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)

Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic peptide widely expressed in the central, peripheral, and enteric nervous systems. CART is also expressed in endocrine cells, including beta-cells during rat development and delta-cells of adult rats. We examined the effect of CART 55-102 on islet hormone secretion, using INS-1(832/13) cells and isolated rat islets. In addition, islet CART expression was examined in two rat models of type 2 diabetes: Goto-Kakizaki (GK) rats and dexamethasone (DEX)-treated rats. At high glucose, CART potentiated cAMP-enhanced insulin secretion via the cAMP/protein kinase A-dependent pathway. In the absence of cAMP-elevating agents, CART was without effect on INS-1 cells but modestly inhibited secretion of insulin, glucagon, and somatostatin from isolated islets. CART was markedly upregulated in the beta-cells of both diabetes models. Thus, in DEX-treated rats, islet CART mRNA expression, and the number of CART-immunoreactive beta-cells were 10-fold higher than in control rats. In GK rats, the relative number of CART-expressing beta-cells was 30-fold higher than in control rats. We conclude that CART is a regulator of islet hormone secretion and that CART is upregulated in the beta-cells of type 2 diabetic rats.
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PMID:CART regulates islet hormone secretion and is expressed in the beta-cells of type 2 diabetic rats. 1644 61

The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic beta-cells to supraphysiological glucose levels decreased selectively the expression of these proteins. This glucotoxic effect was mimicked by cAMP-raising agents and blocked by PKA inhibitors. We demonstrate that the transcriptional repressor ICER, which is induced in a PKA-dependent manner by chronic hyperglycemia and cAMP-raising agents, is responsible for the decline of the four genes. ICER overexpression diminished the level of Granuphilin, Noc2, Rab3a and Rab27a by binding to cAMP responsive elements located in the promoters of these genes and inhibited exocytosis of beta-cells in response to secretagogues. Moreover, the loss in the expression of the genes of the secretory machinery caused by glucose and cAMP-raising agents was prevented by an antisense construct that reduces ICER levels. We propose that induction of inappropriate ICER levels lead to defects in the secretory process of pancreatic beta-cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.
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PMID:ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis. 1649 8

Macro- and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.
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PMID:The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models. 1655 3

Schizophrenia is associated with abnormalities in glucose metabolism that may lead to insulin resistance and a 3 fold higher incidence of type II diabetes mellitus. The goal of the present studies was to assess the role of insulin-dependent Akt signaling in schizophrenia and in animal and cellular models of insulin resistance. Our studies revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the dorsolateral prefrontal cortex (BA46) of medicated schizophrenics relative to control patients using post-mortem brain material. We found approximately 50% decreases in the content and autophosphorylation levels of IRbeta and approximately 76-78% decreases in Akt content and activity (pSer(473)-Akt). The inhibition of IRbeta signaling was accompanied by an elevated content of glycogen synthase kinase (GSK)-3 alpha and GSK-3beta without significant changes in phospho-Ser(21/9) GSK-3 alpha/beta levels. A cellular model of insulin resistance was induced by IRbeta knockdown (siRNA). As in schizophrenia, the IRbeta knockdown cells demonstrated a reduction in the Akt content and activity. Total GSK-3 alpha/beta content remained unaltered, but phospho-Ser(21/9) GSK-3 alpha/beta levels were reduced indicating a net increase in the overall enzyme activity similar to that in schizophrenia. Insulin resistance phenotype was induced in mice by treatment with antipsychotic drug, clozapine. Behavioral testing showed decreases in startle response magnitude in animals treated with clozapine for 68 days. The treatment resulted in a functional inhibition of IRbeta but the Akt activation status remained unaltered. Changes in GSK-3 alpha/beta were consistent with a net decrease in the enzyme activity, as opposed to that in schizophrenia. The results suggest that alterations in insulin-dependent Akt signaling in schizophrenia are similar to those observed in our cellular but not animal models of insulin resistance. In animal model, clozapine ameliorates IRbeta deficits at the GSK-3 alpha/beta level, which may justify its role in treatment of schizophrenia. Our studies suggest that aberrant IR function may be important in the pathophysiology of schizophrenia.
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PMID:Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. 1658 Dec 31

1. Skeletal muscle is a highly plastic tissue that has a remarkable ability to adapt to external demands, such as exercise. Many of these adaptations can be explained by changes in skeletal muscle gene expression. A single bout of exercise is sufficient to induce the expression of some metabolic genes. We have focused our attention on the regulation of glucose transporter isoform 4 (GLUT-4) expression in human skeletal muscle. 2. Glucose transporter isoform 4 gene expression is increased immediately following a single bout of exercise, and the GLUT-4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) transcription factors are required for this response. Glucose transporter isoform enhancer factor and MEF2 DNA binding activities are increased following exercise, and the molecular mechanisms regulating MEF2 in exercising human skeletal muscle have also been examined. 3. These studies find possible roles for histone deacetylase 5 (HDAC5), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and p38 mitogen-activated protein kinase (MAPK) in regulating MEF2 through a series of complex interactions potentially involving MEF2 repression, coactivation and phosphorylation. 4. Given that MEF2 is a transcription factor required for many exercise responsive genes, it is possible that these mechanisms are responsible for regulating the expression of a variety of metabolic genes during exercise. These mechanisms could also provide targets for the treatment and management of metabolic disease states, such as obesity and type 2 diabetes, which are characterized by mitochondrial dysfunction and insulin resistance in skeletal muscle.
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PMID:Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. 1662 Mar 8

The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic beta cells (betaPdk1-/- mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in betaPdk1-/- mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.
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PMID:Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. 1664 23

The metabolic syndrome can be defined as a state of metabolic dysregulation characterized by insulin resistance, central obesity, and a predisposition to type 2 diabetes, dyslipidemia, premature atherosclerosis, and other diseases. An increasing body of evidence has linked the metabolic syndrome to abnormalities in lipid metabolism that ultimately lead to cellular dysfunction. We review here the hypothesis that, in many instances, the cause of these lipid abnormalities could be a dysregulation of the adenosine monophosphate-activated protein kinase (AMPK)/malonyl coenzyme A (CoA) fuel-sensing and signaling mechanism. Such dysregulation could be reflected by isolated increases in malonyl CoA or by concurrent changes in malonyl CoA and AMPK, both of which would alter intracellular fatty acid partitioning. The possibility is also raised that pharmacological agents and other factors that activate AMPK and/or decrease malonyl CoA could be therapeutic targets.
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PMID:Metabolic syndrome: adenosine monophosphate-activated protein kinase and malonyl coenzyme A. 1664 60

We have recently shown that the pancreatic hormone glucagon-induced phosphorylation of mitogen-activated protein (MAP) kinase ERK 1/2 as well as growth and proliferation of rat glomerular mesangial cells (MCs) via activation of cAMP-dependent protein kinase A (PKA)- and phospholipase C (PLC)/Ca2+-mediated signaling pathways. Since circulating glucagon and tissue angiotensin II (Ang II) levels are inappropriately elevated in type 2 diabetes, we tested the hypothesis that glucagon induces phosphorylation of ERK 1/2 in MCs by interacting with Ang II receptor signaling. Stimulation of MCs by glucagon (10 nM) induced a marked increase in intracellular [Ca2+]i that was abolished by [Des-His1, Glu9]-glucagon (1 microM), a selective glucagon receptor antagonist. Both glucagon and Ang II-induced ERK 1/2 phosphorylation (glucagon: 214+/-14%; Ang II: 174+/-16%; p<0.001 versus control), and these responses were inhibited by the AT1 receptor blocker losartan (glucagon + losartan: 77+/-14%; Ang II + losartan: 84+/-18%; p<0.01 versus glucagon or Ang II) and the AT2 receptor blocker PD 123319 (glucagon + PD: 78+/-7%; Ang II + PD: 87+/-7%; p<0.01 versus glucagon or Ang II). Inhibition of cAMP-dependent PKA with H89 (1 microM) or PLC with U73122 (1 microM) also markedly attenuated the phosphorylation of ERK 1/2 induced by glucagon (glucagon + U73122: 109+/-15%; glucagon + H89: 113+/-16%; p<0.01 versus glucagon) or Ang II (Ang II + U73122: 111+/-13%; Ang II + H89: 86+/-10%; p<0.01 versus Ang II). Wortmannin (1 microM), a selective PI 3-kinase inhibitor, also blocked glucagon- or Ang II-induced ERK 1/2 phosphorylation. These results suggest that AT1 receptor-activated cAMP-dependent PKA, PLC and PI 3-kinase signaling is involved in glucagon-induced MAP kinase ERK 1/2 phosphorylation in MCs. The inhibitory effect of PD 123319 on glucagon-induced ERK 1/2 phosphorylation further suggests that AT2 receptors also play a similar role in this response.
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PMID:Cross-talk between angiotensin II and glucagon receptor signaling mediates phosphorylation of mitogen-activated protein kinases ERK 1/2 in rat glomerular mesangial cells. 1664 59

While it has been known for more than 75 years that physical activity is associated with increased mitochondrial content in muscle, the molecular mechanism for this adaptive process has only recently been elucidated. This brief review examines existing studies that have identified AMPK-activated protein kinase (AMPK) and several other key regulators of mitochondrial biogenesis, including peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta, calcium/calmodulin-dependent protein kinase IV, and nitric oxide. In addition, the potential role of mitochondrial dysfunction in the pathogenesis of insulin resistance associated with ageing and type 2 diabetes mellitus is also discussed.
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PMID:The role of AMP-activated protein kinase in mitochondrial biogenesis. 1670 37

Insulin resistance, a major factor in the development of type 2 diabetes, is known to be associated with defects in blood vessel relaxation. The role of Akt on insulin-induced relaxation of vascular smooth muscle cell (VSMC) was investigated using siRNA targeting Akt (siAKTc) and adenovirus constructing myristilated Akt to either suppress endogenous Akt or overexpress constitutively active Akt, respectively. siAKTc decreased both basal and insulin-induced phosphorylations of Akt and glycogen synthase kinase 3beta, abolishing insulin-induced nitric oxide synthase (iNOS) expression. cGMP-dependent kinase 1alpha (cGK1alpha) and myosin-bound phosphatase (MBP) activities, both downstream of iNOS, were also decreased. siAKTc treatment resulted in increased insulin and ANG II-stimulated phosphorylation of contractile apparatus, such as MBP substrate (MYPT1) and myosin light chain (MLC20), accompanied by increased Rho-associated kinase alpha (ROKalpha) activity, demonstrating the requirement of Akt for insulin-induced vasorelaxation. Corroborating these results, constitutively active Akt upregulated the signaling molecules involved in insulin-induced relaxation such as iNOS, cGK1alpha, and MBP activity, even in the absence of insulin stimulation. On the contrary, the contractile response involving the phosphorylation of MYPT1 and MLC20, and increased ROKalpha activity stimulated by ANG II were all abolished by overexpressing active Akt. In conclusion, we demonstrated here that insulin-induced VSMC relaxation is dependent on Akt activation via iNOS, cGK1alpha, and MBP activation, as well as the decreased phosphorylations of MYPT1 and MLC20 and decreased ROKalpha activity.
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PMID:AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. 1685 20


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