Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time- and dose-dependent manner. Tumor necrosis factor (TNF)-alpha treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-alpha and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-alpha on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes.
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PMID:Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo. 1723 15

Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson-Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve beta-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.
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PMID:IGF-I treatment of insulin resistance. 1778 98

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.
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PMID:Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. 1790 1

Insulin-like growth factor (IGF-1) is a polypeptide of 70 amino acids. The circulatory form of IGF-1 is synthesised in the liver. The metabolic activity of IGF-1 is regulated by 6 IGF-binding proteins (BPs), the most important being IGFBP-3. IGF-1 acts via its own receptor, which resembles that of insulin. It has been demonstrated that the effects of growth hormone (GH) on protein metabolism, including growth and the effect on nerve tissue versus trophic effects, are mediated by IGF-1, whereas these 2 hormones are antagonistic in their effects on insulin and some aspects of lipid metabolism. This paper reviews present knowledge on the physiological role of IGF-1 and clinical effects of recombinant IGF-1 (somatomedin-1). The biosynthesis of somatomedin-1 in 1986 enabled the initiation of clinical trials. Somatomedin-1 has many potential uses in the clinic. The most important is replacement therapy in primary IGF-1 deficiency, such as Laron syndrome (primary GH resistance or insensitivity) and in patients who have developed antibodies to hGH. In Laron syndrome, which is characterised by dwarfism, somatomedin-1 stimulates growth and increases muscle and bone mass, as well as normalising blood chemistry. In types 1 and 2 (insulin-dependent and non-insulin-dependent) diabetes mellitus, somatomedin-1 increases the sensitivity to insulin and improves glucose utilisation. Experimental studies indicate that IGF-1 has a role in nerve tissue metabolism, and in humans may contribute to healing of injured nerve tissue. Other current clinical trials using the anabolic properties of somatomedin-1 are studying its effect on osteoporosis, catabolic states (burns, post-operation, AIDS) and haematopoietic disorders. Adverse effects of somatomedin-1 appear to be related to overdosage. In conclusion, somatomedin-1 is an important hormone which has a promising role as replacement therapy and appears to have many other potential applications in the clinic.
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PMID:Somatomedin-1 (recombinant insulin-like growth factor-1): clinical pharmacology and potential treatment of endocrine and metabolic disorders. 1803 Nov 15

Insulin-like growth factors (IGFs) constitute a system of peptides that promote mitosis, growth, and organ development by both paracrine and endocrine pathways, their bioavailability being modulated by at least six specific IGF-binding proteins (IGFBP). In type 1 diabetic pregnancies IGF-I and -II in maternal serum are associated with birth weight and their action modulated by IGFBP-3 and phosphorylated isoforms of IGFBP-1. Pregnancy-associated plasma protein-A (PAPP-A), a proteolytic substance of IGFBPs, is probably a modulator in early diabetic pregnancy while human placental growth hormone (hPGH) regulates the effect of IGF-I in pregnancy of diabetic and non-diabetic pregnancies. IGF-I in maternal serum increases concomitantly with progression of diabetic retinopathy despite good glycemic control in pregnancy. The role of the new insulin analogues in improving this effect has yet to be established. Retinopathy in pregnancy is associated with an elevated level of fibroblast growth factor-2 (FGF-2) and highly-phosphorylated IGFBP-1, the latter further increasing the level of free IGF-I and FGF-2. Thus, the effect on development of retinopathy may be directly mediated by IGF-I or indirectly by a modifying effect of IGFBP-3 and phosphorylated isoforms of IGFBP-1 with FGF-2 as a mediator.
Curr Diabetes Rev 2007 Aug
PMID:The clinical significance of IGF-I in maternal serum during pregnancy in type 1 diabetes. 1822 Jun 71

Data on the functionalities of L-carnitine on obesity, diabetes, and as an ergogenic aid are summarized as follows: Obesity: Total lipid, triglyceride, and total protein increased during the 3T3-L1 cell differentiation. However, nonesterified carnitine (NEC), acid-soluble acylcarnitine (ASAC), and acid-insoluble acylcarnitine (AIAC) concentrations were lower in the differentiated 3T3-L1 cells. In addition, the exogenously added carnitine inhibited the increases in triglyceride and total lipid levels. In an animal study, L-carnitine supplementation reduced serum leptin and abdominal fat weight caused by high-fat diet in C57BL/6J mice. Diabetes: In an animal study, streptozptpcin-induced diabetic rats had markedly lower IGFBP-3 than normal rats, and IGFBP-3 was increased by L-carnitine treatment, demonstrating that L-carnitine treatment of diabetic rats modulates the IGFs/IGFBPs axis. A study of Korean diabetics indicated that there is a remarkable abnormality in lipid and carnitine metabolism in Korean diabetic patients. Ergogenic aids: We investigated the separate and combined effects of L-carnitine and antioxidant supplementation on carnitine and lipid concentrations in trained and non-trained animal and humans. Supplementation of L-carnitine and antioxidants improve lipid profiles and exercise ability in exercise-trained rats. Also, both exercise training and supplementation of carnitine and antioxidants improved lipid profiles and carnitine metabolism in humans, suggesting that carnitine and antioxidant supplementation may improve exercise performance.
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PMID:Effects of L-carnitine on obesity, diabetes, and as an ergogenic aid. 1829 64

Insulin-like growth factors (IGF-I and II) are important endocrine, paracrine and autocrine mediators of physiological growth. They promote cellular proliferation, survival and differentiation. Their effects are mediated mainly through the IGF-I receptor, but IGFs also bind to the IGF-II/mannose 6-phosphate and insulin receptors. IGF activity is modulated by a family of six high-affinity IGF binding proteins (IGFBPs); in most situations, IGFBPs inhibit IGF actions but they may also enhance them. Assays are now available for IGF-I, IGF-II and individual IGFBPs. IGF-I and IGFBP-3 assays have some utility in the diagnosis and management of acromegaly and growth hormone deficiency. There is a large body of in vitro and in vivo evidence supporting a pathogenic role for alterations in the IGF system in many diseases, including diabetes, cancer, cardiovascular disease and neuromuscular disease. More recently, epidemiological studies have linked high IGF-I levels with some cancers and low IGF-I levels with ischaemic heart disease. Preliminary studies of recombinant IGF-I as a treatment for diabetes, osteoporosis and neuromuscular disease have been performed in humans. In contrast, there is considerable interest in developing IGF inhibitors for the treatment of cancer. This apparent paradox highlights the need to develop therapeutics beyond the natural ligands and inhibitors, with characteristics such as ligand and tissue specificity. This will only become possible as we increase our understanding of this complex system. Additionally, as IGF and IGFBP assays are becoming more readily available, their role in the diagnosis and monitoring of diseases should be more clearly defined in the near future.
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PMID:The insulin-like growth factor system: towards clinical applications. 1845 8

One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.
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PMID:Regulation of insulin-response element binding protein-1 in obesity and diabetes: potential role in impaired insulin-induced gene transcription. 1856 19

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
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PMID:(-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. 1913 73

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.
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PMID:Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study. 1934 87


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