Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Triglyceride-rich lipoprotein (TRL) production was studied in Zucker diabetic fatty (ZDF) rats, a model of insulin-resistant type 2 diabetes progression. TRL production was measured in vivo by blocking catabolism with Triton WR-1339. Ten-week ZDF rats are hyperinsulinemic with increased TRL production [both triglyceride and apolipoprotein B (apoB)]. Twenty-week ZDF rats are insulinopenic, and TRL production is similar to lean controls. Insulin infusion suppresses glucose and free fatty acids in 10- and 20-wk ZDF rats. Increased TRL production is not reduced by insulin in 10-wk rats; however, at 20 wk, TRL production is suppressed by insulin. In vitro studies with hepatocytes derived from 10-wk ZDF rats showed minimal insulin dose effects on apoB secretion compared with the response and sensitivity of hepatocytes derived from 20-wk ZDF and control lean rats. Hepatic sterol regulatory-binding protein (SREBP)-1c mRNA levels are increased at 10 wk but return to control levels at 20 wk. ApoB mRNA levels are similar to lean controls at 10 and 20 wk. The following two mechanisms for hypertriglyceridemia associated with hyperinsulinemia are suggested: increased TRL synthesis and loss of TRL suppression. Increased triglyceride production in hyperinsulinemic rats likely relates to increased expression of SREBP-1c, whereas increased apoB production involves posttranscriptional processes.
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PMID:Altered triglyceride-rich lipoprotein production in Zucker diabetic fatty rats. 1497 3

The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to transactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio = 1.42 [1.11-1.82], P = 0.005) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly higher levels of total and LDL cholesterol (P < 0.05) compared with wild-type individuals. In summary, we have conducted the first study of the SREBP-1c gene as a candidate for human insulin resistance. Although the rare mutations identified were functionally silent in the assays used, we obtained some evidence, which requires conformation in other populations, that a common variant in the SREBP-1c gene might influence diabetes risk and plasma cholesterol level.
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PMID:Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes. 1498 72

A critical defect in type 2 diabetes is impaired insulin-stimulated glucose transport and metabolism in muscle and adipocytes. To understand the metabolic adaptations this elicits, we generated mice with targeted disruption of the GLUT4 glucose transporter in both adipocytes and muscle (AMG4KO). In contrast to total body GLUT4-null mice, AMG4KO mice exhibit normal growth, development, adipose mass, and longevity. They develop fasting hyperglycemia and glucose intolerance and are at risk for greater insulin resistance than mice lacking GLUT4 in only one tissue. Hyperinsulinemic-euglycemic clamp studies showed a 75% decrease in glucose infusion rate and markedly reduced 2-deoxyglucose uptake into skeletal muscle (85-90%) and white adipose tissue (65%). However, AMG4KO mice adapt by preferentially utilizing lipid fuels, as evidenced by a lower respiratory quotient and increased clearance of lipids from serum after oral lipid gavage. While insulin action on hepatic glucose production and gluconeogenic enzymes is impaired, hepatic glucokinase expression, incorporation of 14C-glucose into lipids, and hepatic VLDL-triglyceride release are increased. The lipogenic activity may be mediated by increased hepatic expression of SREBP-1c and acetyl-CoA carboxylase. Thus, inter-tissue communication results in adaptations to impaired glucose transport in muscle and adipocytes that involve increased hepatic glucose uptake and lipid synthesis, while muscle adapts by preferentially utilizing lipid fuels. Genetic determinants limiting this "metabolic flexibility" may contribute to insulin resistance and type 2 diabetes in humans.
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PMID:GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. 1557 87

BACKGROUND: Optimal pancreatic beta-cell function is essential for the regulation of glucose homeostasis in both humans and animals and its impairment leads to the development of diabetes. Type 2 diabetes is a polygenic disease aggravated by environmental factors such as low physical activity or a hypercaloric high-fat diet. RESULTS: Free fatty acids represent an important factor linking excess fat mass to type 2 diabetes. Several studies have shown that chronically elevated free fatty acids have a negative effect on beta-cell function leading to elevated insulin secretion basally but with an impaired response to glucose. The transcription factors PPARalpha, PPARgamma and SREBP-1c respond to changing fat concentrations in tissues, thereby coordinating the genomic response to altered metabolic conditions to promote either fat storage or catabolism. These transcription factors have been identified in beta-cells and it appears that each may exert influence on beta-cell function in health and disease. CONCLUSION: The role of the PPARs and SREBP-1c as potential mediators of lipotoxicity is an emerging area of interest.
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PMID:Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic beta-cell function. 1563 55

Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.
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PMID:Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells. 1567 7

Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.
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PMID:Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. 2780 76

GLUT2 is mainly expressed in the liver, beta-cells of the pancreas, and the basolateral membrane of kidney proximal tubules and plays an important role in glucose homeostasis in living organisms. The transcription of the GLUT2 gene is known to be upregulated in the liver during postprandial hyperglycemic states or in type 2 diabetes. However, a molecular mechanism by which glucose activates GLUT2 gene expression is not known. In this study, we report evidence that sterol response element-binding protein (SREBP)-1c plays a key role in glucose-stimulated GLUT2 gene expression. The GLUT2 promoter reporter is activated by SREBP-1c, and the activation is inhibited by a dominant-negative form of SREBP-1c (SREBP-1c DN). Adenoviral expression of SREBP-1c DN suppressed glucose-stimulated GLUT2 mRNA level in primary hepatocytes. An electrophoretic mobility shift assay and mutational analysis of the GLUT2 promoter revealed that SREBP-1c binds to the -84/-76 region of the GLUT2 promoter. Chromatin immunoprecipitation revealed that the binding of SREBP-1c to the -84/-76 region was increased by glucose concentration in a dose-dependent manner. These results indicate that SREBP-1c mediates glucose-stimulated GLUT2 gene expression in hepatocytes.
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PMID:Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. 1591 89

The reduction in insulin secretory capacity and beta-cell mass observed in type 2 diabetes is thought to be caused by glucolipotoxicity secondary to hyperglycemia and hyperlipidemia. Our aim in this study was to elucidate the underlying molecular mechanisms. We found a strong correlation between chronic high-glucose treatment and SREBP-1c activation in INS-1 cells and rat islets. Both high-glucose treatment and SREBP-1c activation in INS-1 cells resulted in lipid accumulation, impaired glucose-stimulated insulin secretion, apoptosis, and strikingly similar gene expression patterns, including upregulation of lipogenic and pro-apoptotic genes and downregulation of IRS2, Bclxl and Pdx1. These lipotoxic effects of high glucose were largely prevented by induction of a dominant-negative mutant of SREBP-1c, suggesting SREBP-1c is a major factor responsible for beta cell glucolipotoxicity. Moreover, overexpression of another lipogenic transcription factor, ChREBP, in INS-1 cells did not cause lipotoxicity. Intriguingly, chronic high glucose treatment in INS-1 cells led to pronounced induction of the ER stress marker genes, BIP and Chop10. Treatment of rat islets with both chronic high glucose and two ER stress inducers, thapsigargin and tunicamycin, enhanced SREBP-1 binding to the human IRS2 promoter. These results suggest that SREBP-1 activation caused by ER stress is implicated in beta-cell glucolipotoxicity.
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PMID:ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. 1609 21

Intramuscular triglyceride (IMTG) deposition in skeletal muscle is associated with obesity and type 2 diabetes (T2DM) and is thought to be related to insulin resistance (IR). Curiously, despite enhanced skeletal muscle insulin sensitivity, highly trained athletes and calorie-restricted (CR) monkeys also have increased IMTG. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate the biosynthesis of cholesterol and fatty acids. SREBP-1 is increased by insulin in skeletal muscle in vitro and in skeletal muscle of IR subjects, but SREBP-1 expression has not been examined in exercise training or calorie restriction. We examined the relationship between IMTG and SREBP-1 expression in animal models of exercise and calorie restriction. Gastrocnemius and soleus muscle biopsies were obtained from 38 Sprague-Dawley rats (18 control and 20 exercise trained). Triglyceride content was higher in the gastrocnemius and soleus muscles of the trained rats. SREBP-1c mRNA, SREBP-1 precursor and mature proteins, and fatty acid synthase (FAS) protein were increased with exercise training. Monkeys (Macaca mulatta) were CR for a mean of 10.4 years, preventing weight gain and IR. Vastus lateralis muscle was obtained from 12 monkeys (6 CR and 6 controls). SREBP-1 precursor and mature proteins and FAS protein were higher in the CR monkeys. In addition, phosphorylation of ERK1/ERK2 was increased in skeletal muscle of CR animals. In summary, SREBP-1 protein and SREBP-1c mRNA are increased in interventions that increase IMTG despite enhanced insulin sensitivity. CR and exercise-induced augmentation of SREBP-1 expression may be responsible for the increased IMTG seen in skeletal muscle of highly conditioned athletes.
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PMID:Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle. 1644 96

The uptake, biosynthesis and metabolism of cholesterol and other lipids are exquisitely regulated by feedback and feed-forward pathways in organisms ranging from Caenorhabditis elegans to humans. As endoplasmic reticulum (ER) membrane-embedded transcription factors that are activated in the Golgi apparatus, sterol regulatory element-binding proteins (SREBPs) are central to the intracellular surveillance of lipid catabolism and de novo biogenesis. The biosynthesis of SREBP proteins, their migration from the ER to the Golgi compartment, intra-membrane proteolysis, nuclear translocation and trans-activation potential are tightly controlled in vivo. Here we summarize recent studies elucidating the transcriptional and post-transcriptional regulation of SREBP-1c through nutrition and the action of hormones, particularly insulin, and the resulting implications for dyslipidemia of obesity, metabolic syndrome and type 2 diabetes.
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PMID:SREBPs: the crossroads of physiological and pathological lipid homeostasis. 1829 68


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