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)

It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
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PMID:Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. 940 43

The serine/threonine kinase Akt (PKB/Rac) has been implicated as playing a role in the insulin-signaling pathway to glucose transport. Little is known regarding the regulation of Akt kinase activity in insulin-sensitive tissues, such as skeletal muscle, or whether this regulation is altered in insulin-resistant states such as NIDDM. We examined the effect of insulin on Akt kinase activity in skeletal muscle from six NIDDM patients and six healthy subjects. Whole-body insulin sensitivity, assessed by the euglycemic-hyperinsulinemic clamp, was significantly lower in NIDDM subjects (P < 0.001), and this was accompanied by impaired in vitro insulin-stimulated glucose transport in skeletal muscle. In both groups, insulin induced a significant increase in Akt kinase activity, but the response to maximal insulin (60 nmol/l) was markedly reduced in skeletal muscle from NIDDM subjects (66% of control levels, P < 0.01). Impaired Akt kinase activity was not accompanied by decreased protein expression of Akt. Instead, a trend toward increased Akt expression was noted in skeletal muscle from NIDDM subjects (P < 0.1). These parallel defects in insulin-stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM.
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PMID:Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. 970 29

Although the precise mechanisms contributing to insulin resistance and type 2 diabetes are unknown, it is believed that defects in downstream components of the insulin signaling pathway may be involved. In this work, we hypothesize that a serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), may be pertinent in this regard. To test this hypothesis, we examined GSK-3 activity in two inbred mouse strains known to be susceptible (C57BL/6J) or resistant (A/J) to diet-induced obesity and diabetes. Examination of GSK-3 in fat, liver, and muscle tissues of C57BL/6J mice revealed that GSK-3 activity increased twofold in the epididymal fat tissue and remained unchanged in muscle and liver of mice fed a high-fat diet, compared with their low-fat diet-fed counterparts. In contrast, GSK-3 activity did not change in the epididymal fat tissue of A/J mice, regardless of the type of diet they were fed. In addition, both basal and diet-induced GSK-3 activity was higher (2.3- and 3.2-fold, respectively) in the adipose tissue of C57BL/6J mice compared with that in A/J mice. Taken together, our studies suggest an unsuspected link between increased GSK-3 activity and development of insulin resistance and type 2 diabetes in fat tissue of C57BL/6J mice, and implicate GSK-3 as a potential factor contributing to susceptibility of C57BL/6J mice to diet-induced diabetes.
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PMID:Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. 1042 88

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
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PMID:AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. 1505 5

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.
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PMID:The molecular basis for oxidative stress-induced insulin resistance. 1599 59

A reduced ability of insulin to activate glucose transport in skeletal muscle, termed insulin resistance, is a primary defect leading to the development of impaired glucose tolerance and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types. An emerging body of evidence has implicated GSK-3 in the multifactorial etiology of skeletal muscle insulin resistance in obese animal models and in obese human type 2 diabetic subjects. Overexpression and overactivity of GSK-3 in skeletal muscle of rodent models of obesity and obese type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase. New insights into the importance of GSK-3 as a regulator of insulin action on glucose transport activity in muscle have come from studies utilizing selective and sensitive inhibitors of GSK-3. These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. An additional important action of these GSK-3 inhibitors in the context of obese-associated type 2 diabetes is a reduction of hepatic glucose production, likely via downregulation of genes associated with gluconeogensis. It is clear from these studies that selectively targeting GSK-3 in skeletal muscle may be an important new strategy for the treatment of obesity-associated insulin-resistant states characterized by GSK-3 overactivity in insulin-sensitive tissues.
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PMID:Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. 1710 May 83

Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes.
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PMID:Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. 1713 Jun 51

Exendin-4 (Ex4) is a peptide found in the lizard Heloderma suspectum, and it has a high similarity to glucagon-like peptide 1 (GLP-1). It induces insulin secretion without the risk of hypoglycemic episodes. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is predominantly expressed in neurons. Recent studies have shown that this kinase regulates glucose-stimulated insulin secretion. Cdk5 inhibition enhances insulin secretion under conditions of stimulation by high glucose, but not low glucose. In the present study, we examined whether R-roscovitine (R-ros), a Cdk5 inhibitor, enhances insulin secretion induced by Ex4. R-ros induced Ex4-dependent insulin secretion under conditions of high glucose, but not low glucose in MIN6B1 cells. The enhancement by R-ros was also observed in db/db mice, a mouse model of type 2 diabetes. Moreover, long-term treatment with Ex4 and R-ros significantly improved HbA1c compared with treatment using only Ex4. These results suggest that a co-application of R-ros and Ex4 may become a promising therapy for the treatment of type 2 diabetes.
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PMID:A Cdk5 inhibitor enhances the induction of insulin secretion by exendin-4 both in vitro and in vivo. 1785 13

Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing beta-cell mass and function and promoting beta-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 beta-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr(308) and Ser(473), and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease.
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PMID:Noncanonical activation of Akt/protein kinase B in {beta}-cells by the incretin hormone glucose-dependent insulinotropic polypeptide. 1923 42

Lipid biosynthesis is essential for the maintenance of cellular homeostasis. The lipids produced by cells (glycerolipids, fatty acids, phospholipids, cholesterol, and sphingolipids) are used as an energy source/reserve, as building blocks for membrane biosynthesis, as precursor molecules for the synthesis of various cellular products, and as signaling molecules. Defects in lipid synthesis or processing contribute to the development of many diseases, including obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cancer. Studies published over the last few years have shown that the target of rapamycin (TOR), a conserved serine/threonine kinase with an important role in regulating cell growth, controls lipid biosynthesis through various mechanisms. Here, we review these findings and briefly discuss their potential relevance for human health and disease.
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PMID:An emerging role of mTOR in lipid biosynthesis. 1994 45


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