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)

Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension. Obesity, especially visceral adiposity, is negatively correlated with insulin sensitivity. The release of free fatty acids from adipocytes can block insulin-signaling pathways and lead to insulin resistance. In addition, recently identified adipocyte-specific chemical messengers, the adipocytokines, such as tumor necrosis factor-alpha, adiponectin, and resistin, appear to modulate the underlying insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or type 2 diabetes can result. The thiazolidinediones are potent peroxisome proliferator-activated receptor-gamma agonists and directly improve insulin resistance and glycemic control in patients with type 2 diabetes. Increasing evidence supports the early use of thiazolidinediones for preventing, delaying, or treating diabetes by improving insulin sensitivity and beta-cell insulin secretion.
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PMID:Insulin resistance as the core defect in type 2 diabetes mellitus. 1223 Oct 73

Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.
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PMID:A futile metabolic cycle activated in adipocytes by antidiabetic agents. 1283 85

New and improved therapies are required for type 1 and type 2 diabetic patients to assist the return of glucose homeostasis to as near normal as possible. More intensive use of existing therapies is proving beneficial, while potential new agents are progressing in development. These include agents to improve and partially mimic insulin action, such as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, stimulants of intracellular insulin signalling intermediates, and inhibitors of substances that deactivate insulin receptor tyrosine kinase activity. Novel agents to enhance nutrient-stimulated insulin release and promote the replication and neogenesis of beta-cells are emerging, along with new agents to combat obesity and dyslipidaemia. Gene therapy approaches to replace defective or destroyed beta-cells are feasible future options for both type 1 and type 2 diabetes.
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PMID:Future therapies. 1236 22

The peroxisome proliferator-activated receptor (PPAR) gamma is an important regulator of adipocyte differentiation and a modulator of intracellular insulin-signaling events. We examined the roles of the Pro12Ala variant of PPAR gamma2 in obesity and insulin resistance in 402 Japanese patients with type 2 diabetes and 116 control subjects. Among the diabetes subjects, the Pro12Pro homozygotes showed significantly higher body mass index (BMI) than those with the Pro12Ala variant (p = 0.020), while there was no association between genotype and BMI in the controls. Furthermore, diabetic subjects with Pro12Pro showed significantly higher fat body mass index (FBMI) than those with Pro12Ala (p = 0.016), while no association between genotype and lean body mass index (LBMI) was observed. Regarding insulin resistance, there was no difference in the HOMA index or in clamp index between Pro12Ala and Pro12Pro variants. These data suggest that the Pro12Ala polymorphism of PPAR gamma2 does not influence insulin resistance but body composition in Japanese diabetic subjects.
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PMID:Impact of Prol2Ala variant in the peroxisome proliferator-activated receptor (PPAR) gamma2 on obesity and insulin resistance in Japanese Type 2 diabetic and healthy subjects. 1237 94

Adiponectin is a recently identified adipose tissue-derived protein (adipocytokine) with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation. Adiponectin expression and/or secretion is increased by insulin like growth factor-1 and ionomycin, and decreased by tumor necrosis factor-alpha, glucocorticoids, beta-adrenergic agonists and cAMP. Data for insulin are somewhat inconclusive. Moreover, adiponectin expression and secretion are increased by activators of peroxisome proliferator-activated receptor (PPAR)-gamma. Besides inhibiting inflammatory pathways, recombinant adiponectin increases insulin sensitivity and improves glucose tolerance in various animal models. This insulin-sensitizing effect appears to be mostly attributable to enhanced suppression of glucose production, but beneficial effects on muscle cannot be excluded. In humans, plasma adiponectin concentrations exceed those of any other hormone by a thousand times; they decrease with obesity and are positively associated with whole-body insulin sensitivity. Therefore, low adiponectin may contribute to the decrease in whole-body insulin sensitivity that accompanies obesity. Furthermore, there is increasing evidence that genetic variants in the adiponectin gene itself and/or in genes encoding adiponectin-regulatory proteins--such as PPAR-gamma--may be associated with hypoadiponectinemia, insulin resistance and type 2 diabetes. This suggests that adiponectin may reflect PPAR-gamma activity in vivo. Finally, reversal or alleviation of hypoadiponectinemia may represent a target for development of drugs improving insulin sensitivity and glucose tolerance.
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PMID:Adiponectin--its role in metabolism and beyond. 1238 22

The thiazolidinediones (TZDs) are a new class of oral antidiabetic agents used in the treatment of type 2 diabetes mellitus. TZDs are selective and potent agonists of peroxisome proliferator-activated receptor-gamma, which is expressed in target tissues for insulin action and in a variety of cells that play an important role in atherosclerosis. TZDs primarily improve glycemic control by reducing insulin resistance in target tissues. Evidence also suggests that the TZDs may have a direct, beneficial effect on beta-cell function. In patients with impaired glucose tolerance (prediabetics), treatment with a TZD improves insulin secretory responses and proinsulin concentrations. These beta-cell-specific effects may result in prolongation of beta-cell function and the enduring glycemic control necessary to prevent microvascular complications. Durable glycemic control has not been clearly demonstrated with other antihyperglycemic agents. The TZDs may prevent or delay the macrovascular complications associated with type 2 diabetes. TZDs improve the characteristic dyslipidemia of type 2 diabetes, promote decreases in blood pressure, and enhance fibrinolysis. In addition, they exert direct effects on the vasculature, including the ability to decrease the intimal medial thickness and inhibit transendothelial migration of monocytes. These demonstrated antiatherogenic effects may reduce the cardiovascular complications commonly associated with type 2 diabetes. TZDs also reduce microalbuminuria to a greater extent than other agents. Use of a TZD early in the course of therapy may reduce the risk of development of many of the long-term microvascular and macrovascular complications associated with type 2 diabetes.
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PMID:Effects of thiazolidinediones for early treatment of type 2 diabetes mellitus. 1240 10

Endothelin is a potent vasoconstrictor peptide isolated from endothelial cells and it induces smooth muscle cell proliferation. Endothelin-1 secretion is increased in atheroma and induces deleterious effects such as vasospasm and atherosclerosis. Oxidized low-density lipoproteins (LDLs) induce atherosclerosis in the vascular wall, as well as endothelin-1 secretion in endothelial cells and are activators of both peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma. PPAR-alpha (fibric acids) and PPAR-gamma (glitazones) activators are used to treat dyslipoproteinemias and type 2 diabetes, respectively. Furthermore, these drugs induce numerous pleiotropic effects, such as inhibiting thrombin-induced endothelin-1 secretion in endothelial cells. This study shows that both PPAR-alpha (Wy 14643) and PPAR-gamma activation (rosiglitazone) partially inhibit oxidized LDL-induced protein kinase C activity and endothelin-1 secretion in endothelial cells at the transcriptional levels and suggests that synthetic PPAR activators are stronger PPAR activators than oxidized LDL. This study also suggests that fibrate and glitazone treatments should have beneficial effects on the vascular wall by reducing endothelin-1 secretion and the resulting vasospasm and atherosclerosis.
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PMID:Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. 1245 15

Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)gamma and PPARalpha potentially provides beneficial effects over existing PPARgamma and alpha preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPARalpha/gamma agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPARgamma preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb A(1c) and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb A(1c) by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPARalpha/gamma agonist ragaglitazar seemed to have beneficial impact over that of the PPARgamma-preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.
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PMID:Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. 1247 52

Beta-cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the beta-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences beta-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that beta-cell "glucotoxicity" is in part indirectly caused by "lipotoxicity," and that beta-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of beta-cell "glucolipotoxicity" that implicates alterations in beta-cell malonyl-CoA concentrations; peroxisome proliferator-activated receptor-alpha and -gamma and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed.
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PMID:Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. 1247 83

Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose tIssue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, and that circulates in human plasma at high levels. It is one of the physiologically active polypeptides secreted by adipose tIssue, whose multiple functions have started to be understood in the last few Years.A reduction in adiponectin expression is associated with insulin resistance in some animal models. Administration of adiponectin has been accompanied by a reduction in plasma glucose and an increase in insulin sensitivity. In addition, thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of the peroxisome proliferator-activated receptor-gamma, increase plasma adiponectin and mRNA levels in mice. On the other hand, this adipocyte protein seems to play a protective role in experimental models of vascular injury. In humans, adiponectin levels are inversely related to the degree of adiposity and positively associated with insulin sensitivity both in healthy subjects and in diabetic patients. Plasma adiponectin levels have been reported to be decreased in some insulin-resistant states, such as obesity and type 2 diabetes mellitus, and also in patients with coronary artery disease. On the contrary, chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased plasma adiponectin levels. Concentrations of plasma adiponectin have been shown to correlate negatively with glucose, insulin, triglyceride levels and body mass index, and positively with high-density lipoprotein-cholesterol levels and insulin-stimulated glucose disposal. Weight loss and therapy with thiazolidinediones increased endogenous adiponectin production in humans. Adiponectin increases insulin sensitivity by increasing tIssue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and muscle. This protein also suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis. In view of these data, it is possible that hypoadiponectinemia may play a role in the development of atherosclerotic vascular disease. In summary, the ability of adiponectin to increase insulin sensitivity in conjunction with its anti-inflammatory and anti-atherogenic properties have made this novel adipocytokine a promising therapeutic tool for the future, with potential applications in states associated with low plasma adiponectin levels.
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PMID:The role of the novel adipocyte-derived hormone adiponectin in human disease. 1261 9


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