor-mediated uptake predominates. Fluid-phase uptake can become an important uptake route as insulin concentrations are increased. Since neomycin stimulates fluid-phase endocytosis, it must also be taken into account when measuring ligand internalization

Effects of Bariatric Surgery on Adipokine-Induced Inflammation and Insulin Resistance

Directory of Open Access Journals (Sweden)

Zeynep eGoktas

2013-06-01

Full Text Available Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance and other metabolic disorders. Obesity is considered a chronic low grade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted towards higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase (JNK and serine kinases inhibitor κB kinase (IKK and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt, and nuclear factor kappa B (NF-kB. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

Molecular Characterization and Expression Analysis of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-1 Genes in Qinghai-Tibet Plateau and Lowland

Directory of Open Access Journals (Sweden)

Ya-bing Chen

2015-01-01

Full Text Available Insulin-like growth factor-1 (IGF-1 and insulin-like growth factor binding protein-1 (IGFBP-1 play a pivotal role in regulating cellular hypoxic response. In this study, we cloned and characterized the genes encoding IGF-1 and IGFBP-1 to improve the current knowledge on their roles in highland Bos grunniens (Yak. We also compared their expression levels in the liver and kidney tissues between yaks and lowland cattle. We obtained full-length 465 bp IGF-1 and 792 bp IGFBP-1, encoding 154 amino acids (AA IGF-1, and 263 AA IGFBP-1 protein, respectively using reverse transcriptase-polyerase chain reaction (RT-PCR technology. Analysis of their corresponding amino acid sequences showed a high identity between B. grunniens and lowland mammals. Moreover, the two genes were proved to be widely distributed in the examined tissues through expression pattern analysis. Real-time PCR results revealed that IGF-1 expression was higher in the liver and kidney tissues in B. grunniens than in Bos taurus (p<0.05. The IGFBP-1 gene was expressed at a higher level in the liver (p<0.05 of B. taurus than B. grunniens, but it has a similar expression level in the kidneys of the two species. These results indicated that upregulated IGF-1 and downregulated IGFBP-1 are associated with hypoxia adaptive response in B. grunniens.

Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

Directory of Open Access Journals (Sweden)

Dhindsa G

2004-04-01

Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

LENUS (Irish Health Repository)

Cooley, Sharon M

2010-05-01

To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery.

Influence of Unweighting on Insulin Signal Transduction in Muscle

Science.gov (United States)

Tischler, Marc E.

2002-01-01

Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

Nature and regulation of the receptors for insulin-like growth factors

International Nuclear Information System (INIS)

Rechler, M.M.; Nissley, S.P.

1985-01-01

Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. Type II IGF receptors do not appear to be homologous to type I receptors. Type II receptors do not appear to be downregulated. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways

Insulin pumps and insulin quality--requirements and problems.

Science.gov (United States)

Brange, J; Havelund, S

1983-01-01

In developing insulin solution suitable for delivery devices the chemical and biological stability, as well as the physical stability, must be taken into consideration. Addition of certain mono- and disaccharides increases the physical stability of neutral insulin solutions, but concurrently the chemical and biological stability decrease to an unacceptable degree. Addition of Ca-ions in low concentrations offers a physiologically acceptable method for stabilizing neutral insulin solutions against heat precipitation without affecting the quality, including the chemical and biological stability.

Diagnostic Usefulness of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor Binding Protein 3 in Children with Suspected Pituitary Dwarfism.

Science.gov (United States)

Zelazowska-Rutkowska, Beata; Trusiak, Marta; Bossowski, Artur; Cylwik, Bogdan

2018-05-01

Pituitary dwarfism (also known as short stature) is a medical condition in which the pituitary gland does not produce enough growth hormone (GH). To confirm the diagnosis of growth hormone deficiency the overnight profile of GH secretion and GH provocative tests are usually performed; however, due to wide GH fluctuations throughout the day and night and the invasiveness of stimulation tests, their clinical utility is limited. Therefore, screening for IGF-1 (insulin-like growth factor 1) and IGFBP-3 (insulin-like growth factor binding protein type 3) is proposed, suggesting that these tests provide a more accurate reflection of the mean plasma GH level, although the results of these tests are still problematic. In this context, the aim of this study was to assess the diagnostic usefulness of IGF-1 and IGFBP-3 in children with suspected pituitary dwarfism. Studies were carried out in 127 children with abnormal growth and low spontaneous 24-hour plasma GH profiles and abnormal results of GH stimulation tests. Fasting serum IGF-1 and IGFBP-3 were determined by chemiluminescent quantitative measurement using the IMMULITE 1000 IGF-1 and IGFBP-3 kits (Siemens Healthcare Diagnostics, United Kingdom) on the IMMULITE 1000 analyzer (Siemens Healthcare Diagnostics, USA). Results were compared to the normal range by children's age. Mean serum IGF-1 concentrations were within the lower normal range (41.7% cases), and 58.3% results were below the normal reference range in the study group. The average serum IGFBP-3 levels were within the lower normal range. We conclude that IGF-1 test can be a useful tool in the diagnosis of pituitary dwarfism in children suspected of this condition, but due to relatively poor sensitivity the testing cannot be performed alone, but in combination with other tests. The IGFBP-3 test is not useful for the diagnosis of this disease.

Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia.

Science.gov (United States)

van Beveren, N J M; Schwarz, E; Noll, R; Guest, P C; Meijer, C; de Haan, L; Bahn, S

2014-08-26

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.

Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression.

Science.gov (United States)

Wagner, Henrik; Fischer, Helene; Degerblad, Marie; Alvarsson, Michael; Gustafsson, Thomas

2016-09-01

Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2. Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression. A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations. The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies. © The Author(s) 2016.

Insulin sensitivity and albuminuria

DEFF Research Database (Denmark)

Pilz, Stefan; Rutters, Femke; Nijpels, Giel

2014-01-01

OBJECTIVE: Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases. We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN...... AND METHODS: We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 ± 8.3 years; 54.3% women) from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity...... was assessed by hyperinsulinemic-euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS...

Effect of cigarette smoking on insulin resistance risk.

Science.gov (United States)

Haj Mouhamed, D; Ezzaher, A; Neffati, F; Douki, W; Gaha, L; Najjar, M F

2016-02-01

Smoking is one of the main risk factors for cardiovascular disease (CVD). The mechanism(s) of the effects of smoking on CVD are not clearly understood; however, a number of atherogenic characteristics, such as insulin resistance have been reported. We aim to investigate the effects of cigarette smoking on insulin resistance and to determine the correlation between this parameter with smoking status characteristics. This study was conducted on 138 non-smokers and 162 smokers aged respectively 35.6±16.0 and 38.5±21.9 years. All subjects are not diabetic. Fasting glucose was determined by enzymatic methods and insulin by chemiluminescence method. Insulin resistance (IR) was estimated using the Homeostasis Model of Assessment equation: HOMA-IR=[fasting insulin (mU/L)×fasting glucose (mmol/L)]/22.5. IR was defined as the upper quartile of HOMA-IR. Values above 2.5 were taken as abnormal and reflect insulin resistance. Compared to non-smokers, smokers had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index. These associations remained significant after adjustment for confounding factors (age, gender, BMI and alcohol consumption). A statistically significant association was noted between the smoking status parameters, including both the number of cigarettes smoked/day and the duration of smoking, and fasting insulin levels as well for HOMA-IR index. Among smokers, we noted a positive correlation between HOMA-IR index and both plasma thiocyanates and urinary cotinine. Our results show that smokers have a high risk to developing an insulin resistance and hyperinsulinemia, compared with a matched group of non-smokers, and may help to explain the high risk of cardiovascular diseases in smokers. Copyright © 2015. Published by Elsevier SAS.

Importance of radioimmunoassay of insulin secretion disorder as atherogenic factor

Energy Technology Data Exchange (ETDEWEB)

Knyazev, Yu A; Bespalova, V A; Vakhrusheva, L L; Kirbasova, N P; Severtseva, V V

1984-11-01

Using a radioimmunoassay a C-peptide levei was revealed in children, pregnant and lying-in women as well as in patients with insulin-dependent diabetes mellitus. After breakfast and insulin administration wich curative purposes the IRI concentration in children increased whereas the C-peptide level changed insignificantly. Changes of the insulin secretion were more noticeable in severe diabetes mejlitus with vascular complications and in disease decompensation. The atherogenic nature of the lipid metaboiism (an increase in the cholesterol, triglyceride and ..beta..-lipoprotein levels), changes in the liver and tendency to vascular involvement are results of insulin effect inadequacy. Such metabolic derangements in pregnant women create unfavorable conditions for the development of fetus and may lead to early atherogenic processes.

Interleukin-Driven Insulin-Like Growth Factor Promotes Prostatic Inflammatory Hyperplasia

Science.gov (United States)

Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee

2014-01-01

Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1–driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation. PMID:25292180

Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

Science.gov (United States)

Seto-Young, D; Avtanski, D; Varadinova, M; Park, A; Suwandhi, P; Leiser, A; Parikh, G; Poretsky, L

2011-06-01

Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (pprogesterone production by 13-18% (pprogesterone production by 17-20% (pprogesterone production by 20-30% (pprogesterone production by 40-60% (pprogesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis. © Georg Thieme Verlag KG Stuttgart · New York.

Expression of insulin-like growth factor I, insulin-like growth factor binding proteins, and collagen mRNA in mechanically loaded plantaris tendon

DEFF Research Database (Denmark)

Olesen, Jens L; Heinemeier, Katja M; Haddad, Fadia

2006-01-01

Insulin-like growth factor I (IGF-I) is known to exert an anabolic effect on tendon fibroblast production of collagen. IGF-I's regulation is complex and involves six different IGF binding proteins (IGFBPs). Of these, IGFBP-4 and -5 could potentially influence the effect of IGF-I in the tendon...... because they both are produced in fibroblast; however, the response of IGFBP-4 and -5 to mechanical loading and their role in IGF-I regulation in tendinous tissue are unknown. A splice variant of IGF-I, mechano-growth factor (MGF) is upregulated and known to be important for adaptation in loaded muscle....... However, it is not known whether MGF is expressed and upregulated in mechanically loaded tendon. This study examined the effect of mechanical load on tendon collagen mRNA in relation to changes in the IGF-I systems mRNA expression. Data were collected at 2, 4, 8 and 16 days after surgical removal...

Insulin resistance and chronic inflammation

Directory of Open Access Journals (Sweden)

Natalia Matulewicz

2016-12-01

Full Text Available Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFκB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low-grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance.

Cardiometabolic risk factors and insulin resistance in obese children and adolescents: relation to puberty.

Science.gov (United States)

Tobisch, B; Blatniczky, L; Barkai, L

2015-02-01

The prevalence of obesity with concomitant increasing risk for having cardiometabolic diseases is rising in the childhood population. Insulin resistance has a key role in metabolic changes in these children. Insulin levels elevate as puberty commences in every individual. Children with increased risk for cardiometabolic diseases show significant differences in insulin levels even before the onset of puberty compared with those without risks. The pattern of appearance of dyslipidaemia also varies in children with risk factors even in the pre-pubertal group from those without risk. Children with metabolic syndrome display considerably pronounced changes in their metabolic parameters before the onset of puberty, which become more pronounced as puberty passes. Insulin resistance (IR) has a key role in the metabolic changes in obese children. In commencing puberty, the insulin levels elevate. It is not clear, however, how insulin levels develop if the metabolic syndrome appears. Metabolic changes were assessed in obese children before, during and after puberty to analyse the relationship between IR and puberty in subjects with and without metabolic syndrome. Three hundred thirty-four obese children (5-19 years) attended the study. The criteria of the International Diabetes Federation were used to assess the presence of cardiometabolic risks (CMRs). Subjects with increased CMR were compared with those without risk (nCMR). Pubertal staging, lipid levels, plasma glucose and insulin levels during oral glucose tolerance test were determined in each participant. IR was expressed by homeostasis model assessment (HOMA-IR) and the ratio of glucose and insulin areas under the curve (AUC-IR). Significantly higher AUC-IR were found in pre-pubertal CMR children compared with nCMR subjects (11.84 ± 1.03 vs. 8.00 ± 0.69; P puberty. HOMA-IR differs between CMR and nCMR only in post-puberty (6.03 ± 1.26 vs. 2.54 ± 0.23; P puberty. CMR is associated with increased

Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations.

Directory of Open Access Journals (Sweden)

José Manuel Fernández-Real

Full Text Available Fibroblast growth factor 23 (FGF-23 is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD. Circulating intact FGF-23 (iFGF-23 and C-terminal (CtFGF-23 concentrations (ELISA were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1; and in association with fat mass and bone mineral density (DEXA and atherosclerosis (intima media thickness, IMT in 78 subjects (52 women with a wide range of adiposity (Cohort 2. Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

Insulin and insulin-like growth factor-I (IGF-I) receptor phosphorylation in µ-calpain knockout mice

Science.gov (United States)

Numerous cellular processes are controlled by insulin and IGF-I signaling pathways. Due to previous work in our laboratories, we hypothesized that insulin (IR) and type 1 IGF-I (IGF-IR) receptor signaling is decreased due to increased protein tyrosine phosphatase 1B (PTP1B) activity. C57BL/6J mice...

Expression and localization of insulin-like growth factor system in corpus luteum during different stages of estrous cycle in water buffaloes (Bubalus bubalis) and the effect of insulin-like growth factor I on production of vascular endothelial growth factor and progesterone in luteal cells cultured in vitro.

Science.gov (United States)

Uniyal, S; Panda, R P; Chouhan, V S; Yadav, V P; Hyder, I; Dangi, S S; Gupta, M; Khan, F A; Sharma, G T; Bag, S; Sarkar, M

2015-01-01

This study investigated the expression and localization of insulin-like growth factor (IGF) system at different stages of buffalo CL and the role of IGF-I in stimulating vascular endothelial growth factor (VEGF) and progesterone (P4) production in cultured luteal cells. The mRNA expression of IGF system, VEGF, steroidogenic acute regulatory protein, P450scc, and hydroxysteroid dehydrogenase (HSD) was investigated by quantitative real-time polymerase chain reaction (PCR). Protein expression of IGF was demonstrated by Western blot and localization by immunohistochemistry. Progesterone and VEGF production was assayed using RIA and ELISA. A relatively high mRNA expression of IGF-I and IGF-II in early, mid- and late luteal phases with immunoreactivity mostly restricted to cytoplasm of large luteal cells indicates their autocrine role, whereas very weak immunoreactivity in endothelial cells during the mid-luteal phase indicates their paracrine role. Insulin-like growth factor receptors, IGF-IR and IGF-IIR, were restricted to large luteal cells with high mRNA and protein expressions in the mid-luteal phase. The significantly higher expression of insulin-like growth factor binding protein (IGFBP)-1, -3, -5, and -6 in the early or mid-luteal phase suggested their stimulatory role, whereas that of IGFBP-2 and -4 in mid-, late, and regressive luteal stages implied their inhibitory role. The mRNA expressions of key steroidogenic factors and VEGF were significantly higher (P production (P production of VEGF in luteal cells and steroid synthesis through the production of key steroidogenic factors. Copyright © 2015 Elsevier Inc. All rights reserved.

Insulin use and persistence in patients with type 2 diabetes adding mealtime insulin to a basal regimen: a retrospective database analysis

Directory of Open Access Journals (Sweden)

Torres Amelito M

2011-01-01

Full Text Available Abstract Background The objective of this study was to characterize insulin use and examine factors associated with persistence to mealtime insulin among patients with type 2 diabetes (T2D on stable basal insulin therapy initiating mealtime insulin therapy. Methods Insulin use among patients with T2D initiating mealtime insulin was investigated using Thomson Reuters MarketScan® research databases from July 2001 through September 2006. The first mealtime insulin claim preceded by 6 months with 2 claims for basal insulin was used as the index event. A total of 21 months of continuous health plan enrollment was required. Patients were required to have a second mealtime insulin claim during the 12-month follow-up period. Persistence measure 1 defined non-persistence as the presence of a 90-day gap in mealtime insulin claims, effective the date of the last claim prior to the gap. Persistence measure 2 required 1 claim per quarter to be persistent. Risk factors for non-persistence were assessed using logistic regression. Results Patients initiating mealtime insulin (n = 4752; 51% male, mean age = 60.3 years primarily used vial/syringe (87% and insulin analogs (60%. Patients filled a median of 2, 3, and 4 mealtime insulin claims at 3, 6, and 12 months, respectively, with a median time of 76 days between refills. According to measure 1, persistence to mealtime insulin was 40.7%, 30.2%, and 19.1% at 3, 6, and 12 months, respectively. Results for measure 2 were considerably higher: 74.3%, 55.3%, and 42.2% of patients were persistent at 3, 6, and 12 months, respectively. Initiating mealtime insulin with human insulin was a risk factor for non-persistence by both measures (OR Conclusions Mealtime insulin use and persistence were both considerably lower than expected, and were significantly lower for human insulin compared to analogs.

Insulin-like growth factor binding protein-2, 28 kDa an 24 kDa insulin-like growth factor binding protein levels are decreased in fluid of dominant follicles, obtained from normal and polycystic ovaries

NARCIS (Netherlands)

A.G.P. Schuller (Alwin); D.J. Lindenbergh-Kortleve (Dicky); T.D. Pache; E.C. Zwarthoff (Ellen); B.C.J.M. Fauser (Bart); S.L.S. Drop (Stenvert)

1993-01-01

textabstractIn order to investigate potential changes in insulin-like growth factor binding proteins (IGFBPs) during human follicle maturation, we examined the IGFBP profiles in follicular fluid from follicles in different stages of maturation. Samples were obtained from ovaries of women with

Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

Science.gov (United States)

Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

2013-01-01

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

Counter-regulatory hormone responses to spontaneous hypoglycaemia during treatment with insulin Aspart or human soluble insulin

DEFF Research Database (Denmark)

Brock Jacobsen, I; Vind, B F; Korsholm, Lars

2011-01-01

examined in a randomized, double-blinded cross-over study for two periods of 8 weeks. Sixteen patients with type 1 diabetes were subjected to three daily injections of human soluble insulin or Aspart in addition to Neutral Protamine Hagedorn (NPH) insulin twice daily. Each intervention period was followed......-regulatory responses regarding growth hormone, glucagon and ghrelin whereas no differences were found in relation to free fatty acid, cortisol, insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins 1 and 2. Treatment with insulin Aspart resulted in well-defined peaks in serum insulin concentrations...... elicited a slightly different physiological response to spontaneous hypoglycaemia compared with human insulin. Keywords hypoglycaemia counter-regulation, insulin Aspart, type 1 diabetes....

Insulin sensitivity deteriorates after short-term lifestyle intervention in the insulin sensitive phenotype of obesity.

Science.gov (United States)

Gilardini, Luisa; Vallone, Luciana; Cottafava, Raffaella; Redaelli, Gabriella; Croci, Marina; Conti, Antonio; Pasqualinotto, Lucia; Invitti, Cecilia

2012-01-01

To investigate the effects of a 3-month lifestyle intervention on insulin sensitivity and its related cardiometabolic factors in obese patients. Anthropometry, body composition, oral glucose tolerance test, lipids, alanine aminotransferase, insulin sensitivity (insulinogenic index (ISI), homeostasis model assessment, β-cell performance (disposition index)) were evaluated in 263 obese women and 93 obese men before and after 3 months of hypocaloric low fat/high protein diet associated with physical activity 30 min/day. Patients were divided into 3 groups according to the intervention-induced ISI changes: group 1 (decrease), group 2 (stability) and group 3 (increase). Insulin sensitivity and the disposition index were significantly higher before the intervention in group 1 than in group 3. BMI, waist circumference, and fat mass significantly decreased in groups 1 and 3 in both sexes. β-cell performance decreased in group 1 and increased in group 3. Metabolic variables improved in group 3, whereas glucose levels increased in women of group 1. The post-intervention insulin sensitivity was lower in group 1 than in group 3. Lifestyle intervention induces changes in insulin sensitivity and metabolic factors that depend on the pre-intervention degree of insulin sensitivity. Weight loss leads to metabolic benefits in insulin-resistant, obese patients, whereas it may paradoxically worsen the metabolic conditions in the insulin-sensitive phenotype of obesity. Copyright © 2012 S. Karger GmbH, Freiburg.

Retinopathy of prematurity and serum level of insulin-like growth factor-1.

Science.gov (United States)

Banjac, Lidija; Bokan, Vesna

2012-06-01

The aim of our study was to measure and compare serum insulin-like growth factor-1 (IGF-1) levels at postmenstrual age of 33 weeks between preterm infants with and without retinopathy of prematurity (ROP). ROP occurs in two phases. Low serum levels of IGF-1 during ROP phase 1 have been found to correlate with the severity of ROP. ROP phase 2 begins around postmenstrual week 33. We conducted a prospective cohort study to measure serum IGF-1 levels in premature infants at postmenstrual age of 33 weeks. The study included all premature infants (N = 74), gestational age large controlled study with repeated measurement of IGF-1 level in the neonatal period is needed to confirm that restoration of IGF-I level occurs in ROP phase 2, i.e. that the low level of IGF-1 is only a feature of ROP phase 1.

INSULIN-LIKE GROWTH FACTOR (IGF-1 IN CNS AND CEREBROVASCULAR AGING

Directory of Open Access Journals (Sweden)

William E Sonntag

2013-07-01

Full Text Available Insulin-like growth factor-1 (IGF-1 is an important anabolic hormone that decreases with age. In the past two decades extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age.

Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum

DEFF Research Database (Denmark)

Albrethsen, Jakob; Frederiksen, Hanne; Andersson, Anna-Maria

2018-01-01

BACKGROUND: The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method for quantificat......BACKGROUND: The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method...

Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin-glucose metabolism: a 10 d interventional study in young men.

Science.gov (United States)

Hoppe, Camilla; Kristensen, Mette; Boiesen, Marlene; Kudsk, Jane; Fleischer Michaelsen, Kim; Mølgaard, Christian

2009-10-01

In the Western world, a trend towards increased consumption of carbonated soft drinks combined with a decreasing intake of milk is observed. This may affect circulating insulin-like growth factor I (IGF-I) and fasting insulin, as seen in pre-pubertal children. The present study was designed to reflect the trend of replacing milk with carbonated beverages in young men and to study the effects of this replacement on IGF-I, IGF-binding protein 3 (IGFBP-3), IGF-I:IGFBP-3 and glucose-insulin metabolism. A randomised, controlled crossover intervention study, in which eleven men aged 22-29 years were given a low-Ca diet in two 10 d periods with 10 d washout in between. In one period, they drank 2.5 litres of Coca Cola(R) per day and the other period 2.5 litres of semi-skimmed milk. Serum IGF-I, IGFBP-3 (RIA), insulin (fluoro immunoassay) and glucose (Cobas) were determined at baseline and end point of each intervention period. Insulin resistance and beta-cell function were calculated with the homeostasis model assessment. A decrease in serum IGF-I was observed in the cola period compared with the milk period (P cola over a 10 d period decreases total IGF-I compared with a high intake of milk, with no effect on glucose-insulin metabolism in adult men. It is unknown whether this is a transient phenomenon or whether it has long-term consequences.

Insulin dysfunction and Tau pathology

Directory of Open Access Journals (Sweden)

Noura eEl Khoury

2014-02-01

Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

Insulin resistance in therapeutic clinic

Directory of Open Access Journals (Sweden)

Anna V. Pashentseva

2017-09-01

Full Text Available Today an obesity became the global epidemic striking both children, and adults and represents one of the most important problems of health care worldwide. Excess accumulation of fatty tissue is resulted by insulin resistance and a compensatory hyperinsulinaemia which are the main predictors of development of a diabetes mellitus type 2. Insulin resistance is also one of key links of a pathogenesis of such diseases as cardiovascular pathology, not-alcoholic fatty liver disease, a polycystic ovary syndrome, gestational diabetes and many others. Depression of sensitivity of tissues to insulin can be physiological reaction of an organism to stress factors and pathological process. The endogenic reasons also take part in development of insulin resistance besides factors of the external environment. The role of genetic predisposition, a subclinical inflammation of fatty tissue, thyroid hormones, adipokines and vitamin D in formation of this pathological process is studied. As insulin resistance takes part in a pathogenesis of various diseases, methods of its diagnostics and correction are of great importance in therapeutic practice. At purpose of treatment it is worth giving preference to the drugs which are positively influencing sensitivity of tissues to insulin.

Relationships between plasma insulin-like growth factor-1 and insulin concentrations in multiparous dairy cows with cytological endometritis.

Science.gov (United States)

Valdmann, Merle; Kurykin, Jevgeni; Kaart, Tanel; Mällo, Gret-Kristel; Waldmann, Andres

2018-04-21

Cytological endometritis (CYTO) is a uterine inflammation characterised by the percentage of polymorphonuclear neutrophils in endometrial cytology. This observational study evaluated the association of blood plasma insulin-like growth factor-1 (IGF-1) and insulin concentrations at -2 weeks prepartum, +1 week and +3 weeks postpartum with the development of CYTO in 119 multiparous Holstein cows. Overall CYTO prevalence was 30.3 per cent. Multivariable logistic regression model revealed the odds of developing CYTO were 3.54 times (P=0.018) greater in cows with week -2 prepartum IGF-1 concentrations less than 74.6 ng/ml and 4.41 times (P=0.004) higher in cows with week +1 postpartum IGF-1 concentrations less than 13.2 ng/ml than the odds of this health outcome in cows with IGF-1 concentrations at least 74.6 and13.2 ng/ml, respectively. Additionally, cows with body condition score (BCS) up to 2.75 at week -2 prepartum and cows experiencing calving-related disorders and/or ill health had higher risk for CYTO compared with cows with BCS=3.50-3.75 (OR=6.8, P=0.049) and cows without health complications (OR=3.1, P=0.030). Insulin was not a significant predictor for CYTO in the model. Our findings provide further evidence that reduced dairy cow fertility associated with low plasma concentrations of IGF-1 is in part mediated through the inflammatory status of the uterus. © British Veterinary Association (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Insulin-Like Growth Factor I Does Not Drive New Bone Formation in Experimental Arthritis

NARCIS (Netherlands)

van Tok, Melissa N.; Yeremenko, Nataliya G.; Teitsma, Christine A.; Kream, Barbara E.; Knaup, Véronique L.; Lories, Rik J.; Baeten, Dominique L.; van Duivenvoorde, Leonie M.

2016-01-01

Insulin like growth factor (IGF)-I can act on a variety of cells involved in cartilage and bone repair, yet IGF-I has not been studied extensively in the context of inflammatory arthritis. The objective of this study was to investigate whether IGF-I overexpression in the osteoblast lineage could

Insulin-like growth factors and leucine kinetics during exercise training in children with cystic fibrosis

NARCIS (Netherlands)

Gulmans, [No Value; van der Laag, J; Wattimena, D; van Doorn, J; Oostveen, D; Berger, R; van de Meer, K

Background: Little is known about the metabolic effects of exercise training in children with cystic fibrosis. The hypothesis for the current study was that in patients with declining clinical status, exercise increases circulating insulin-like growth factors (IGFs) and improves protein kinetics.

Linking lifestyle factors and insulin resistance, based on fasting plasma insulin and HOMA-IR in middle-aged Japanese men: a cross-sectional study.

Science.gov (United States)

Otake, Toshie; Fukumoto, Jin; Abe, Masao; Takemura, Shigeki; Mihn, Pham Ngoc; Mizoue, Tetsuya; Kiyohara, Chikako

2014-09-01

Insulin resistance (IR) is regarded as one of the earliest features of many metabolic diseases, and major efforts are aimed at improving insulin function to confront this issue. The aim of this study was to investigate the relationship of body mass index (BMI), cigarette smoking, alcohol intake, physical activity, green tea and coffee consumption to IR. We performed a cross-sectional study of 1542 male self defense officials. IR was defined as the highest quartile of the fasting plasma insulin (≥ 50 pmol/L) or the homeostasis model assessment-estimated IR (HOMA-IR ≥ 1.81). An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between IR and influential factors. Stratified analysis by obesity status (BMI IR was significantly positively related to BMI and glucose tolerance, negatively related to alcohol use. Independent of obesity status, significant trends were observed between IR and alcohol use. Drinking 30 mL or more of ethanol per day reduced IR by less than 40%. Strong physical activity was associated with decreased risk of IR based on fasting plasma insulin only in the obese. Coffee consumption was inversely associated with the risk of IR based on HOMA-IR in the non-obese group. Higher coffee consumption may be protective against IR among only the non-obese. Further studies are warranted to examine the effect modification of the obesity status on the coffee-IR association.

Insulin-like growth factor-1 levels in children with Beta-thalassemia minor

OpenAIRE

Mehran Karimi; Hamdollah Karamifar; Nargrs Sobhani

2008-01-01

Objective: Growth retardation in children with b-thalassemia major is multifactorial. Some etiologies described for this condition are hemochromatosis, disturbed growth hormone (GH) / insulin growth factor-1 (IGF-1) axis, undernutrition and hypermetabolism. It has also been proven that growth retardation is present in b-thalassemia major children despite regular transfusion and chelation. Our aim was to evaluate the level of IGF-1 in b-thalassemia minor subjects and compare it with that in he...

Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus

NARCIS (Netherlands)

J.A.M.J.L. Janssen (Joseph); M.L. Jacobs (Marloes); F.H.M. Derkx (Frans); R.F.A. Weber (Robert); A-J. van der Lely (Aart-Jan); S.W.J. Lamberts (Steven)

1997-01-01

textabstractThe existing literature on serum insulin-like growth factor I (IGF-I) levels in insulin-dependent diabetes mellitus (IDDM) is conflicting. Free IGF-I may have greater physiological and clinical relevance than total IGF-I. Recently, a validated method has

Serum insulin-like growth factor 1 in the aging horse

DEFF Research Database (Denmark)

Lygren, Tone; Hansen, Sanni; Langberg, Henning

2014-01-01

BACKGROUND: Insulin-like growth factor 1 (IGF-1) has important roles in anabolic processes in the musculoskeletal system and has been reported to decrease with age in both people and horses. OBJECTIVES: The objective of this study was to determine serum IGF-1 levels in the aging horse from early...... was found between serum IGF-1 levels and age in the cross-sectional study. In the longitudinal study, a latent variable model fitted to the data revealed that horses in general experienced a 5.2% increase of serum IGF-1 levels over a 5-year period, but horses crossing a change point around 9 years of age...... between the 2 samples experienced an 11.0% decrease. CONCLUSIONS: In this study, there was no evidence for aging being a factor in changes of IGF-1 levels in an adult and old horse population....

The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

International Nuclear Information System (INIS)

Shousha, M.A.; Soliman, S.Et

2012-01-01

We aimed to study how smoking influences the relationship between fat mass ,soluble tumor necrosis factor-α, (TNF?) receptors 1 and 2 (sTNFR1 and sTNFR2),highly sensitive C-reactive protein(hs-CRP), adiponectin, leptin and insulin resistance.A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m 2 ), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNF α) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs- CRP and insulin sensitivity index.Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9 ±0.8 ng/ml, π=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (π = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (π = 0.18) and between IR and IS subjects (π = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

International Nuclear Information System (INIS)

Shousha, M.A.; Soliman, S.Et.

2011-01-01

The study aimed to investigate how smoking influences the relationship between fat mass, soluble tumor necrosis factor-α , (TNFα ) receptors 1 and 2 (sTNFR1 and sTNFR2), highly sensitive C-reactive protein (hs-CRP), adiponectin, leptin and insulin resistance. A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m2), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNFα ) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs-CRP and insulin sensitivity index. Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9±0.8 ng/ml, P=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

Study on serum insulin-like growth factor 1 and insulin-like growth factor-binding protein-3 in patients with benign prostatic hyperplasia

International Nuclear Information System (INIS)

Yu Jingping; Wu Xiumei; Yang Qixian; Chen Jianguo; Liu Weiming

2003-01-01

Objective: To determine the serum level changes of insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) in patients with benign prostatic hyperplasia (BPH) and to evaluate its significance. Methods: The serum IGF-1 and IGFBP-3 levels were measured with immunoradiometric assay (IRMA) in 64 cases of BPH and in 30 controls. The patients were divided into 3 groups according to the prostate volume (PV): Group 118 cases (PV ≤ 30 ml), Group 224 cases (PV 31-50 ml) and Group 322 cases (PV ≥ 50 ml). Results: Both IGF-1 and IGFBP-3 levels were no statistical difference between BPH and healthy subjects (Both p > 0.05). Both IGF-1 and IGFBP-3 levels in group 3 were significantly higher than those in group 1 (Both p < 0.05). A positive correlation existed between the serum levels of IGF-1, IGFBP-3 and PV (p < 0.05). Conclusion: These observations implicated that IGF-1 and IGFBP-3 were important factors in the pathogenesis of BPH

The role of insulin-like growth factor in prediction and prevention of preterm delivery

Directory of Open Access Journals (Sweden)

Bogavac Mirjana

2010-01-01

Full Text Available Background/Aim. Prediction and prevention of preterm delivery remain great challenge. It is important to include in everyday medical practice determination of certain markers that could help identifying pregnant women with preterm delivery. Insulin like growth factor (IGF is involved in the control mechanism of fetal and placental growth and development. The aim of this study was to examine the presence of insulin-like growth factor binding protein 1 (IGFBP-1 in cervicovaginal secretion of pregnant women with symptoms of preterm labor, but with apparently intact fetal membranes and to point out a possible application of the strip test for detection of phIGFBP-1 in diagnosis of preterm premature rupture of total membranes (PPROM in everyday medical practice. Methods. The study was performed at the Department for Obstetrics and Gynecology, Clinical Center of Vojvodina between October 2008 and May 2009. The study included 54 pregnant women between 20-35 weeks of gestation (WG, divided into two groups: the study group (16 pregnant women with symptoms of preterm delivery that gave birth before 37 WG and the control group (38 pregnant women with the normal course of pregnancy that gave birth on term. In cervicovaginal secretion of the examined pregnant women the level of IGFBP-1 was determined by the immunochromatographic assay with monoclonal antibodies 6303 as a detecting antibody (Actim PROM test, Medix Biochemica, Kauniainen, Finland. Results. Gestational age (GA at delivery in the study group was 32.6 WG and in the control group it was 38.4 WG. Weight of newborns in the study group was 2,021 g and in the control group 3,430 g. IGFBP test was positive in 15 women (93.75% of the study group, while in the control group it was positive only in 1 woman (2.63%. Conclusion. Test on phIGFBP-1 in cervicovaginal mucus was positive in 93.75% women with preterm delivery, suggesting that this test could be used in diagnosis of silent rupture of fetal

Glucose tolerance, insulin release, and insulin binding to monocytes in kidney transplant recipients

International Nuclear Information System (INIS)

Briggs, W.A.; Wielechowski, K.S.; Mahajan, S.K.; Migdal, S.D.; McDonald, F.D.

1982-01-01

In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific 125 I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulin release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific 125 I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity

A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

Science.gov (United States)

Nordqvist, A C; Peyrard, M; Pettersson, H; Mathiesen, T; Collins, V P; Dumanski, J P; Schalling, M

1997-07-01

Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways.

Science.gov (United States)

Zanou, Nadège; Gailly, Philippe

2013-11-01

Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.

Nutritional Modulation of Insulin Resistance

Directory of Open Access Journals (Sweden)

Martin O. Weickert

2012-01-01

Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development

International Nuclear Information System (INIS)

McMorris, F.A.; Smith, T.M.; DeSalvo, S.; Furlanetto, R.W.

1986-01-01

Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. Radioligand binding assays were done. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition

Insulin-like growth factor I (IGF-1 Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

Directory of Open Access Journals (Sweden)

Werner Schlegel

Full Text Available Human insulin-like growth factor 1 Ec (IGF-1Ec, also called mechano growth factor (MGF, is a splice variant of insulin-like growth factor 1 (IGF-1, which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

Differential regulation of insulin-like growth factor binding protein-1 and -2 by insulin in the baboon (Papio anubis endometrium

Directory of Open Access Journals (Sweden)

Fazleabas Asgerally T

2008-01-01

Full Text Available Abstract Background The purpose of this study was to examine the effect of insulin on expression and synthesis of IGFBP-1 and IGFBP-2 in the baboon endometrium in vitro. Methods Baboon endometrial explants collected from cycling, ovariectomized, steroid-treated, simulated-pregnant and pregnant animals were cultured for 48 h in the presence or absence of insulin, with or without estradiol, progesterone and hCG. Results Insulin clearly inhibited IGFBP-1 production and mRNA expression in a time- and dose-dependent manner, whereas IGFBP-2 synthesis was not significantly affected. The inhibitory effects of insulin on IGFBP-1 were more evident in explants of non-pregnant tissue or tissue away from the implantation site. In the absence of insulin, synthesis of IGFBP-1 was induced in explants with low levels of de novo synthesis whereas IGFBP-2 synthesis was inhibited. This effect was potentiated by steroids and hCG in the explant cultures. Conclusion Insulin differentially regulates endometrial IGFBP-1 and IGFBP-2 secretion in the baboon.

Insulin resistance and polycystic ovary syndrome.

Science.gov (United States)

Galluzzo, Aldo; Amato, Marco Calogero; Giordano, Carla

2008-09-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.

Diagnostic criteria for sarcopenia relate differently to insulin resistance

NARCIS (Netherlands)

Bijlsma, A.Y.; Meskers, C.G.M.; van Heemst, D.; Westendorp, R.G.J.; Craen, A.J.M.; Maier, A.B.

2013-01-01

Skeletal muscle is important in insulinstimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in

Evaluation of current trends and recent development in insulin therapy for management of diabetes mellitus.

Science.gov (United States)

Nawaz, Muhammad Sarfraz; Shah, Kifayat Ullah; Khan, Tahir Mehmood; Rehman, Asim Ur; Rashid, Haroon Ur; Mahmood, Sajid; Khan, Shahzeb; Farrukh, Muhammad Junaid

2017-12-01

Diabetes mellitus is a major health problem in developing countries. There are various insulin therapies to manage diabetes mellitus. This systematic review evaluates various insulin therapies for management of diabetes mellitus worldwide. This review also focuses on recent developments being explored for better management of diabetes mellitus. We reviewed a number of published articles from 2002 to 2016 to find out the appropriate management of diabetes mellitus. The paramount parameters of the selected studies include the insulin type & its dose, type of diabetes, duration and comparison of different insulin protocols. In addition, various newly developed approaches for insulin delivery with potential output have also been evaluated. A great variability was observed in managing diabetes mellitus through insulin therapy and the important controlling factors found for this therapy include; dose titration, duration of insulin use, type of insulin used and combination therapy of different insulin. A range of research articles on current trends and recent advances in insulin has been summarized, which led us to the conclusion that multiple daily insulin injections or continuous subcutaneous insulin infusion (insulin pump) is the best method to manage diabetes mellitus. In future perspectives, development of the oral and inhalant insulin would be a tremendous breakthrough in Insulin therapy. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

The adipose transcriptional response to insulin is determined by obesity, not insulin sensitivity

DEFF Research Database (Denmark)

Rydén, Mikael; Hrydziuszko, Olga; Mileti, Enrichetta

2016-01-01

Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy...... non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response to insulin, which differed from the small...... effects observed in NO subjects. In the obese, 231 genes were altered; 71 were enriched in ISO subjects (e.g., phosphorylation processes), and 52 were enriched in IRO subjects (e.g., cellular stimuli). Common cardio-metabolic risk factors and gender do not influence these findings. This study demonstrates...

The effect of aerobic training on CXL5, tumor necrosis factor α and insulin resistance index (HOMA-IR) in sedentary obese women.

Science.gov (United States)

Zehsaz, Farzad; Farhangi, Negin; Mirheidari, Lamia

2014-01-01

The purpose of the present study was to investigate the effects of a 12-week training program on serum CXC ligand 5, tumor necrosis factor α (TNF-α) and insulin resistance index in obese sedentary women. To this end, twenty-four obese sedentary women were evaluated before and after a 12-week exercise program including a brief warm-up, followed by ~45 min per session of aerobic exercise at an intensity of 60-75% of age-predicted maximum heart rate (~300 kcal/day), followed by a brief cool down, five times per week. After the exercise program, body weight, waist circumference, waist to hip ratio, percentage body fat mass, fasting glucose and insulin of participants were decreased. Furthermore, serum CXCL5 levels were significantly decreased from 2693.2 ±375.8 to 2290.2 ±345.9 pg/ml (p HOMA-IR (p < 0.001) and TNF-α (p < 0.001). Exercise training induced weight loss resulted in a significant reduction in serum CXCL5 concentrations and caused an improvement in insulin resistance in obese sedentary women.

Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor I

International Nuclear Information System (INIS)

Drago, J.; Murphy, M.; Carroll, S.M.; Harvey, R.P.; Bartlett, P.F.

1991-01-01

Fibroblast growth factor stimulates proliferation and subsequent differentiation of precursor cells isolated from the neuroepithelium of embryonic day 10 mice in vitro. Here we show that fibroblast growth factor-induced proliferation is dependent on the presence of insulin-like growth factors (IGFs) and that IGF-I is endogenously produced by the neuroepithelial cells. Blocking of endogenous IGF-I activity with anti-IGF-I antibodies results in complete inhibition of fibroblast growth factor-mediated proliferation and in cell death. IGF-I alone acts as a survival agent. These observations correlate with the detection of transcripts for IGF-I and basic fibroblast growth factor in freshly isolated neuroepithelium and are consistent with an autocrine action of these factors in early brain development in vivo

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

Energy Technology Data Exchange (ETDEWEB)

Affholter, J.A.; Roth, R.A. (Stanford Univ. School of Medicine, CA (USA)); Cascieri, M.A.; Bayne, M.L. (Merck Sharp and Dohme Research Labs., Rahway, NJ (USA)); Brange, J. (Novo Research Institute, Bagsvaerd (Denmark)); Casaretto, M. (Deutsches Wollforschungsinstitut an der Technischen, Aachen (West Germany))

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants (B25-Asp)insulin and (B25-His)insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants (B1-24-His{sup 25}-NH{sub 2})insulin and (B1-24-Leu{sup 25}-NH{sub 2})insulin, but not (B1-24-Trp{sup 25}-NH{sub 2})insulin and (B1-24-Tyr{sup 25}-NH{sub 2})insulin. The truncated analogue with the lowest affinity for IDE ((B1-24-His{sup 25}-NH{sub 2})insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

International Nuclear Information System (INIS)

Affholter, J.A.; Roth, R.A.; Cascieri, M.A.; Bayne, M.L.; Brange, J.; Casaretto, M.

1990-01-01

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants [B1-24-His 25 -NH 2 ]insulin and [B1-24-Leu 25 -NH 2 ]insulin, but not [B1-24-Trp 25 -NH 2 ]insulin and [B1-24-Tyr 25 -NH 2 ]insulin. The truncated analogue with the lowest affinity for IDE ([B1-24-His 25 -NH 2 ]insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ

Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma.

LENUS (Irish Health Repository)

Donohoe, C L

2012-03-01

Epidemiological studies have linked obesity with many cancers. The insulin-like growth factor (IGF) 1 axis may be an important mediator in obesity-associated cancer. This study examined the relationship between IGF-1 and its receptor (IGF-1R) in oesophageal adenocarcinoma, a cancer strongly linked to obesity.

Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus

NARCIS (Netherlands)

J.A.M.J.L. Janssen (Joseph); M.L. Jacobs (Marloes); F.H.M. Derkx (Frans); R.F.A. Weber (Rob); A-J. van der Lely (Aart-Jan); S.W.J. Lamberts (Steven)

1997-01-01

textabstractThe existing literature on serum insulin-like growth factor I (IGF-I) levels in insulin-dependent diabetes mellitus (IDDM) is conflicting. Free IGF-I may have greater physiological and clinical relevance than total IGF- I. Recently, a validated method has been developed to measure free

Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1

DEFF Research Database (Denmark)

Argetsinger, L S; Hsu, G W; Myers, M G

1995-01-01

), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts......., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia...... to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well...

Insulin Signaling and Heart Failure

Science.gov (United States)

Riehle, Christian; Abel, E. Dale

2016-01-01

Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral milieu leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead (FOXO) transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

Visceral adiposity, insulin resistance and cancer risk

LENUS (Irish Health Repository)

Donohoe, Claire L

2011-06-22

Abstract Background There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. Methods Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Results Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. Conclusions There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention.

Somatomedin-C/insulin-like growth factor-I and Insulin-like growth factor-II mRNAs in rate fetal and adult tissues

International Nuclear Information System (INIS)

Lund, P.K.; Moats-Staats, B.M.; Hynes, M.A.; Simmons, J.G.; Jansen, M.; D'ercole, A.J.; Van Wyk, J.J.

1986-01-01

Somatomedin-C or insulin-like growth factor I (Sm-C/IGF-I) and insulin-like growth factor II (IGF-II) have been implicated in the regulation of fetal growth and development. In the present study 32 P-labeled complementary DNA probes encoding human and mouse Sm-C/IGF-I and human IGF-II were used in Northern blot hybridizations to analyze rat Sm-C/IGF-I and IGF-II mRNAs in poly(A + ) RNAs from intestine, liver, lung, and brain of adult rats and fetal rats between day 14 and 17 of gestation. In fetal rats, all four tissues contained a major mRNA of 1.7 kilobase (kb) that hybridized with the human Sm-C/IGF-I cDNA and mRNAs of 7.5, 4.7, 1.7, and 1.2 kb that hybridized with the mouse Sm-C/IGF-I cDNA. Adult rat intestine, liver, and lung also contained these mRNAs but Sm-C/IGF-I mRNAs were not detected in adult rat brain. These findings provide direct support for prior observations that multiple tissues in the fetus synthesize immunoreactive Sm-C/IGF-I and imply a role for Sm-C/IGF-I in fetal development as well as postnatally. Multiple IGF-II mRNAs of estimated sizes 4.7, 3.9, 2.2, 1.75, and 1.2 kb were observed in fetal rat intestine, liver, lung, and brain. The 4.7- and 3.9-kb mRNAs were the major hybridizing IGF-II mRNAs in all fetal tissues. Higher abundance of IGF-II mRNAs in rat fetal tissues compared with adult tissues supports prior hypotheses, based on serum IGF-II concentrations, that IGF-II is predominantly a fetal somatomedin. IGF-II mRNAs are present, however, in some poly(A + ) RNAs from adult rat tissues. The brain was the only tissue in the adult rat where the 4.7- and 3.9-kb IGF-II mRNAs were consistently detected. These findings suggest that a role for IGF-II in the adult rat, particularly in the central nervous system, cannot be excluded

Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

International Nuclear Information System (INIS)

Lesniak, M.A.; Hill, J.M.; Kiess, W.; Rojeski, M.; Pert, C.B.; Roth, J.

1988-01-01

Receptors for insulin-like growth factor I (IGF-I) in rat brain were visualized using autoradiography with [125I]IGF-I. The binding of the labeled peptide was competed for fully by high concentrations of unlabeled IGF-I. At intermediate concentrations of unlabeled peptide the binding of [125I]IGF-I was competed for by unlabeled IGF-I more effectively than by IGF-II or insulin, which is typical of receptors for IGF-I. Essentially every brain section shows specific binding of IGF-I, and the pattern of binding of IGF-I to its receptors correlated well with the cytoarchitectonic structures. In parallel studies we showed that [125I]IGF-II was bound to tissue sections of rat brain and that the binding was competed for by an excess of unlabeled IGF-II. However, intermediate concentrations of unlabeled peptides gave inconclusive results. To confirm that the binding of [125I]IGF-II was to IGF-II receptors, we showed that antibodies specific for the IGF-II receptor inhibited the binding of labeled IGF-II. Furthermore, the binding of the antibody to regions of the brain section, visualized by the application of [125I]protein-A, gave patterns indistinguishable from those obtained with [125I]IGF-II alone. Again, the binding was very widely distributed throughout the central nervous system, and the patterns of distribution corresponded well to the underlying neural structures. Densitometric analysis of the receptors enabled us to compare the distribution of IGF-I receptors with that of IGF-II receptors as well as retrospectively with that of insulin receptors

The Therapeutic Potential of Insulin-Like Growth Factor-1 in Central Nervous System Disorders

Science.gov (United States)

Costales, Jesse; Kolevzon, Alexander

2016-01-01

Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD. PMID:26780584

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

Science.gov (United States)

Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

Science.gov (United States)

Zheng, Hongzhi; Fu, Jingqi; Xue, Peng; Zhao, Rui; Dong, Jian; Liu, Dianxin; Yamamoto, Masayuki; Tong, Qingchun; Teng, Weiping; Qu, Weidong; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo

2015-04-01

The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.

The role of serial measurements of serum insulin-like growth factor 1 levels in the development of retinopathy of prematurity.

Science.gov (United States)

Dorum, Bayram Ali; Yılmaz, Cansu Canbolat; Köksal, Nilgün; Özkan, Hilal; Yıldız, Meral; Özmen, Ahmet Tuncer

2017-03-01

To determine the role of serum insulin-like growth factor-1 levels in the development of retinopathy of prematurity, which is a major cause of childhood blindness worldwide. We prospectively studied newborn infants born at a postmenstrual age of prematurity screening and follow-up. Retinopathy of prematurity was classified according to the international classification of retinopathy of prematurity. Serum Insulin like growth factor 1 levels were measured serially in blood samples on the 1 st , 3 rd , 7 th , 21 st , and 28 th day. Among the 40 infants, 11 (27.5%) constituted the retinopathy of prematurity group and 29 comprised the non-retinopathy of prematurity group. In the retinopathy of prematurity group, the mean gestational age and birth weight was significantly lower. The demographic features of the study cohort were similar. The duration of mechanical ventilation was significantly greater in the retinopathy of prematurity group compared with the non-retinopathy of prematurity group (p=0.036). In terms of neonatal morbidities such as respiratory distress syndrome, intraventricular hemorrhage, bronchopulmonary dysplasia, patent ductus arteriosus, and necrotizing enterocolitis, no differences were detected between the groups. The mean serum insulin-like growth factor-1 levels in retinopathy of prematurity group were significantly lower than those in the non-retinopathy of prematurity group at each time point (1 st , 3 rd , 7 th , 21 st , and 28 th day of postnatal life) (p=0.001). This study demonstrated the low serum insulin-like growth factor-1 levels was associated with retinopathy of prematurity development.

The role of insulin-like growth factor-I in the physiopathology of hearing

Directory of Open Access Journals (Sweden)

Silvia eMurillo-Cuesta

2011-07-01

Full Text Available Insulin like growth factor I (IGF-I belongs to the family of polypeptides of insulin, which play a central role in embryonic development and adult nervous system homeostasis by endocrine, autocrine and paracrine mechanisms. IGF-I is fundamental for the regulation of cochlear development, growth and differentiation, and its mutations are associated with hearing loss in mice and men. Low levels of IGF-I have been shown to correlate with different human syndromes showing hearing loss and with presbyacusis. Animal models are fundamental to understand the genetic, epigenetic, and environmental factors that contribute to human hearing loss. In the mouse, IGF-I serum levels decrease with ageing and there is a concomitant hearing loss and retinal degeneration. In the Igf1-/- null mouse, hearing loss is due to neuronal loss, poor innervation of the sensory hair cells and age-related stria vascularis alterations. In the inner ear, IGF-I actions are mediated by intracellular signaling networks, RAF, AKT and p38 MAPK protein kinases modulate the expression and activity of transcription factors, as AP1, MEF2, FoxM1 and FoxP3, leading to the regulation of cell cycle and metabolism. Therapy with rhIGF-I has been approved in humans for the treatment of poor linear growth and certain neurodegenerative diseases. This review will discuss these findings and their implications in new IGF-I-based treatments for the protection or repair of hearing loss.

Single-donor islet transplantation and long-term insulin independence in select patients with type 1 diabetes mellitus.

Science.gov (United States)

Al-Adra, David P; Gill, Richdeep S; Imes, Sharleen; O'Gorman, Doug; Kin, Tatsuya; Axford, Sara J; Shi, Xinzhe; Senior, Peter A; Shapiro, A M James

2014-11-15

Islet transplantation is a recognized treatment option for select patients with type I diabetes mellitus. However, islet infusions from multiple donors are often required to achieve insulin independence. Ideally, insulin independence would be achieved routinely with only a single donor. Identification of factors associated with insulin independence after single-donor islet transplantation may help to select recipient-donor combinations with the highest probability of success. Subjects undergoing islet transplantation at a single center (Edmonton, Canada) between March 1999 and August 2013 were included. Recipient, donor, and transplant characteristics were collected and compared between recipients who became insulin independent after one islet transplantation and those who did not. Thirty-one patients achieved insulin independence after a single-donor islet transplantation, and 149 did not. Long-term insulin-free survival was not different between the groups. Factors significantly associated with single-donor success included recipient age, insulin requirement at baseline, donor weight, donor body mass index, islet transplant mass, and peritransplant heparin and insulin administration. On multivariate analysis, pretransplantation daily insulin requirements, the use of peritransplantation heparin and insulin infusions, and islet transplant mass remained significant. We have identified clinically relevant differences defining the achievement of insulin independence after single-donor transplantation. Based on these differences, a preoperative insulin requirement of less than 0.6 U/kg per day and receiving more than 5,646 islet equivalents (IEQ)/kg have a sensitivity of 84% and 71% and specificity of 50% and 50%, respectively, for insulin independence after single-donor islet transplantation. With ideal patient selection, this finding could potentially increase single-donor transplantation success and may be especially relevant for presensitized subjects or those who

The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

Science.gov (United States)

Warnhoff, Kurt; Murphy, John T; Kumar, Sandeep; Schneider, Daniel L; Peterson, Michelle; Hsu, Simon; Guthrie, James; Robertson, J David; Kornfeld, Kerry

2014-10-01

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme.

Science.gov (United States)

Affholter, J A; Cascieri, M A; Bayne, M L; Brange, J; Casaretto, M; Roth, R A

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, we have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor I (25 nM and approximately 16,000 nM, respectively), the first set of analogues studied were hybrid molecules of insulin and IGF I. IGF I mutants [insB1-17,17-70]IGF I, [Tyr55,Gln56]IGF I, and [Phe23,Phe24,Tyr25]IGF I have been synthesized and share the property of having insulin-like amino acids at positions corresponding to primary sites of cleavage of insulin by IDE. Whereas the first two exhibit affinities for IDE similar to that of wild type IGF I, the [Phe23,Phe24,Tyr25]IGF I analogue has a 32-fold greater affinity for the immobilized enzyme. Replacement of Phe-23 by Ser eliminates this increase. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

Science.gov (United States)

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Toward understanding insulin fibrillation.

Science.gov (United States)

Brange, J; Andersen, L; Laursen, E D; Meyn, G; Rasmussen, E

1997-05-01

Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear aggregates. Shielding of hydrophobic domains is the main driving force for this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues, including A2, A3, B11, and B15, plays a crucial role in the fibrillation process. Recent crystal analyses and molecular modeling studies have suggested that when insulin fibrillates this exposed domain interacts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils did not elicit an increased immune response with respect to formation of IgG insulin antibodies when compared with native insulin. In contrast, the IgE response increased with increasing content of insulin in fibrillar form. Strategies and practical approaches to prevent insulin from forming fibrils are reviewed. Stabilization of the insulin hexameric structure and blockage of hydrophobic interfaces by addition of surfactants are the most effective means of counteracting insulin fibrillation.

Expression of the insulin-like growth factor (IGF) system and steroidgenic enzymes in canine testis tumors

NARCIS (Netherlands)

Peters, M.A.J.; Mol, J.A.; Wolferen, van M.E.; Oosterlaken-Dijksterhuis, M.A.; Teerds, K.J.; Sluijs, van F.J.

2003-01-01

Testis tumors occur frequently in dogs. The main types of tumors are Sertoli cell tumors, seminomas, and Leydig cell tumors. Mixed tumors and bilateral occurrence of tumors may be encountered frequently. To elucidate the possible relationship between the insulin-like growth factor (IGF) system and

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

Science.gov (United States)

Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

2016-03-01

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important

Insulin Resistance of Puberty.

Science.gov (United States)

Kelsey, Megan M; Zeitler, Philip S

2016-07-01

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

The insulin-like growth factor system is modulated by exercise in breast cancer survivors: a systematic review and meta-analysis.

Science.gov (United States)

Meneses-Echávez, José Francisco; Jiménez, Emilio González; Río-Valle, Jacqueline Schmidt; Correa-Bautista, Jorge Enrique; Izquierdo, Mikel; Ramírez-Vélez, Robinson

2016-08-25

Insulin-like growth factors (IGF´s) play a crucial role in controlling cancer cell proliferation, differentiation and apoptosis. Exercise has been postulated as an effective intervention in improving cancer-related outcomes and survival, although its effects on IGF´s are not well understood. This meta-analysis aimed to determine the effects of exercise in modulating IGF´s system in breast cancer survivors. Databases of PuMed, EMBASE, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials.gov, SPORTDiscus, LILACS and Scopus were systematically searched up to November 2014. Effect estimates were calculated through a random-effects model of meta-analysis according to the DerSimonian and Laird method. Heterogeneity was evaluated with the I (2) test. Risk of bias and methodological quality were evaluated using the PEDro score. Five randomized controlled trials (n = 235) were included. Most women were post-menopausal. High-quality and low risk of bias were found (mean PEDro score = 6.2 ± 1). Exercise resulted in significant improvements on IGF-I, IGF-II, IGFBP-I, IGFBP-3, Insulin and Insulin resistance (P breast cancer survivors. These findings provide novel insight regarding the molecular effects of exercise on tumoral microenvironment, apoptosis and survival in breast cancer survivors.

Anti-inflammatory effects of insulin.

Science.gov (United States)

Dandona, Paresh; Chaudhuri, Ajay; Mohanty, Priya; Ghanim, Husam

2007-07-01

This review deals with the recent observations on the pro-inflammatory effects of glucose and the anti-inflammatory actions of insulin. Apart from being novel, they are central to our understanding of why hyperglycemia is a prognosticator of bad clinical outcomes including patients with acute coronary syndromes, stroke and in patients in the intensive care unit. The pro-inflammatory effect of glucose as well as that of other macronutrients including fast food meals provides the basis of chronic oxidative stress and inflammation in the obese and their propensity to atherosclerotic disease. The anti-inflammatory action of insulin provides a neutralizing effect to balance macronutrient induced inflammation on the one hand and the possibility of using insulin as an anti-inflammatory drug on the other. The actions of macronutrients and insulin described above explain why insulin resistant states like obesity and type 2 diabetes are associated with oxidative stress, inflammation and atherosclerosis. They also suggest that insulin may be antiatherogenic.

Treatment of Type 1 and Type 2 Diabetes Mellitus with Insulin Detemir, a Long-Acting Insulin Analog

Directory of Open Access Journals (Sweden)

Jason R. Young

2010-01-01

Full Text Available Insulin detemir is a long-acting basal insulin approved for use in patients with type 1 (T1DM or type 2 diabetes (T2DM. Insulin detemir has demonstrated equivalent glycemic control and hypoglycemic risk when compared to insulin glargine, and insulin detemir has generally but not consistently demonstrated less weight gain than insulin glargine in T2DM. The benefits of basal insulin analogs relative to NPH insulin are well recognized, including less FBG variability, lower risk of hypoglycemia, and less weight gain specifically with insulin detemir. However, NPH insulin continues to be widely prescribed, which may be due in part to economic considerations. While NPH insulin generally costs less per prescription, insulin detemir has been shown to be cost effective compared to NPH insulin as well as insulin glargine. Therefore, insulin detemir is an effective option from both clinical and economic perspectives for patients with T1DM or T2DM who require basal insulin to achieve glycemic control.

Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training.

Science.gov (United States)

Joham, Anju E; Teede, Helena J; Hutchison, Samantha K; Stepto, Nigel K; Harrison, Cheryce L; Strauss, Boyd J; Paul, Eldho; Watt, Matthew J

2012-12-01

Pigment epithelium-derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight-matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non-PCOS weight-matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic-hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non-PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 ± 96.3 and 257.2 ± 64.3 mg.m(-2).min(-1)) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = -0.41, P = 0.03) and high-density lipoprotein (HDL) (r = -0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status.

Patient Perspectives on Biosimilar Insulin.

Science.gov (United States)

Wilkins, Alasdair R; Venkat, Manu V; Brown, Adam S; Dong, Jessica P; Ran, Nina A; Hirsch, James S; Close, Kelly L

2014-01-01

Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would "definitely" or "likely" use a biosimilar insulin, while 17% reported that they were "unlikely" to use or would "definitely not use" such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. © 2014 Diabetes Technology Society.

Levels of insulin, insulin-like growth factor-I and thyroid hormones in relation to the body condition score changes in periparturient dairy cows

Directory of Open Access Journals (Sweden)

Fratrić Natalija

2013-01-01

Full Text Available The objective of this study was to determine the levels of insulin, insulin like growth factor I (IGF-I and thyroid hormones in relation to the body condition score (BCS of periparturient dairy cows. The study was carried out on twenty Holstein-Friesian dairy cows with average milk production of 7000 L/305 days in the previous lactation, parity ranging from 2-4. All cows were BCS scored during the early dry period, 7±3 days before and after parturition. Based on the BCS at the early dry period, cows were divided in two groups: cows with high BCS (3.75- 4.25, HBCS, n=10, and cows with moderate BCS (2.75-3.75, MBCS, n=10. Blood samples were taken at the time of BCS evaluation. Concentrations of insulin, IGF-I, triiodothyroinine (T3 and thyroxine (T4 were determined by radioimmunoassay (RIA, INEP-Zemun, Serbia. Statistical differences between mean values were determined using Student t-test (p0.05. IGF-I level in HBCS cows at days 7±3 before calving was significantly higher (16.28±3.07:11.76±2.28, p<0.01, with a reverse relationship after calving (3.77±1.64:8.46±2.37, p<0.01. Insulin level was significantly lower at 7±3 days before calving in HBCS cows (16.26±4.60:20.18±4.96mIU/L, p<0.05. Thyroid hormones levels were significantly lower in HBCS group et all examined periods. [Projekat Ministarstva nauke Republike Srbije, br. III 46002 i br. 31003

The association between newborn regional body composition and cord blood concentrations of C-peptide and insulin-like growth factor I

DEFF Research Database (Denmark)

Carlsen, Emma M; Renault, Kristina M; Jensen, Rikke B

2015-01-01

BACKGROUND: Third trimester fetal growth is partially regulated by C-peptide and insulin-like growth factor I (IGF-I). Prenatal exposures including maternal obesity and high gestational weight gain as well as high birth weight have been linked to subsequent metabolic disease. We evaluated...... with both C-peptide (p tissue accumulation was associated with cord blood C-peptide and IGF-I. Total and abdominal fat masses were related to C-peptide but not to IGF-I. Thus, newborn adiposity is partially mediated through C-peptide and early...

Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

Institute of Scientific and Technical Information of China (English)

无

2007-01-01

BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear.OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes.DESIGN: A non-randomized concurrent controlled study.SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College.PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children.METHODS: ① The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization.

Science.gov (United States)

Kim, Jung; Bilder, David; Neufeld, Thomas P

2018-01-15

Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. © 2018 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans

DEFF Research Database (Denmark)

Hansen, Mette; Boesen, Anders; Holm, Lars

2013-01-01

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin-like growth factor I (IGF-I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing, but t...

Prevalence and Associated Factors of Insulin Resistance in Adults from Maracaibo City, Venezuela

Directory of Open Access Journals (Sweden)

Valmore Bermudez

2016-01-01

Full Text Available Background and Aim. Insulin resistance (IR is a prominent pathophysiologic component in a myriad of metabolic disorders, including obesity, prediabetes, and type 2 diabetes mellitus, which are common in our locality. The objective of this study was to determine the prevalence of IR and factors associated with this condition in an adult population from Maracaibo city, Venezuela. Methodology. A cross-sectional, descriptive study with multistaged randomized sampling was carried out in 2026 adults. IR was defined as HOMA2-IR ≥ 2. A multiple logistic regression model was constructed in order to evaluate factors associated with IR. Results. The prevalence of IR was 46.5% (n=943, with 46.7% (n=450 in the general population, 46.4% (n=493 in females, and 47.90% (n=970 in males (p=0.895. IR prevalence tended to increase with age and was significantly greater in subjects aged ≥30 years (χ2=16.726; p=2.33×10-4. Employment, alcohol consumption, obesity, high triacylglycerides, low HDL-C, and dysglycemia were associated with greater odds of IR, whereas a high level of physical activity appeared to be weak protective factor against IR. Conclusions. The prevalence of IR is elevated in our locality. The main determinants of this condition appear to be the presence of obesity, high triacylglycerides, low HDL-C, dysglycemia, and alcohol intake.

Diabetes and pre-diabetes are associated with cardiovascular risk factors and carotid/femoral intima-media thickness independently of markers of insulin resistance and adiposity

Directory of Open Access Journals (Sweden)

Paccaud Fred

2007-10-01

Full Text Available Abstract Background Impaired glucose regulation (IGR is associated with detrimental cardiovascular outcomes such as cardiovascular disease risk factors (CVD risk factors or intima-media thickness (IMT. Our aim was to examine whether these associations are mediated by body mass index (BMI, waist circumference (waist or fasting serum insulin (insulin in a population in the African region. Methods Major CVD risk factors (systolic blood pressure, smoking, LDL-cholesterol, HDL-cholesterol, were measured in a random sample of adults aged 25–64 in the Seychelles (n = 1255, participation rate: 80.2%. According to the criteria of the American Diabetes Association, IGR was divided in four ordered categories: 1 normal fasting glucose (NFG, 2 impaired fasting glucose (IFG and normal glucose tolerance (IFG/NGT, 3 IFG and impaired glucose tolerance (IFG/IGT, and 4 diabetes mellitus (DM. Carotid and femoral IMT was assessed by ultrasound (n = 496. Results Age-adjusted levels of the major CVD risk factors worsened gradually across IGR categories (NFG Conclusion We found graded relationships between IGR categories and both major CVD risk factors and carotid/femoral IMT. These relationships were only partly accounted for by BMI, waist and insulin. This suggests that increased CVD-risk associated with IGR is also mediated by factors other than the considered markers of adiposity and insulin resistance. The results also imply that IGR and associated major CVD risk factors should be systematically screened and appropriately managed.

Human conditions of insulin-like growth factor-I (IGF-I) deficiency

Science.gov (United States)

2012-01-01

Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range. PMID:23148873

Human conditions of insulin-like growth factor-I (IGF-I deficiency

Directory of Open Access Journals (Sweden)

Puche Juan E

2012-11-01

Full Text Available Abstract Insulin-like growth factor I (IGF-I is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions. IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.

Diet-induced obesity, gut microbiota and bone, including alveolar bone loss.

Science.gov (United States)

Eaimworawuthikul, Sathima; Thiennimitr, Parameth; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-06-01

Obesity is a major risk factor for several pathologies, including jaw bone resorption. The underlying mechanisms involved in pathological conditions resulting from obesity include chronic systemic inflammation and the development of insulin resistance. Although numerous studies have indicated the importance of the role of gut microbiota in the pathogenesis of inflammation and insulin resistance in obesity, only a few studies have established a relationship between obesity, gut microbiota and status of the jaw bone. This review aims to summarize current findings relating to these issues, focusing on the role of obesity and gut microbiota on jaw bone health, including possible mechanisms which can explain this link. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet

Science.gov (United States)

Stolarczyk, Emilie; Vong, Chi Teng; Perucha, Esperanza; Jackson, Ian; Cawthorne, Michael A.; Wargent, Edward T.; Powell, Nick; Canavan, James B.; Lord, Graham M.; Howard, Jane K.

2013-01-01

Summary Low-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet−/− mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet−/− mice also lacking adaptive immunity (T-bet−/−xRag2−/−), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4+ T cells to Rag2−/− mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance. PMID:23562076

The Effect of Insulin-like Growth Factor-1, Cysteamine and β-Mercaptoethanol on the In Vitro Maturation of Immature Mice Oocytes

Directory of Open Access Journals (Sweden)

A Dehghan Manshadi

2015-11-01

Full Text Available Background & aim: In vitro maturation of oocytes is a promising technique for reducing the costs and complications of ovarian stimulation by gonadotropins. The aim of this study was to investigate the effects of combination of insulin-like growth factor-1 and antioxidant cysteamine and &beta-Mercaptoethanol on maturation and fertilization of immature oocytes. Methods: in this experimental study, following 48 hrs injection of 7.5 IU PMSG to immature female mice, the germinal vesicle oocytes from ovaries were removed and transferred to TCM199 culture medium containing 50 ng /ml insulin-like growth factor-1 and 100 &mumol Cysteamine and &beta -Mercaptoethanol. After 24 hrs of culture, the oocytes of MII in IVF were fertilized and embryonic development to the two cells was studied under an inverted microscope. Data analysis was performed by using ANOVA and Post hoc Tukey test. Results: The results showed that the rate of maturation, fertilization and 2-cell embryo formation in GV oocytes with cumulus cells in TCM199 medium containing insulin-like growth factor-1, Cysteamine and BME were 92.10, 93.30, 80.60% and in the GV oocytes without Cumulus cells were cultured in the same medium were 65.80, 64.00, 58.60% respectively which were statistically significant (P <0.001. Conclusion: In the present study, the simultaneous combination of insulin-like growth factor-1, &beta-Mercaptoethanol and CYS increased maturation, fertilization and developmental rate to 2-cells stage with cumulus cells more than the oocyte without cumulus cells to a greater extent. This represented the need of adding supplemental growth factors and antioxidants to the medium and is associated with cumulus cells.

Factors that drive insulin-dosing decisions of diabetes care providers: a vignette-based study in the Netherlands

NARCIS (Netherlands)

Simon, A. C. R.; Schopman, J. E.; Hoekstra, J. B. L.; Abu-Hanna, A.; Gerdes, V. E. A.; Peek, N.; Holleman, F.

2015-01-01

To test how certain patient factors would influence the decision of Dutch care providers regarding insulin dose adjustments. We hypothesize that some of these decisions would diverge from recent evidence and consensus statements. We developed narrative vignettes describing clinical scenarios of

Effects of vitamin D supplementation on insulin resistance and cardiometabolic risk factors in children with metabolic syndrome: a triple-masked controlled trial

Directory of Open Access Journals (Sweden)

Roya Kelishadi

2014-01-01

Full Text Available OBJECTIVE: this triple-masked controlled trial aimed to assess the effects of vitamin D supplementation on insulin resistance and cardiometabolic risk factors in obese children and adolescents. METHODS: the study comprised 50 participants, aged 10 to16 years, who were randomly assigned into two groups of equal number. In this 12-week trial, one group received oral vitamin D (300,000 IU and the other group received placebo. Cardiometabolic risk factors, insulin resistance, and a continuous value of metabolic syndrome (cMetS were determined. Statistical analysis was conducted after adjustment for covariate interactions. RESULTS: overall, 21 patients in the vitamin D group and 22 in the placebo group completed the trial. No significant difference was observed in the baseline characteristics of the two groups. After the trial, in the vitamin D group, serum insulin and triglyceride concentrations, as well as HOM -IR and C-MetS decreased significantly, both when compared with the baseline and with the placebo group. No significant difference was observed when comparing total cholesterol, LDL-C, HDL-C, fasting blood glucose, and blood pressure. CONCLUSION: the present findings support the favorable effects of vitamin D supplementation on reducing insulin resistance and cardiometabolic risk factors in obese children.

Effects of vitamin D supplementation on insulin resistance and cardiometabolic risk factors in children with metabolic syndrome: a triple-masked controlled trial.

Science.gov (United States)

Kelishadi, Roya; Salek, Shadi; Salek, Mehdi; Hashemipour, Mahin; Movahedian, Mahsa

2014-01-01

This triple-masked controlled trial aimed to assess the effects of vitamin D supplementation on insulin resistance and cardiometabolic risk factors in obese children and adolescents. The study comprised 50 participants, aged 10 to 16 years, who were randomly assigned into two groups of equal number. In this 12-week trial, one group received oral vitamin D (300,000 IU) and the other group received placebo. Cardiometabolic risk factors, insulin resistance, and a continuous value of metabolic syndrome (cMetS) were determined. Statistical analysis was conducted after adjustment for covariate interactions. Overall, 21 patients in the vitamin D group and 22 in the placebo group completed the trial. No significant difference was observed in the baseline characteristics of the two groups. After the trial, in the vitamin D group, serum insulin and triglyceride concentrations, as well as HOM -IR and C-MetS decreased significantly, both when compared with the baseline and with the placebo group. No significant difference was observed when comparing total cholesterol, LDL-C, HDL-C, fasting blood glucose, and blood pressure. The present findings support the favorable effects of vitamin D supplementation on reducing insulin resistance and cardiometabolic risk factors in obese children. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

[News and perspectives in insulin treatment].

Science.gov (United States)

Haluzík, Martin

2014-09-01

Insulin therapy is a therapeutic cornerstone in patients with type 1 diabetes and also in numerous patients with type 2 diabetes especially with longer history of diabetes. The initiation of insulin therapy in type 2 diabetes patients is often delayed which is at least partially due to suboptimal pharmacokinetic characteristics of available insulins. The development of novel insulins with more favorable characteristics than those of current insulins is therefore still ongoing. The aim of this paper is to review current knowledge of novel insulins that have been recently introduced to the market or are getting close to routine clinical use. We will also focus on the perspectives of insulin therapy in the long-term run including the alternative routes of insulin administration beyond its classical subcutaneous injection treatment.Key words: alternative routes of insulin administration - diabetes mellitus - hypoglycemia - insulin - insulin analogues.

Parity Increases Insulin Requirements in Pregnant Women With Type 1 Diabetes.

Science.gov (United States)

Skajaa, Gitte Ø; Fuglsang, Jens; Kampmann, Ulla; Ovesen, Per G

2018-06-01

Tight glycemic control throughout pregnancy in women with type 1 diabetes is crucial, and knowledge about which factors that affect insulin sensitivity could improve the outcome for both mother and offspring. To evaluate insulin requirements in women with type 1 diabetes during pregnancy and test whether parity affects insulin requirements. Observational cohort study consisting of women with type 1 diabetes who gave birth at Aarhus University Hospital, Denmark, from 2004 to 2014. Daily insulin requirement (the hypothesis that parity could affect insulin resistance was formulated before data collection). A total of 380 women with a total of 536 pregnancies were included in the study. Mean age was 31.1 years, and prepregnancy hemoglobin A1c was 60 mmol/mol. Parity was as follows: P0, 43%; P1, 40%; P2, 14%; and P3+4, 3%. Insulin requirements from weeks 11 to 16 decreased significantly by 4% (P = 0.0004) and rose from week 19 to delivery with a peak of 70% (P insulin requirements increased significantly with parity. The unadjusted differences between P0 and P1, P2, and P3+4 were 9% (P insulin requirements from week to week in pregnancy and indicate that insulin requirements increase with parity. This suggests that the patient's parity probably should be considered in choosing insulin dosages for pregnant women with type 1 diabetes.

Gastric emptying and timing of insulin injection in insulin-treated diabetics Using99m Te-sulfur colloid

International Nuclear Information System (INIS)

Sheta, M.; El-Borrolossy, H.; El-Tawil, A.

1997-01-01

Gastric emptying of 99m Tc labelled liquid and solid meals were studied in 112 long-standing insulin insulin treated diabetics to evaluate the relationship of gastroparesis to patients age, sex, gastrointestinal symptoms, diabetic neuropathic complication and glycemic control, and to evaluate the influence of gastric emptying and timing of insulin injection as modifying factors for blood glucose control aiming at objective optimization of timing of insulin injection for every individual patient using the proposed equation: time of insulin injection=onset of insulin action -solid lag time. Patients were classified into three group: A) no neuropathy; B) peripheral neuropathy; and C) peripheral and autonomic neuropathy and compared to healthy volunteers as controls. Diabetics showed statistically significant prolonged gastric lag time and T1/2 for both liquid and solid meals compared to those of controls

Concentrated insulins: the new basal insulins

Directory of Open Access Journals (Sweden)

Lamos EM

2016-03-01

Full Text Available Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Introduction: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered: This review highlights the published reports of the pharmacokinetic (PK and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion: Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration

Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders

DEFF Research Database (Denmark)

Bay, K; Hartung, S; Ivell, R

2005-01-01

Insulin-like factor 3 (INSL3) serum levels were measured in 135 andrologically well-characterized normal men and 85 patients with testicular disorders to investigate how the hormone, which is a major secretory product of human Leydig cells, is related to testosterone (T), LH, and semen quality. I...

Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes

NARCIS (Netherlands)

S. Jainandunsing (Sjaam); Koole, H.R. (H. Rita); van Miert, J.N.I. (Joram N.I.); T. Rietveld (Trinet); J.L.D. Wattimena (Josias); E.J.G. Sijbrands (Eric); F.W.M. de Rooij (Felix)

2018-01-01

textabstractTranscription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, primarily through impairing the insulin secretion by pancreatic β cells. However, the exact in vivo mechanisms remain poorly understood. We performed a family study and determined if the T risk

Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes.

Science.gov (United States)

Chuang, L M; Hausdorff, S F; Myers, M G; White, M F; Birnbaum, M J; Kahn, C R

1994-11-04

Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. The Ras-enhanced oocyte maturation response, but not the elevated basal level of MAP and S6 kinase, was partially blocked by the SH2-p85, but not SH2-GRB2. These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins.

Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance?

NARCIS (Netherlands)

Li, Naishi; Fu, Jingyuan; Koonen, Debby P.; Kuivenhoven, Jan Albert; Snieder, Harold; Hofker, Marten H.

Insulin resistance often occurs with dyslipidemia as part of the metabolic syndrome and the current dominant paradigm is that insulin resistance leads to dyslipidemia. However, dyslipidemia may also cause insulin resistance; this was postulated 30 years ago, but has never been substantiated.

Insulin Resistance and Mitochondrial Dysfunction.

Science.gov (United States)

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

High insulin-like growth factor-binding protein-1 (IGFBP-1) is associated with low relative muscle mass in older women

DEFF Research Database (Denmark)

Stilling, Frej; Wallenius, Sara; Michaëlsson, Karl

2017-01-01

. In the present study we investigate the association between serum IGFBP-1 and muscle mass. Design Cross-sectional analysis of 4908 women, between 55 and 85 years old, participating in the Swedish Mammography Cohort-Clinical. Methods We defined low relative muscle mass (LRMM) as an appendicular lean mass divided...... relative muscle mass. High IGFBP-1 may be a marker of a catabolic state.......Objective Skeletal muscles serve several important roles in maintaining good health. Insulin-like growth factor-1 (IGF-1) is a promoter of protein synthesis in skeletal muscle. Its binding protein, Insulin-like growth factor-binding protein-1 (IGFBP-1) can be one determinant of IGF-1 activity...

Diversification of the insulin-like growth factor 1 gene in mammals.

Directory of Open Access Journals (Sweden)

Peter Rotwein

Full Text Available Insulin-like growth factor 1 (IGF1, a small, secreted peptide growth factor, is involved in a variety of physiological and patho-physiological processes, including somatic growth, tissue repair, and metabolism of carbohydrates, proteins, and lipids. IGF1 gene expression appears to be controlled by several different signaling cascades in the few species in which it has been evaluated, with growth hormone playing a major role by activating a pathway involving the Stat5b transcription factor. Here, genes encoding IGF1 have been evaluated in 25 different mammalian species representing 15 different orders and ranging over ~180 million years of evolutionary diversification. Parts of the IGF1 gene have been fairly well conserved. Like rat Igf1 and human IGF1, 21 of 23 other genes are composed of 6 exons and 5 introns, and all 23 also contain recognizable tandem promoters, each with a unique leader exon. Exon and intron lengths are similar in most species, and DNA sequence conservation is moderately high in orthologous exons and proximal promoter regions. In contrast, putative growth hormone-activated Stat5b-binding enhancers found in analogous locations in rodent Igf1 and in human IGF1 loci, have undergone substantial variation in other mammals, and a processed retro-transposed IGF1 pseudogene is found in the sloth locus, but not in other mammalian genomes. Taken together, the fairly high level of organizational and nucleotide sequence similarity in the IGF1 gene among these 25 species supports the contention that some common regulatory pathways had existed prior to the beginning of mammalian speciation.

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR): A Better Marker for Evaluating Insulin Resistance Than Fasting Insulin in Women with Polycystic Ovarian Syndrome.

Science.gov (United States)

Majid, Hafsa; Masood, Qamar; Khan, Aysha Habib

2017-03-01

To assess the utility of HOMA-IR in assessing insulin resistance in patients with polycystic ovary syndrome (PCOS) and compare it with fasting insulin for assessing insulin resistance (IR). Observational study. Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2009 to September 2012. Medical chart review of all women diagnosed with PCOS was performed. Of the 400 PCOS women reviewed, 91 met the inclusion criteria. Insulin resistance was assessed by calculating HOMA-IR using the formula (fasting glucose x fasting insulin)/405, taking normal value HOMA-IR of women was 3.1 ±1.7, respectively with IR in 69% (n=63) women, while hyperinsulinemia was present in 60% (n=55) women (fasting Insulin 18.5 ±5.8 µIU/ml). Hyperandrogenism was present in 53.8% (n=49), whereas 38.5% (n=35) women had primary infertility or subfertility, while 65.9% (n=60) had menstrual irregularities; and higher frequencies were observed in women with IR. Eight subjects with IR and endocrine abnormalities were missed by fasting insulin. Insulin resistance is common in PCOS and it is likely a pathogenic factor for development of PCOS. HOMAIR model performed better than hyperinsulinemia alone for diagnosing IR.

Characterization of the growth of murine fibroblasts that express human insulin receptors. I. The effect of insulin in the absence of other growth factors

International Nuclear Information System (INIS)

Randazzo, P.A.; Morey, V.A.; Polishook, A.K.; Jarett, L.

1990-01-01

The effect of insulin on the growth of murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental cells (NIH/3T3) was characterized. Insulin in the absence of other mitogens increased the rate of incorporation of thymidine into NIH 3T3/HIR cells with a half-maximal response occurring at an insulin concentration of 35 ng/ml and a maximal response that was equivalent to that elicited by 10% fetal calf serum. The thymidine incorporation rate was increased by 12 h, was maximal at approximately 16 h, and returned to basal rates at 24 h after the addition of insulin. Insulin induced a maximum of 65% of cells to incorporate thymidine. The increased DNA synthesis was accompanied by net growth. Addition of insulin to the NIH 3T3/HIR cells resulted in increased DNA content with a half-maximal response occurring at approximately 30 ng/ml insulin and a maximal response equivalent to that elicited by serum. An increase in cell number detected after the addition of insulin to the NIH 3T3/HIR suggests that the cells had progressed through mitosis. Insulin did not increase the rate of thymidine incorporation, DNA content, or number of the parental NIH 3T3 cells. These data show that insulin, in the absence of a second mitogen, is able to induce NIH 3T3/HIR fibroblasts to traverse the cell cycle

Challenges constraining access to insulin in the private-sector market of Delhi, India.

Science.gov (United States)

Sharma, Abhishek; Kaplan, Warren A

2016-01-01

India's majority of patients-including those living with diabetes-seek healthcare in the private sector through out-of-pocket (OOP) payments. We studied access to insulin in the private-sector market of Delhi state, India. A modified World Health Organization/Health Action International (WHO/HAI) standard survey to assess insulin availability and prices, and qualitative interviews with insulin retailers (pharmacists) and wholesalers to understand insulin market dynamics. In 40 pharmacy outlets analysed, mean availability of the human and analogue insulins on the 2013 Delhi essential medicine list was 44.4% and 13.1%, respectively. 82% of pharmacies had domestically manufactured human insulin phials, primarily was made in India under licence to overseas pharmaceutical companies. Analogue insulin was only in cartridge and pen forms that were 4.42 and 5.81 times, respectively, the price of human insulin phials. Domestically manufactured human phial and cartridge insulin (produced for foreign and Indian companies) was less expensive than their imported counterparts. The lowest paid unskilled government worker in Delhi would work about 1.5 and 8.6 days, respectively, to be able to pay OOP for a monthly supply of human phial and analogue cartridge insulin. Interviews suggest that the Delhi insulin market is dominated by a few multinational companies that import and/or license in-country production. Several factors influence insulin uptake by patients, including doctor's prescribing preference. Wholesalers have negative perceptions about domestic insulin manufacturing. The Delhi insulin market is an oligopoly with limited market competition. Increasing competition from Indian companies is going to require some additional policies, not presently in place. As more Indian companies produce biosimilars, brand substitution policies are needed to be able to benefit from market competition.

Challenges constraining access to insulin in the private-sector market of Delhi, India

Science.gov (United States)

Kaplan, Warren A

2016-01-01

Objective India's majority of patients—including those living with diabetes—seek healthcare in the private sector through out-of-pocket (OOP) payments. We studied access to insulin in the private-sector market of Delhi state, India. Methods A modified World Health Organization/Health Action International (WHO/HAI) standard survey to assess insulin availability and prices, and qualitative interviews with insulin retailers (pharmacists) and wholesalers to understand insulin market dynamics. Results In 40 pharmacy outlets analysed, mean availability of the human and analogue insulins on the 2013 Delhi essential medicine list was 44.4% and 13.1%, respectively. 82% of pharmacies had domestically manufactured human insulin phials, primarily was made in India under licence to overseas pharmaceutical companies. Analogue insulin was only in cartridge and pen forms that were 4.42 and 5.81 times, respectively, the price of human insulin phials. Domestically manufactured human phial and cartridge insulin (produced for foreign and Indian companies) was less expensive than their imported counterparts. The lowest paid unskilled government worker in Delhi would work about 1.5 and 8.6 days, respectively, to be able to pay OOP for a monthly supply of human phial and analogue cartridge insulin. Interviews suggest that the Delhi insulin market is dominated by a few multinational companies that import and/or license in-country production. Several factors influence insulin uptake by patients, including doctor's prescribing preference. Wholesalers have negative perceptions about domestic insulin manufacturing. Conclusions The Delhi insulin market is an oligopoly with limited market competition. Increasing competition from Indian companies is going to require some additional policies, not presently in place. As more Indian companies produce biosimilars, brand substitution policies are needed to be able to benefit from market competition. PMID:28588966

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization

DEFF Research Database (Denmark)

Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne

2016-01-01

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotid...

Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study

DEFF Research Database (Denmark)

van der Spoel, Evie; Rozing, Maarten P; Houwing-Duistermaat, Jeanine J

2015-01-01

Reduced insulin/insulin-like growth factor 1 (IGF-1) signaling has been associated with longevity in various model organisms. However, the role of insulin/IGF-1 signaling in human survival remains controversial. The aim of this study was to test whether circulating IGF-1 axis parameters associate...... with old age survival and functional status in nonagenarians from the Leiden Longevity Study. This study examined 858 Dutch nonagenarian (males≥89 years; females≥91 years) siblings from 409 families, without selection on health or demographic characteristics. Nonagenarians were divided over sex...

An additional bolus of rapid-acting insulin to normalise postprandial cardiovascular risk factors following a high-carbohydrate high-fat meal in patients with type 1 diabetes: A randomised controlled trial.

Science.gov (United States)

Campbell, Matthew D; Walker, Mark; Ajjan, Ramzi A; Birch, Karen M; Gonzalez, Javier T; West, Daniel J

2017-07-01

To evaluate an additional rapid-acting insulin bolus on postprandial lipaemia, inflammation and pro-coagulation following high-carbohydrate high-fat feeding in people with type 1 diabetes. A total of 10 males with type 1 diabetes [HbA 1c 52.5 ± 5.9 mmol/mol (7.0% ± 0.5%)] underwent three conditions: (1) a low-fat (LF) meal with normal bolus insulin, (2), a high-fat (HF) meal with normal bolus insulin and (3) a high-fat meal with normal bolus insulin with an additional 30% insulin bolus administered 3-h post-meal (HFA). Meals had identical carbohydrate and protein content and bolus insulin dose determined by carbohydrate-counting. Blood was sampled periodically for 6-h post-meal and analysed for triglyceride, non-esterified-fatty acids, apolipoprotein B48, glucagon, tumour necrosis factor alpha, fibrinogen, human tissue factor activity and plasminogen activator inhibitor-1. Continuous glucose monitoring captured interstitial glucose responses. Triglyceride concentrations following LF remained similar to baseline, whereas triglyceride levels following HF were significantly greater throughout the 6-h observation period. The additional insulin bolus (HFA) normalised triglyceride similarly to low fat 3-6 h following the meal. HF was associated with late postprandial elevations in tumour necrosis factor alpha, whereas LF and HFA was not. Fibrinogen, plasminogen activator inhibitor-1 and tissue factor pathway levels were similar between conditions. Additional bolus insulin 3 h following a high-carbohydrate high-fat meal prevents late rises in postprandial triglycerides and tumour necrosis factor alpha, thus improving cardiovascular risk profile.

The measurement of insulin-like growth factor 1 in sheep plasma.

Science.gov (United States)

Bruce, L A; Atkinson, T; Hutchinson, J S; Shakespear, R A; MacRae, J C

1991-02-01

A method is described for the radioimmunoassay (RIA) of insulin-like growth factor 1 (IGF-1) in neutralised formic acid-ethanol extracts of sheep plasma. The ability of the acid-ethanol pretreatment to remove the IGF-1 binding proteins (BPs), which interfere in the assay has been examined. Comparative plasma IGF-1 concentrations determined by the method correlated closely (P less than 0.001) with corresponding values where BPs were removed by acid gel filtration. The method has been applied to studies in which sheep were given exogenous growth hormone and indicated that plasma IGF-1 levels respond rapidly to the onset and termination of treatment.

Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss

DEFF Research Database (Denmark)

Rasmussen, Michael; Wildschiødtz, Gordon; Juul, Anders

2008-01-01

compared with nonobese subjects After diet-induced weight loss the differences in GH, free IGF-I, and leptin were no longer present between previously obese and nonobese subjects, whereas a significant difference in sleep duration and total IGF-I levels persisted. Rapid eye movement (REM) sleep, non-REM......Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have...... investigated sleep in relation to the GH-IGF-I axis and weight loss in obese subjects. In this study polygraphic sleep recordings, 24-h GH release, 24-h leptin levels, free-IGF-I, total-IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), cortisol and insulin sensitivity were determined in six...

Mactosylceramide Prevents Glial Cell Overgrowth by Inhibiting Insulin and Fibroblast Growth Factor Receptor Signaling

DEFF Research Database (Denmark)

Gerdøe-Kristensen, Stine; Lund, Viktor K; Wandall, Hans H

2017-01-01

, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what...... of the Drosophila Insulin Receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK...... hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of Insulin and Fibroblast Growth Factor Receptors in Drosophila glia. This article is protected by copyright. All rights reserved....

Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease.

Science.gov (United States)

Tiitinen, A E; Laatikainen, T J; Seppälä, M T

1993-07-01

To study the serum levels of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) in relation to clomiphene citrate (CC) responsiveness in women with polycystic ovarian disease (PCOD). Prospective. PATIENTS, SETTING: Twenty-three women with PCOD admitted consecutively to the University Infertility Clinic, a tertiary referral center. Blood samples were taken at fasting state and during oral glucose tolerance test (OGTT) for the determination of insulin, IGF-I, and IGFBP-1. A dose of 50 to 200 mg/d CC was given for ovulation induction. With CC treatment, ovulation was achieved in 13 of 23 PCOD patients. The IGFBP-1 concentration was lower in CC nonresponders than in CC responders (20.5 +/- 4.0 ng/mL versus 41.0 +/- 8.5 ng/mL) (P PCOD patients. Lean CC nonresponders (n = 7) had almost threefold lower serum IGFBP-1 levels than lean CC responders (n = 6) (24.0 +/- 3.1 ng/mL versus 61.8 +/- 8.6 ng/mL) (P PCOD patients, the IGFBP-1 levels were low irrespective of CC responsiveness (14.8 +/- 8.0 ng/mL versus 16.7 +/- 7.2 ng/mL). The differences remained during OGTT. The concentrations of IGF-I, insulin, sex hormone-binding globulin, LH, FSH, and androgens showed no significant differences between CC responders and nonresponders. There was an inverse correlation between serum insulin and IGFBP-1 levels in obese PCOD patients, whereas this was not seen in lean patients. In lean PCOD patients, low serum IGFBP-1 concentration is related to CC unresponsiveness by a mechanism unrelated to insulin.

MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin

International Nuclear Information System (INIS)

Zhang, Zi-wei; Guo, Rui-wei; Lv, Jin-lin; Wang, Xian-mei; Ye, Jin-shan; Lu, Ni-hong; Liang, Xing; Yang, Li-xia

2017-01-01

Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis. - Highlights: • Suggesting a new mechanism of insulin-triggered VSMC functions. • Providing a new therapeutic strategies that target atherosclerosis in T2DM patients. • Providing a new strategies that target in-stent restenosis in T2DM patients.

High cumulative insulin exposure : a risk factor of atherosclerosis in type 1 diabetes?

NARCIS (Netherlands)

Muis, MJ; Bots, ML; Bilo, HJG; Hoogma, RPLM; Hoekstra, JBL; Grobbee, DE; Stolk, RP

Background: Since insulin therapy might have an atherogenic effect, we studied the relationship between cumulative insulin dose and atherosclerosis in type 1 diabetes. We have focused on patients with type 1 diabetes instead of type 2 diabetes to minimise the effect of insulin resistance as a

High cumulative insulin exposure: a risk factor of atherosclerosis in type 1 diabetes?

NARCIS (Netherlands)

Muis, Marian J.; Bots, Michiel L.; Bilo, Henk J. G.; Hoogma, Roel P. L. M.; Hoekstra, Joost B. L.; Grobbee, Diederick E.; Stolk, Ronald P.

2005-01-01

Background: Since insulin therapy might have an atherogenic effect, we studied the relationship between cumulative insulin dose and atherosclerosis in type 1 diabetes. We have focused on patients with type 1 diabetes instead of type 2 diabetes to minimise the effect of insulin resistance as a

Insulin-like Growth Factor Binding Protein 7 Mediates Glioma Cell Growth and Migration

Directory of Open Access Journals (Sweden)

Wei Jiang

2008-12-01

Full Text Available Insulin-like growth factor binding protein 7 (IGFBP-7 is the only member of the IGFBP superfamily that binds strongly to insulin, suggesting that IGFBP-7 may have different functions from other IGFBPs. Unlike other IGFBPs, the expression and functions of IGFBP-7 in glioma tumors have not been reported. Using cDNA microarray analysis, we found that expression of IGFBP-7 correlated with the grade of glioma tumors and the overall patient survival. This finding was further validated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. We used RNAi to examine the role of IGFBP-7 in glioma cells, inhibiting IGFBP-7 expression by short interfering RNA transfection. Cell proliferation was suppressed after IGFBP-7 expression was inhibited for 5 days, and glioma cell growth was stimulated consistently by the addition of recombinant IGFBP-7 protein. Moreover, glioma cell migration was attenuated by IGFBP-7 depletion but enhanced by IGFBP-7 overexpression and addition. Overexpression of AKT1 in IGFBP-7-overxpressed cells attenuated the IGFBP-7-promoted migration and further enhanced inhibition of IGFBP-7 depletion on the migration. Phosphorylation of AKT and Erk1/2 was also inversely regulated by IGFBP-7 expression. These two factors together suggest that IGFBP-7 can regulate glioma cell migration through the AKT-ERK pathway, thereby playing an important role in glioma growth and migration.

Crystallization and preliminary X-ray analysis of the complexes between a Fab and two forms of human insulin-like growth factor II

International Nuclear Information System (INIS)

Newman, Janet; Cohen, Edward H.; Cosgrove, Leah; Kopacz, Kris; Dransfield, Daniel T.; Adams, Timothy E.; Peat, Thomas S.

2009-01-01

Complexes of both hIGF-II and hIGF-IIE with a Fab have been crystallized and investigated by X-ray analysis. Elevated expression of insulin-like growth factor II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon and liver cancer. As IGF-II can deliver a mitogenic signal through both the type 1 insulin-like growth factor receptor (IGF-IR) and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is an attractive therapeutic option. One method of doing this would be to find antibodies that bind tightly and specifically to the peptide, which could be used as protein therapeutics to lower the peptide levels in vivo and/or to block the peptide from binding to the IGF-IR or IR-A. To address this, Fabs were selected from a phage-display library using a biotinylated precursor form of the growth factor known as IGF-IIE as a target. Fabs were isolated that were specific for the E-domain C-terminal extension and for mature IGF-II. Four Fabs selected from the library were produced, complexed with IGF-II and set up in crystallization trials. One of the Fab–IGF-II complexes (M64-F02–IGF-II) crystallized readily, yielding crystals that diffracted to 2.2 Å resolution and belonged to space group P2 1 2 1 2 1 , with unit-cell parameters a = 50.7, b = 106.9, c = 110.7 Å. There was one molecule of the complete complex in the asymmetric unit. The same Fab was also crystallized with a longer form of the growth factor, IGF-IIE. This complex crystallized in space group P2 1 2 1 2 1 , with unit-cell parameters a = 50.7, b = 107, c = 111.5 Å, and also diffracted X-rays to 2.2 Å resolution

Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls.

Science.gov (United States)

Legro, Richard S; Castracane, V Daniel; Kauffman, Robert P

2004-02-01

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.

Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts

International Nuclear Information System (INIS)

Flier, J.S.; Usher, P.; Moses, A.C.

1986-01-01

Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [ 3 H]thymidine into DNA in these cells, the identify of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody αIR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125 I-labeled IGF-I but not 125 I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. αIR-3 competitively inhibits IGF-I-mediated stimulation of [ 3 H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of αIR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of 3 H]thymidine incorporation is not inhibited by αIR-3. However, the incremental effects of higher concentrations (> 1 μg/ml) of insulin on [ 3 H]thymidine incorporation are inhibited by αIR-3. αIR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself

Peripheral nervous system insulin resistance in ob/ob mice

Science.gov (United States)

2013-01-01

Background A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Results The results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. Conclusions These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy. PMID:24252636

Reduced Insulin/Insulin-like Growth Factor-1 Signaling and Dietary Restriction Inhibit Translation but Preserve Muscle Mass in Caenorhabditis elegans

Energy Technology Data Exchange (ETDEWEB)

Depuydt, Geert; Xie, Fang; Petyuk, Vladislav A.; Shanmugam, Nilesh; Smolders, Arne; Dhondt, Ineke; Brewer, Heather M.; Camp, David G.; Smith, Richard D.; Braeckman, Bart P.

2013-09-03

Reduced signaling through the C. elegans insulin/IGF1 like tyrosine kinase receptor daf2 and dietary restriction via bacterial dilution are two well-characterized lifespan-extending interventions that operate in parallel or through (partially) independent mechanisms. Using accurate mass and time tag LCMS/MS quantitative proteomics we detected that the abundance of a large number of ribosomal subunits is decreased in response to dietary restriction as well as in the daf2(e1370) insulin/IGF1 receptor mutant. In addition, general protein synthesis levels in these long-lived worms are repressed. Surprisingly, ribosomal transcript levels were not correlated to actual protein abundance, suggesting that posttranscriptional regulation determines ribosome content. Proteomics also revealed increased presence of many structural muscle cell components in long-lived worms, which appears to result from prioritized preservation of muscle cell volume in nutrient-poor conditions or low insulin-like signaling. Activation of DAF16, but not diet-restriction, stimulates mRNA expression of muscle-related genes to prevent muscle atrophy. Important daf2 specific proteome changes include overexpression of aerobic metabolism enzymes and a general activation of stress responsive and immune defense systems, while increased abundance of many protein subunits of the proteasome core complex is a DR-specific characteristic.

Metabolic syndrome, insulin resistance and other cardiovascular risk factors in university students

Directory of Open Access Journals (Sweden)

José Bonifácio Barbosa

2016-04-01

Full Text Available Abstract A cross-sectional population-based study using questionnaire and anthropometric data was conducted on 968 university students of São Luís, Brazil, from which 590 showed up for blood collection. In the statistical analysis the Student t-test, Mann-Whitney and chi-square tests were used. The prevalence of metabolic syndrome by the Joint Interim Statement (JIS criteria was 20.5%, almost three times more prevalent in men (32.2% than in women (13.5% (P < 0.001. The prevalence of insulin resistance was 7.3% and the prevalence of low HDL-cholesterol was high (61.2%, both with no statistically significant differences by sex. Men showed a higher percentage of smoking, overweight, high blood pressure, high blood glucose and increased fasting hypertriglyceridemia. Women were more sedentary. University students of private institutions had higher prevalences of sedentary lifestyle, obesity, abdominal obesity, elevated triglycerides and metabolic syndrome than students from public institutions. High prevalences of metabolic syndrome, insulin resistance and other cardiovascular risk factors were found in this young population. This suggests that the burden of these diseases in the future will be increased.

Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children.

Science.gov (United States)

Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R; Mlcak, Ronald P; Qian, Ting; Chinkes, David L; Herndon, David N

2010-06-01

To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. Prospective, randomized study. An acute pediatric burn unit in a tertiary teaching hospital. Children, 4-18 yrs old, with total body surface area burned > or =40% and who arrived within 1 wk after injury were enrolled in the study. Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 +/- 124 to 1925 +/- 291 kcal/m(2) x day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 +/- 0.8 conventional insulin therapy vs. 6.8 +/- 0.9 mg/kg x min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 +/- 1.3 intensive insulin therapy versus 4.8 +/- 0.6 mg/kg x min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 +/- 0.9 vs. 2.5 +/- 0.6 mg/kg x min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 +/- 0.1 to 1.7 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .004; and 0.7 +/- 0.1 to 1.3 +/- 0.1 microm O(2)/CS/mg protein/min for state 4, p protocol improves insulin sensitivity and mitochondrial

Association of Tumor Growth Factor-β and Interferon-γ Serum Levels With Insulin Resistance in Normal Pregnancy.

Science.gov (United States)

Sotoodeh Jahromi, Abdolreza; Sanie, Mohammad Sadegh; Yusefi, Alireza; Zabetian, Hassan; Zareian, Parvin; Hakimelahi, Hossein; Madani, Abdolhossien; Hojjat-Farsangi, Mohammad

2015-09-28

Pregnancy is related to change in glucose metabolism and insulin production. The aim of our study was to determine the association of serum IFN-γ and TGF- β levels with insulin resistance during normal pregnancy. This cross sectional study was carried out on 97 healthy pregnant (in different trimesters) and 28 healthy non-pregnant women. Serum TGF-β and IFN- γ level were measured by ELISA method. Pregnant women had high level TGF-β and low level IFN-γ as compared non-pregnant women. Maternal serum TGF-β concentration significantly increased in third trimester as compared first and second trimester of pregnancy. Maternal serum IFN-γ concentration significantly decreased in third trimester as compared first and second trimester of pregnancy. Pregnant women exhibited higher score of HOMA IR as compared non-pregnant women. There were association between gestational age with body mass index (r=0.28, P=0.005), TGF-β (r=0.45, PInsulin resistance and TGF-β (r=0.17, p=0.05). Our findings suggest that changes in maternal cytokine level in healthy pregnant women were anti-inflammatory. Furthermore, Tumor Growth Factor-β appears has a role in induction insulin resistance in healthy pregnant women. However, further studies needed to evaluate role of different cytokines on insulin resistance in normal pregnancy.

Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers.

Science.gov (United States)

Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke; Solomon, Thomas P J; Lehrskov-Schmidt, Lars; Holst, Jens Juul; Møller, Kirsten

2013-11-01

Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. Copyright © 2013 John Wiley & Sons, Ltd.

Experiments on the inclusion of insulin in lecithin microvesicles using 125I insulin and 131I lecithin as indicators

International Nuclear Information System (INIS)

Sarrach, D.; Lachmann, U.; Zipper, J.; Axt, J.; Akademie der Wissenschaften der DDR, Berlin. Inst. fuer Wirkstofforschung)

1980-01-01

Egg lecithin was labelled with 131 ICl and used together with 125 I insulin for studying the insulin inclusion in lecithin monolayer liposomes. The application of ultrasonics led to the formation of insulin-containing microvesicles which were characterized by electron microscopy and gel chromatography. With growing insulin concentration the yield of bound insulin increased to a value comparable to the included water volume. In the presence of lecithin insulin disintegration by ultrasonics was strongly reduced The bound insulin proved to be in good immunological state. (author)

Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects

DEFF Research Database (Denmark)

Rasmussen, M H; Hvidberg, A; Juul, A

1995-01-01

levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9...... using anthropometric measurements and dual energy x-ray absorptiometry scanning (DXA). In the obese subjects, 24-h spontaneous GH release profiles and the GH responses to insulin-induced hypoglycemia and L-arginine as well as basal IGF-I levels and the IGF-I/IGFBP-3 molar ratio were decreased, whereas...

Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action.

Science.gov (United States)

Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob; Kahn, C Ronald; Emanuelli, Brice

2018-07-01

Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1 -/- and IRS-2 -/- mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1. These regulated sites included previously reported substrates of the insulin/IGF-1 signalling pathway, as well as novel substrates including Nuclear Factor I X and Semaphorin-4B. In silico prediction suggests the protein kinase B (PKB), protein kinase C (PKC), and cyclin-dependent kinase (CDK) as the main mediators of these phosphorylation events. Importantly, we found preferential phosphorylation patterns depending on the presence of either IRS-1 or IRS-2, which was associated with specific sets of kinases involved in signal transduction downstream of these substrates such as PDHK1, MAPK3, and PKD1 for IRS-1, and PIN1 and PKC beta for IRS-2. Overall, by generating a comprehensive phosphoproteomic profile from brown preadipocyte cells in response to IGF-1 stimulation, we reveal both common and distinct insulin/IGF-1 signalling events mediated by specific IRS proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of Avocado Soybean Unsaponifiables on Insulin Secretion and Insulin Sensitivity in Patients with Obesity

Directory of Open Access Journals (Sweden)

Esperanza Martínez-Abundis

2013-10-01

Full Text Available Aim: To evaluate the effect of avocado soybean unsaponifiables (ASU on insulin secretion and insulin sensitivity in patients with obesity. Methods: A randomized, double-blind, placebo-controlled, clinical trial was carried out in 14 obese adult volunteers. After random allocation of the intervention, 7 patients received 300 mg of ASU or placebo during a fasting state for 3 months. A metabolic profile including IL-6 and high-sensitivity C-reactive protein (hs-CRP levels was carried out prior to the intervention. A hyperglycemic-hyperinsulinemic clamp technique was used to assess insulin secretion and insulin sensitivity phases. Mann-Whitney U test and Wilcoxon test were performed for statistical analyses. The study was approved by the local ethics committee of our institution. Results: At baseline, both groups were similar according to clinical and laboratory characteristics. There was no significant difference in insulin secretion and insulin sensitivity with ASU. Conclusions: ASU administration for 3 months did not modify insulin secretion and insulin sensitivity in patients with obesity.

Fluvastatin increases insulin-like growth factor-1 gene expression in rat model of metabolic syndrome

International Nuclear Information System (INIS)

Mansy, Wael H.; Sourour, Doaa A.; Shaker, Olfat G.; Mahfouz, Mahmoud M.

2008-01-01

Insulin-like growth factor-1 (IGF-1) was found to have a role in both glucose homeostasis and cardiovascular diseases. The present study was designed to compare the effects of fluvastatin and metformin on IGF-1 mRNA expression within the liver and other individual components of the metabolic syndrome induced in rats by high fructose feeding. Rats fed 60% fructose in diet for 6 weeks were treated daily with fluvastatin (3.75 mg/kg/day) during the last two weeks and were compared with untreated fructose fed group. Fasting levels of plasma cholesterol, triglyceride, glucose, insulin, nitric oxide products, IGF-1 mRNA within the liver as well as systolic blood pressure and body weight were determined. Compared to control rats, the fructose fed group developed hypertension, hyperlipidemia, hyperinsulinemia, hyperglycemia and endothelial dysfunction as well as decreased levels of plasma IGF-1 and its mRNA within the liver. Fructose fed rats treated with fluvastatin or metformin for 2 weeks showed significant decrease in plasma cholesterol, triglyceride, insulin and glucose levels compared to untreated fructose fed group. Also, both drugs increased significantly plasma levels of nitric oxide products and IGF-1 together with significant increase in IGF-1 mRNA within the liver. However, only metformin treated rats showed significant decrease in systolic blood pressure compared to fructose fed group. This study showed that in a rat model of insulin resistance, fluvastatin improves the metabolic profile and increases plasma level of IGF-1 and its gene expression as effective as metformin. (author)

Chronic hepatitis C infection is associated with insulin resistance and lipid profiles.

Science.gov (United States)

Dai, Chia-Yen; Yeh, Ming-Lun; Huang, Chung-Feng; Hou, Chen-Hsiu; Hsieh, Ming-Yen; Huang, Jee-Fu; Lin, I-Ling; Lin, Zu-Yau; Chen, Shinn-Chern; Wang, Liang-Yen; Chuang, Wan-Long; Yu, Ming-Lung; Tung, Hung-Da

2015-05-01

Chronic hepatitis C virus (HCV) infection has been suggested to be associated with non-insulin-dependent diabetes mellitus and lipid profiles. This study aimed to investigate the possible relationships of insulin resistance (IR) and lipid profiles with chronic hepatitis C (CHC) patients in Taiwan. We enrolled 160 hospital-based CHC patients with liver biopsy and the 480 controlled individuals without CHC and chronic hepatitis B from communities without known history of non-insulin-dependent diabetes mellitus. Fasting plasma glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), alanine aminotransferase, and serum insulin levels, and homeostasis model assessment (HOMA-IR) were tested. When comparing factors between CHC patients, and sex- and age-matched controls who had no HCV infection, patients with HCV infection had a significantly higher alanine aminotransferase level, fasting plasma glucose level, insulin level, and HOMA-IR (P C and LDL-C levels (all P  2.5]), a high body mass index, TGs, and HCV RNA level are independent factors significantly associated with high HOMA-IR in multivariate logistic analyses. Chronic HCV infection was associated with metabolic characteristics including IR and lipid profile. IR was also associated with virological characteristics. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Insulin resistance in polycystic ovary syndrome

OpenAIRE

Hutchison, Samantha Kate

2017-01-01

Polycystic ovary syndrome (PCOS) affects 8-18% of women, presenting a major public health and economic burden. Women with PCOS have insulin resistance (IR) independent of obesity. IR has an integral aetiological role in the reproductive and metabolic consequences of PCOS including obesity, type 2 diabetes (diabetes) and cardiovascular risk factors. Excess weight exacerbates IR and increases PCOS severity. PCOS combined with obesity presents a useful model to study IR before confounding hyperg...

The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

Directory of Open Access Journals (Sweden)

Kurt Warnhoff

2014-10-01

Full Text Available The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

Selective Insulin Resistance in Adipocytes*

Science.gov (United States)

Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

2015-01-01

Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

Insulin secretion and action in North Indian women during pregnancy

DEFF Research Database (Denmark)

Arora, G P; Almgren, P; Thaman, R G

2017-01-01

. RESULTS: Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women......AIM: The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999...... independently associated with increased insulin resistance. CONCLUSIONS: Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more...

Insulin secretion and sensitivity in space flight: diabetogenic effects

Science.gov (United States)

Tobin, Brian W.; Uchakin, Peter N.; Leeper-Woodford, Sandra K.

2002-01-01

Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone.

Science.gov (United States)

Farmer, John T; Weigent, Douglas A

2007-01-01

In the present study, we report the upregulation of functional IGF-2Rs in cells overexpressing growth hormone (GH). EL4 lymphoma cells stably transfected with an rGH cDNA overexpression vector (GHo) exhibited an increase in the binding of (125)I-IGF-2 with no change in the binding affinity compared to vector alone controls. An increase in the expression of the insulin-like growth factor-2 receptor (IGF-2R) in cells overexpressing GH was confirmed by Western blot analysis and IGF-2R promoter luciferase assays. EL4 cells produce insulin-like growth factor-2 (IGF-2) as detected by the reverse transcription-polymerase chain reaction (RT-PCR); however, no IGF-2 protein was detected by Western analysis. The increase in the expression of the IGF-2R resulted in greater levels of IGF-2 uptake in GHo cells compared to vector alone controls. The data suggest that one of the consequences of the overexpression of GH is an increase in the expression of the IGF-2R.

The Barbados Insulin Matters (BIM study: Barriers to insulin therapy among a population-based sample of people with type 2 diabetes in the Caribbean island of Barbados

Directory of Open Access Journals (Sweden)

Charles G. Taylor, Jr.

2017-06-01

Conclusions: Multiple factors related to patient beliefs and attitudes need to be considered and addressed when initiating insulin in order to minimise psychological insulin resistance and delay. Patients using insulin had less negative perceptions than those not on insulin.

Vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness

NARCIS (Netherlands)

Ameri, P.; Canepa, M.; Fabbi, P.; Leoncini, G.; Milaneschi, Y.; Mussap, M.; AlGhatrif, M.; Balbi, M.; Viazzi, F.; Murialdo, G.; Pontremoli, R.; Brunelli, C.; Ferrucci, L.

2014-01-01

Objective: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT

Suppressive Effects of Insulin on Tumor Necrosis Factor-Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus.

Science.gov (United States)

Hamada, Daisuke; Maynard, Robert; Schott, Eric; Drinkwater, Christopher J; Ketz, John P; Kates, Stephen L; Jonason, Jennifer H; Hilton, Matthew J; Zuscik, Michael J; Mooney, Robert A

2016-06-01

Obesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity-associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance. The effects of TNF and insulin on catabolic gene expression were determined in fibroblast-like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high-fat (HF) diet-fed obese mice with type 2 DM and TNF-knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM. Insulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose-dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF-knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin-dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM. TNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin

Dietary fiber, plasma insulin, and obesity.

Science.gov (United States)

Albrink, M J

1978-10-01

The relationship between obesity, insulin resistance, and hyperinsulinemia is briefly reviewed. The possibility is considered that excess insulin secretion is the cause rather than the result of insulin resistance and obesity. Glucose administration is one of the most frequently studied of those factors known to stimulate insulin secretion. Much less well documented is the fact that meals of equal protein, fat, and carbohydrate content may cause different responses of plasma glucose and insulin. An experiment is reported in which the effects of a high-carbohydrate, high-fiber meal administered to seven healthy young adults were compared with the effects of a meal equally high in carbohydrate but composed largely of glucose in liquid formula form. The high-fiber meal caused an insulin rise less than half that caused by the liquid formula meal although the plasma glucose response to the two meals was not significantly different. The hypothesis is proposed that a high-carbohydrate, fiber-depleted diet, high in simple sugars, by repeatedly stimulating an excessive insulin response, may lead to insulin resistance and obesity in susceptible individuals and may play a role in the common occurrence of obesity in industrialized societies.

Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk

DEFF Research Database (Denmark)

Pearce, Celeste Leigh; Doherty, Jennifer A; Van Den Berg, David J

2011-01-01

The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial...... disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at Pcases and 5382 additional controls and were able to independently replicate our initial...... findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81–0.93, P-trend=7.4 × 10-5). No heterogeneity of effect across study centers was observed (phet=0.25). IGF2 is emerging...

Direct demonstration of rapid insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like growth factor II degradation by modulating the IGF-II receptor recycling process

International Nuclear Information System (INIS)

Oka, Y.; Rozek, L.M.; Czech, M.P.

1985-01-01

The photoactive insulin-like growth factor (IGF)-II analogue 4-azidobenzoyl- 125 I-IGF-II was synthesized and used to label specifically and covalently the Mr = 250,000 Type II IGF receptor. When rat adipocytes are irradiated after a 10-min incubation with 4-azidobenzoyl- 125 I-IGF-II at 10 degrees C and immediately homogenized, most of the labeled IGF-II receptors are associated with the plasma membrane fraction, indicating that receptors accessible to the labeling reagent at low temperature are on the cell surface. However, when the photolabeled cells are incubated at 37 degrees C for various times before homogenization, labeled IGF-II receptors are rapidly internalized with a half-time of 3.5 min as evidenced by a loss from the plasma membrane fraction and a concomitant appearance in the low density microsome fraction. The steady state level of cell surface IGF-II receptors in the presence or absence of IGF-II remains constant under these conditions, demonstrating that IGF-II receptors rapidly recycle back to the cell surface at the same rate as receptor internalization. Using the above methodology, it is shown that acute insulin action: 1) increases the steady state number of cell surface IGF-II receptors; 2) increases the number of ligand-bound IGF-II receptors that are internalized per unit of time; and 3) increases the rate of cellular 125 I-IGF-II degradation by a process that is blocked by anti-IGF-II receptor antibody

Comparison of plasma pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP-4), chitinase-3-like protein 1 (YKL-40) and brain-derived neurotrophic factor (BDNF) for the identification of insulin resistance.

Science.gov (United States)

Toloza, F J K; Pérez-Matos, M C; Ricardo-Silgado, M L; Morales-Álvarez, M C; Mantilla-Rivas, J O; Pinzón-Cortés, J A; Pérez-Mayorga, M; Arévalo-García, M L; Tolosa-González, G; Mendivil, C O

2017-09-01

To evaluate and compare the association of four potential insulin resistance (IR) biomarkers (pigment-epithelium-derived factor [PEDF], retinol-binding-protein-4 [RBP-4], chitinase-3-like protein 1 [YKL-40] and brain-derived neurotrophic factor [BDNF]) with objective measures of IR. We studied 81 subjects with different metabolic profiles. All participants underwent a 5-point OGTT with calculation of multiple IR indexes. A subgroup of 21 participants additionally underwent a hyperinsulinemic-euglycemic clamp. IR was defined as belonging to the highest quartile of incremental area under the insulin curve (iAUCins), or to the lowest quartile of the insulin sensitivity index (ISI). PEDF was associated with adiposity variables. PEDF and RBP4 increased linearly across quartiles of iAUCins (for PEDF p-trend=0.029; for RBP-4 p-trend=0.053). YKL-40 and BDNF were not associated with any adiposity or IR variable. PEDF and RBP-4 levels identified individuals with IR by the iAUCins definition: A PEDF cutoff of 11.9ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6ng/mL had 70% sensitivity and 57% specificity. In multiple regression analyses simultaneously including clinical variables and the studied biomarkers, only BMI, PEDF and RBP-4 remained significant predictors of IR. Plasma PEDF and RBP4 identified IR in subjects with no prior diagnosis of diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of insect behavior via the insulin-signaling pathway