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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An impressive body of epidemiologic data collected over the past decade indicates that the risk of colon cancer is elevated in those with metabolic syndrome. This evidence includes studies that examined the risk of colon cancer or adenoma in relation to determinants of the metabolic syndrome (obesity, abdominal distribution of adiposity, and physical inactivity), clinical consequences of this syndrome (type 2 diabetes and hypertension), plasma or serum components of the definition of metabolic syndrome (hypertriglyceridemia, hyperglycemia, and low HDL cholesterol), and markers of hyperinsulinemia or insulin resistance (insulin and C-peptide), which is the underlying metabolic defect of the metabolic syndrome. The mechanism underlying these associations is unknown but may involve the influence of hyperinsulinemia in enhancing free or bioavailable concentrations of insulin-like growth factor-1. Future studies should also be based on better measurements of insulin resistance, beta-cell depletion, and insulin responses to better assess which aspects of insulin resistance are most closely related to the risk of colon neoplasia.
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PMID:Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. 1826 77

Patients with insulin resistance and type 2 diabetes have an excessive risk of cardiovascular disease (CVD); this increased risk is not fully explained by traditional risk factors such as hypertension and dyslipidaemias. There is now compelling evidence to suggest that abnormalities of insulin-like growth factor-I (IGF-I) and one of its binding proteins, insulin-like growth factor-binding protein-1 (IGFBP-1), occur in insulin-resistant states and may be significant factors in the pathophysiology of CVD. We reviewed articles and relevant bibliographies following a systematic search of MEDLINE for English language articles between 1966 and the present, using an initial search strategy combining the MeSH terms: IGF, diabetes and CVD. Our aim was first to review the role of IGF-I in vascular homeostasis and to explore the mechanisms by which it may exert its effects. We also present an overview of the physiology of the IGF-binding proteins, and finally, we sought to summarize the evidence to date describing the changes in the insulin/IGF-I/IGFBP-1 axis that occur in type 2 diabetes and CVD; in particular, we have focused on the potential vasculoprotective effects of both IGF-I and IGFBP-1. We conclude that this system represents an interesting and novel therapeutic target in the prevention of CVD in type 2 diabetes.
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PMID:The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. 1826 35

The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.
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PMID:Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor. 1856 89

Previous studies from this laboratory have characterized RAW117-P murine large cell B-cell lymphoma and its in vivo selected highly malignant and liver metastatic RAW117-H10 subline for their biological and biochemical properties. In this study, to understand the molecular basis of low and high metastatic behavior of these variant sublines, we have investigated the molecular phenotypes of these cells using differential display techniques and cDNA array analysis. Differential display analysis indicated a significant difference in expression of several genes between these two metastatic variant lymphoma cells. Further analyses of these cells using microarray showed an increased expression of several genes including uPAR1, CRE-BP1, Chop-10, IGF, insulin-like growth factor-IA, STAT6, Cyclin-D1, Cyclin-E, ERBB-3, Alpha NGF, Kruppel-like factor LKLF, (P)19INK4 in metastatic RAW117-H10 cells compared to parental RAW117-P cells. On the other hand, MIP1beta, CD14 antigen, Cathepsin B and MOD are expressed more in RAW117-P cells compared to RAW117-H10 cells. Differential expression of the selected genes was confirmed using semiquantitative RT-PCR techniques. The combination of plasminogen activator and its receptor and IGF-like growth factors, cell cycle regulatory molecules and transcription factors might provide an ideal environment for RAW117-H10 cells to metastasize to distant organs and colonize. Thus these results identify certain differentially expressed genes that are involved in the metastatic properties of these lymphoma cells and lay foundation for further in depth analyses to use this information to develop therapy for metastatic lymphoma.
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PMID:Differential gene expression in murine large cell B-cell lymphoma metastatic variants. 1860 72

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.
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PMID:Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control. 1877 56

Alzheimer's disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-beta or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that obesity and T2DM may contribute to, but are not sufficient to cause AD.
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PMID:Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus. 1878 Sep 65

This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic beta-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association.
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PMID:The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. 1914 87

Genome-wide association studies showed variation in insulin-like growth factor-2 binding protein 2 (IGF2BP2) to be associated with type 2 diabetes mellitus (T2DM). We examined a 20-kb region of IGF2BP2 for association with T2DM-related quantitative traits in Mexican American families of a proband with gestational diabetes mellitus (GDM) from the BetaGene study. We genotyped 14 single-nucleotide polymorphisms (SNPs) in 717 individuals from 146 families phenotyped by oral glucose tolerance test (OGTT), intravenous glucose tolerance tests (IVGTTs) with minimal model analysis, and dual-energy X-ray absorptiometry scan for percent body fat. Three SNPs and one SNP combination that captured the majority of the variation in the region were tested for association with T2DM-related quantitative traits using a variance components framework. After correction for multiple testing, rs11705701 showed association with percent body fat (P(ACT) = 0.041) with body fat decreasing approximately 1.5-2% per copy of the A allele. We next tested whether the interaction between rs11705701 and body fat was associated with T2DM-relative quantitative traits. rs11705701 was significantly associated with insulin sensitivity (Bonferroni P = 0.028) and marginally associated with OGTT 2-h insulin (Bonferroni P = 0.066) and disposition index (DI) (Bonferroni P = 0.072). We conclude that rs11705701 in IGF2BP2 is associated with body fat and this effect on body fat influences insulin resistance which may contribute to T2DM risk.
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PMID:Variation in IGF2BP2 interacts with adiposity to alter insulin sensitivity in Mexican Americans. 1914 20

We have demonstrated that 3-phosphoinositide-dependent protein kinase 1 (PDK1) contributes to signaling by insulin or insulin-like growth factor-1 (IGF-1) that is responsible for the regulation of both the number and size of pancreatic beta cells in mice. Complete ablation of PDK1 in pancreatic beta cells leads to progressive hyperglycemia as a result of loss of beta cell mass. In this study, we generated heterozygous pancreatic beta cell-specific PDK1 knockout (betaPDK1+/-) mice and fed them a high-fat diet as a model of human type 2 diabetes. The betaPDK1+/- mice exhibited normal glucose tolerance even on a high-fat diet. Further, islet morphology and beta cell mass were normal in betaPDK1+/- mice, and haploinsufficiency of PDK1 did not impair the compensatory hyperplasia of beta cells on a high-fat diet. The phosphorylation and expression of the molecules that are expressed downstream of PDK1 were similar in the islets of the betaPDK1+/- and control mice. Eventually, we concluded that glucose homeostasis and islet mass were maintained in betaPDK1+/- mice.
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PMID:Pancreatic beta cell mass preserved in heterozygous PDK1 knockout mice. 1924 67

Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be associated with cognitive impairment or early neurodegeneration. Previously, we showed that diet-induced obesity with T2DM and NASH results in mild neurodegeneration with some features of AD, including brain insulin resistance. In a companion study, we correlated obesity/T2DM/NASH-associated central nervous system (CNS) abnormalities with increased pro-ceramide gene expression in liver. Since ceramides are neurotoxic and cause insulin resistance, we directly investigated the role of ceramides as mediators of neurodegeneration using an in vitro culture model. We treated PNET2 human CNS neuronal cells with D-erythro-Ceramide analogs (C2Cer:N-acetylsphinganine and C6Cer:N-hexanoylsphinganine), or the inactive dihydroceramide analog (C2DCer) for 48 h, and probed for changes in genes and proteins that are critical to insulin/IGF signaling, and associated with neurodegeneration. Exposure to C6Cer>C2Cer impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AbetaPP-Abeta and pTau, whereas C2D had no significant effect on these parameters. CNS exposure to neurotoxic ceramides from exogenous sources, including liver, can cause neurodegeneration with impairments in insulin and IGF signaling mechanisms, similar to the findings in experimental models of obesity/T2DM, and NASH.
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PMID:Mechanisms of ceramide-mediated neurodegeneration. 1938 7


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