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)

Obesity-related increase in body fat mass is a risk factor for many diseases, including type 2 diabetes. Controlling adiposity by targeted modulation of adipocyte enzymes could offer an attractive alternative to current dietary approaches. Brown adipose tissue, which is present in rodents but not in adult humans, expresses the mitochondrial uncoupling protein 1 (UCP1) that promotes cellular energy dissipation as heat. Here, we report on the direct metabolic effects of forced UCP1 expression in white adipocytes derived from a murine (3T3-L1) preadipocyte cell line. After stable integration, the ucp1 gene product was continuously expressed during differentiation and reduced the total lipid accumulation by approximately 30% without affecting other adipocyte markers, such as cytosolic glycerol-3-phosphate dehydrogenase activity and leptin production. The expression of UCP1 also decreased glycerol output and increased glucose uptake, lactate output, and the sensitivity of cellular ATP content to nutrient removal. However, oxygen consumption and beta-oxidation were minimally affected. Together, our results suggest that the reduction in intracellular lipid by constitutive expression of UCP1 reflects a downregulation of fat synthesis rather than an upregulation of fatty acid oxidation.
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PMID:Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism. 1720 29

Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 +/- 6.6 vs. 28.9 +/- 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)beta transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.
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PMID:A functional variant of the adipocyte glycerol channel aquaporin 7 gene is associated with obesity and related metabolic abnormalities. 1735 Nov 48

The endocannabinoid system has been recently recognized as an important modulatory system in the function of brain, endocrine, and immune tissues. It appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and response to stress. The important elements of this system are: endocannabinoid receptors (types CB1 and CB2), their endogenous ligands (N-arachidonoylethanolamide, 2-arachidonoyl glycerol), enzymes involved in their synthesis and degradation, as well as cannabinoid antagonists. In humans this system also controls energy homeostasis and mainly influences the function of the food intake centers of the central nervous system and gastrointestinal tract activity. The endocannabinoid system regulates not only the central and peripheral mechanisms of food intake, but also lipids synthesis and turnover in the liver and adipose tissue as well as glucose metabolism in muscle cells. Rimonabant, a new and selective central and peripheral cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factor (metabolic syndrome) in obese patients by increasing HDL-cholesterol and adiponectin blood levels as well as decreasing LDL-cholesterol, leptin, and C-reactive protein (a proinflammatory marker) concentrations. It is therefore possible to speculate about a future clinical use of CB1 antagonists, as a means of improving gonadotrophin pulsatility and fertilization capacity as well as the prevention of cardiovasculary disease and type 2 diabetes mellitus. Drugs acting as agonists of CB1 receptors (Dronabinol, Dexanabinol) are currently proposed for evaluation as drugs to treat neurodegenerative disorders (Alzheimer's and Parkinson's diseases), epilepsy, anxiety, and stroke.
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PMID:[The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans]. 1736 78

Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.
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PMID:Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. 1738 95

The liver plays a key role for the maintenance of blood glucose homeostasis under widely changing physiological conditions. In the overnight fasted state, breakdown of hepatic glycogen and synthesis of glucose from lactate, amino acids, glycerol, and pyruvate contribute about equally to hepatic glucose production. Postprandial glucose uptake by the liver is determined by the size of the glucose load reaching the liver, the rise in insulin concentration, and the route of glucose delivery. Hepatic glycogen stores are depleted within 36 to 48 hours of fasting, but gluconeogenesis continues to provide glucose for tissues with an obligatory glucose requirement. Glucose output from the liver increases during exercise; during short-term intensive exertion, hepatic glycogenolysis is the primary source of extra glucose for skeletal muscle, and during prolonged exercise, hepatic gluconeogenesis becomes gradually more important in keeping with falling insulin and rising glucagon levels. Type 1 diabetes is accompanied by diminished hepatic glycogen stores, augmented gluconeogenesis, and increased basal hepatic glucose production in proportion to the severity of the diabetic state. The hyperglycemia of type 2 diabetes is in part caused by an overproduction of glucose from the liver that is secondary to accelerated gluconeogenesis.
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PMID:Splanchnic regulation of glucose production. 1746 53

Deteriorating islet beta-cell function is key in the progression of an impaired glucose tolerance state to overt type 2 diabetes (T2D), a transition that can be delayed by exercise. We have previously shown that trained rats are protected from heart ischemia-reperfusion injury in correlation with an increase in cardiac tissue fatty-acid oxidation. This trained metabolic phenotype, if induced in the islet, could also prevent beta-cell failure in the pathogenesis of T2D. To assess the effect of training on islet lipid metabolism and insulin secretion, female Sprague-Dawley rats were exercised on a treadmill for 90 min/d, 4 d/week, for 10 weeks. Islet fatty-acid oxidation, the expression of key lipid metabolism genes, and glucose-stimulated insulin secretion were determined in freshly isolated islets from trained and sedentary control rats after a 48 h rest period from the last exercise. Although this moderate training reduced plasma glycerol, free fatty acids, and triglyceride levels by about 40%, consistent with reduced lipolysis from adipose tissue, it did not alter islet fatty-acid oxidation, nor the islet expression of key transcription factors and enzymes of lipid metabolism. The training also had no effect on glucose-stimulated insulin secretion or its amplification by free fatty acids. In summary, chronic exercise training did not cause an intrinsic change in islet lipid metabolism. Training did, however, substantially reduce the exposure of islets to exogenous lipid, thereby providing a potential mechanism by which exercise can prevent islet beta-cell failure leading to T2D.
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PMID:Circulating lipids are lowered but pancreatic islet lipid metabolism and insulin secretion are unaltered in exercise-trained female rats. 1748 65

Dipeptidyl peptidase IV (DPPIV), which belongs to the prolyl oligopeptidase family of serine proteases, is known to have a variety of regulatory biological functions and has been shown to be implicated in type 2 diabetes. It is therefore important to develop selective human DPPIV (hDPPIV) inhibitors. In this study, we determined the crystal structure of apo hDPPIV at 1.9 A resolution. Our high-resolution crystal structure of apo hDPPIV revealed the presence of sodium ion and glycerol molecules at the active site. In order to elucidate the hDPPIV binding mode and substrate specificity, we determined the crystal structure of hDPPIV-diprotin B (Val-Pro-Leu) complex at 2.1 A resolution, and clarified the difference in binding mode between diprotin B and diprotin A (Ile-Pro-Ile) into the active site of hDPPIV. Comparison between our crystal structures and the reported apo hDPPIV structures revealed that positively charged functional groups and conserved water molecules contributed to the interaction of ligands with hDPPIV. These results are useful for the design of potent hDPPIV inhibitors.
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PMID:Crystal structures of human dipeptidyl peptidase IV in its apo and diprotin B-complexed forms. 1749 30

The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities.
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PMID:PCK1 and PCK2 as candidate diabetes and obesity genes. 1770 78

Failure of insulin to elicit an increase in glucose uptake and metabolism in target tissues such as skeletal muscle is a major characteristic of non-insulin dependent type 2 diabetes mellitus. A strong correlation between intramyocellular triacylglycerol concentrations and the severity of insulin resistance has been found and led to the assumption that lipid oversupply to skeletal muscle contributes to reduced insulin action. However, the molecular mechanism that links intramyocellular lipid content with the generation of muscle insulin resistance is still unclear. It appears unlikely that the neutral lipid metabolite triacylglycerol directly impairs insulin action. Hence it is believed that intermediates in fatty acid metabolism, such as fatty acyl-CoA, ceramides or diacylglycerol (DAG) link fat deposition in the muscle to compromised insulin signaling. DAG is identified as a potential mediator of lipid-induced insulin resistance, as increased DAG levels are associated with protein kinase C activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and PI3 kinase activity. As DAG is an intermediate in the synthesis of triacylglycerol from fatty acids and glycerol, its level can be lowered by either improving the oxidation of cellular fatty acids or by accelerating the incorporation of fatty acids into triacylglycerol. This review discusses the evidence that implicates DAG being central in the development of muscular insulin resistance. Furthermore, we will discuss if and how modulation of skeletal muscle DAG levels could function as a possible therapeutic target for the treatment of type 2 diabetes mellitus.
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PMID:Muscular diacylglycerol metabolism and insulin resistance. 1820 74

Glyceroneogenesis, that is, formation of triglyceride-glycerol from pyruvate, is a critical component of triglyceride fatty acid cycling in vivo. The quantitative contribution of glyceroneogenesis to triglyceride-glycerol and its hormonal regulation have not been examined in humans. We have quantified the contribution of pyruvate to very low-density lipoprotein (VLDL) triglycerides in subjects with type 2 diabetes mellitus using the deuterium labeling of body water technique. Subjects with type 2 diabetes mellitus were studied before and after a 6-month behavioral intervention therapy, during fasting and during a hyperinsulinemic normoglycemic clamp. Response to glucagon infusion was examined in 5 healthy subjects after an overnight fast. Glyceroneogenesis contributed approximately 54% to VLDL triglyceride-glycerol in type 2 diabetes mellitus as compared with approximately 12% contribution of plasma glucose. There was no effect of insulin plus glucose during hyperinsulinemic clamp on glyceroneogenesis even after clinical interventions, when insulin sensitivity had improved. In healthy subjects, the contribution of triosephosphates to plasma VLDL triglycerides was approximately 45%. Glyceroneogenesis, in contrast to glycolysis, is the predominant source of triglyceride-glycerol carbon for VLDL triglycerides in subjects with type 2 diabetes mellitus. The contribution of glyceroneogenesis to triglyceride-glycerol is not affected by short (4 hours) infusion of insulin in type 2 diabetes mellitus.
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PMID:Estimates of hepatic glyceroneogenesis in type 2 diabetes mellitus in humans. 1824


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