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)

Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPKalpha2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases.
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PMID:Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. 1506 58

Insulin resistance is characterized by a peripheral resistance to insulin-mediated glucose uptake, and an hepatic resistance of glucose production to insulin. Insulin resistance in skeletal muscle is of a particular importance, and could be the consequence of an increase in intracellular and circulating fatty acids and triglycerides. Adipose tIssue plays an important role to regulate mobilization and release of fatty acids. Adipose tIssue is an endocrine organ which secretes several factors, including adiponectin. Adiponectin improves insulin sensitivity in skeletal muscle and liver, through a stimulation of fatty acid oxidation and glucose utilization. Thiazolidinediones enhance adiponectin expression and synthesis through PPARgamma, although the precise mechanism remains controversial. AMP-activated protein kinase (AMPK) is the main adiponectin target. Adiponectin, clearly, is a major modulator of glucose and lipid metabolism in insulin-sensitive tIssue and/or regulator of insulin-sensitivity, in obese and/or glucose intolerant subjects, as well as in type 2 diabetes mellitus. Recent works and the links between insulin resistance, adipose tIssue, adiponectin and its PPARgamma-enhanced secretion are reviewed in this paper.
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PMID:[Adiponectin: from adipocyte to skeletal muscle]. 1516 22

Impaired insulin action is a characteristic feature of type 2 diabetes. The study aims were to investigate whether after prolonged culture skeletal muscle cultures from insulin-resistant, type 2 diabetic patients (taking >100 U insulin/d) displayed impaired insulin signaling effects compared with cultures from nondiabetic controls and to determine whether retained abnormalities were limited to insulin action by studying an alternative pathway of stimulated glucose uptake. Studies were performed on myotubes differentiated for 7 d between passages 4 and 6. Insulin-stimulated glucose uptake (100 nm; P < 0.05) and insulin-stimulated glycogen synthesis (1 nm; P < 0.01) were significantly impaired in the diabetic vs. control cultures. Protein kinase B (PKB) expression and phosphorylated PKB levels in response to insulin stimulation (20 nm) were comparable in the diabetic and control cultures. 5-Amino-4-imidazolecarboxamide riboside (AICAR) mimics the effect of exercise on glucose uptake by activating AMP-activated protein kinase. There was no difference in AICAR (2 mm)-stimulated glucose uptake between diabetic vs. control myotube cultures (P = not significant). In conclusion, diabetic muscle cultures retain signaling defects after prolonged culture that appear specific to the insulin signaling pathway, but not involving PKB. This supports an intrinsic abnormality of the diabetic muscle cells that is most likely to have a genetic basis.
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PMID:Cultured muscle cells from insulin-resistant type 2 diabetes patients have impaired insulin, but normal 5-amino-4-imidazolecarboxamide riboside-stimulated, glucose uptake. 1524 Jun 29

From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues. Deficiencies of leptin or leptin receptor, adiponectin and IL-6 are associated with obesity, insulin resistance and a propensity to type 2 diabetes. In addition, a lack of adiponectin has been linked to atherosclerosis. Whether this pathology reflects a deficient activation of AMP-activated protein kinase in peripheral tissues remains to be determined. Finally, recent studies have suggested that skeletal muscle may also function as an endocrine organ when it releases the cytokine IL-6 into the circulation during sustained exercise. Interestingly, one of the apparent effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. Thus, hormonal communications exist between the adipocyte and muscle that could enable them to talk to each other. The physiological relevance of this cross talk clearly warrants further study.
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PMID:Metabolic and hormonal interactions between muscle and adipose tissue. 1529 59

Obesity in humans is associated with lipid accumulation in skeletal muscle, insulin and leptin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) is an important regulator of fatty acid (FA) metabolism in skeletal muscle. To address the hypothesis that lipid accumulation in skeletal muscle of obese subjects may be due to down-regulation of AMPK, we measured mRNA and protein levels of AMPK isoforms, AMPKalpha1 and -alpha2 activity, AMPK kinase activity, acetyl-coenzyme A carboxylase (ACCbeta) expression and phosphorylation, and FA metabolism in biopsies of rectus abdominus muscle from lean and obese women. We also examined the effect of 5-aminoimidazole-4-carboxamide riboside (AICAR) on AMPK activity and the effects of AICAR and leptin on FA metabolism. Skeletal muscle of obese subjects had increased total FA uptake and triglyceride esterification, and leptin failed to stimulate FA oxidation. However, AMPK mRNA and protein expression, AMPKalpha1 and -alpha2 activities, AMPK kinase activity, ACCbeta phosphorylation, and FA oxidation were similar in lean and obese subjects. Moreover, AICAR increased AMPKalpha2 activity, ACCbeta phosphorylation, and palmitate oxidation to a similar degree in muscle from lean and obese subjects. We conclude that the abnormal lipid metabolism and leptin resistance of skeletal muscle of obese subjects is not due to down-regulation of AMPK. In addition, the similar stimulation by AICAR of AMPK in skeletal muscle of lean and obese subjects suggests that direct pharmacological activation of AMPK may be a therapeutic approach for stimulating FA oxidation in the treatment of human obesity.
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PMID:AMP-activated protein kinase is not down-regulated in human skeletal muscle of obese females. 1535 65

Insulin secretion from pancreatic islet beta cells is a tightly regulated process, under the close control of blood glucose concentrations, neural inputs and circulating hormones. Defects in glucose-triggered insulin secretion, possibly exacerbated by a decrease in beta cell mass, are ultimately responsible for the development of type 2 diabetes. A full understanding of the mechanisms by which glucose and other nutrients trigger insulin secretion will probably be essential to allow for the development of new therapies of type 2 diabetes and for the derivation of "artificial" beta cells from embryonic stem cells as a treatment for type 1 diabetes. I focus here on recent developments in our understanding of beta cell glucose sensing, achieved in part through the development of recombinant targeted probes (luciferase, green fluorescent protein) that allow islet beta cell metabolism and Ca(2+) handling to be imaged in situ in the intact islet with single cell resolution. Combined with classical biochemistry, these techniques show that the beta cell is uniquely poised, thanks to the expression of low levels of lactate dehydrogenase and plasma membrane lactate/monocarboxylate transporters, to channel glucose carbons towards oxidative metabolism, ATP synthesis and inhibition of AMP-activated protein kinase, a newly defined regulator of insulin release. I also discuss the molecular basis of the recruitment of secretory vesicles to the cell surface, analysed by the use of new imaging techniques including total internal reflection of fluorescence, as well as the "nanomechanics" of the exocytotic event itself.
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PMID:Visualising insulin secretion. The Minkowski Lecture 2004. 1555 Oct 48

Stimulation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver is seen as an exciting prospect for the treatment of type 2 diabetes. However, we have recently demonstrated that changes in AMPK activity accompany the exposure of pancreatic islet beta-cells to elevated glucose concentrations and may be involved in the activation of insulin secretion. Here, we discuss this hypothesis and explore the potential role of changes in AMPK activity in the actions of other secretagogues. Amino acids decreased AMPK activity in MIN6 beta-cells with an order of potency for inhibition: arg=leu < gln= leu + glu < glucose, which was closely correlated with the stimulation of insulin release (r2=0.76). By contrast, increases in intracellular Ca2+ concentration provoked by cell depolarization with KCl activated AMPK in the face of increased free intracellular ATP concentrations. Elevation of intracellular cAMP levels with isobutylmethylxanthine or forskolin had no effect on AMPK activity. We conclude that metabolizable amino acids regulate AMPK in the beta-cell via increases in the cytosolic ATP/AMP ratio and via phosphorylation by the upstream kinase LKB1. Intracellular Ca2+ ions may activate AMPK by calmodulin kinase 1 kinase-mediated phosphorylation. The latter may act as a novel feedback mechanism to inhibit excessive insulin secretion under some circumstances.
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PMID:AMP-activated protein kinase: a new beta-cell glucose sensor?: Regulation by amino acids and calcium ions. 1556 25

Accumulation of triglyceride in islets may contribute to the loss of glucose-stimulated insulin secretion (GSIS) in some forms of type 2 diabetes (Diraison et al., Biochem J 373:769-778, 2004). Here, we use adenoviral vectors and oligonucleotide microarrays to determine the effects of the forced expression of SREBP1c on the gene expression profile of rat islets. Sterol regulatory element binding protein-1c (SREBP1c) overexpression led to highly significant (P <0.1 with respect to null adenovirus) changes in the expression of 1,238 genes or expressed sequence tags, of which 1,180 (95.3%) were upregulated. By contrast, overexpression of constitutively active AMP-activated protein kinase (AMPK), expected to promote lipolysis, altered the expression of 752 genes, of which 702 (93%) were upregulated. To identify specific targets for SREBP1c or AMPK, we eliminated messages that were 1) affected in the same direction by the expression of either protein, 2) changed by less than twofold, or 3) failed a positive false discovery test; 206 SREBP1c-regulated genes (195; 95% upregulated) and 48 AMPK-regulated genes (33; 69% upregulated) remained. As expected, SREBP1c-induced genes included those involved in cholesterol (6), fatty acid (3), and eicosanoid synthesis. Interestingly, somatostatin receptor (sstr1) expression was increased by SREBP1c, whereas AMPK induced the expression of peptide YY, the early endocrine pancreas marker.
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PMID:Impact of adenoviral transduction with SREBP1c or AMPK on pancreatic islet gene expression profile: analysis with oligonucleotide microarrays. 1556 28

Metformin reduces the incidence of progression to type 2 diabetes in humans with obesity or impaired glucose tolerance. We used an animal model to investigate whether metformin could prevent acute lipid-induced insulin resistance and the mechanisms involved. Metformin or vehicle was administered to rats daily for 1 week. Rats were studied basally, after 3.75 h of intralipid-heparin or glycerol infusion, or after 5 h of infusion with a hyperinsulinemic-euglycemic clamp between 3 and 5 h. Metformin had no effect on plasma triacylglycerol or nonesterified fatty acid concentrations and did not alter glucose turnover or gluconeogenic enzyme mRNA after lipid infusion. However, metformin normalized hepatic glucose output and increased liver glycogen during lipid infusion and clamp. Basal liver (but not muscle or fat) AMP-activated protein kinase activity was increased by metformin (by 310%; P < 0.01), associated with increased phosphorylation of acetyl CoA carboxylase. Postclamp liver but not muscle phosphorylated/total Akt protein was increased, whereas basal c-Jun NH2-terminal kinase-1 and -2 protein expression were reduced (by 39 and 53%, respectively; P < 0.05). Metformin also increased hepatic basal IkappaBalpha levels (by 260%; P < 0.001) but had no effect on tyrosine phosphorylation or expression of insulin receptor substrate-1 (IRS-1). In summary, metformin opposes the development of acute lipid-induced insulin resistance in the liver through alterations in multiple signaling pathways.
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PMID:Metformin prevents the development of acute lipid-induced insulin resistance in the rat through altered hepatic signaling mechanisms. 1556 58

Strength training enhances insulin sensitivity and represents an alternative to endurance training for patients with type 2 diabetes (T2DM). The 5'AMP-activated protein kinase (AMPK) may mediate adaptations in skeletal muscle in response to exercise training; however, little is known about adaptations within the AMPK system itself. We investigated the effect of strength training and T2DM on the isoform expression and the heterotrimeric composition of the AMPK in human skeletal muscle. Ten patients with T2DM and seven healthy subjects strength trained (T) one leg for 6 weeks, while the other leg remained untrained (UT). Muscle biopsies were obtained before and after the training period. Basal AMPK activity and protein/mRNA expression of both catalytic (alpha1 and alpha2) and regulatory (beta1, beta2, gamma1, gamma2a, gamma2b and gamma3) AMPK isoforms were independent of T2DM, whereas the protein content of alpha1 (+16%), beta2 (+14%) and gamma1 (+29%) was higher and the gamma3 content was lower (-48%) in trained compared with untrained muscle (all P < 0.01). The majority of alpha protein co-immunoprecipitated with beta2 and alpha2/beta2 accounted for the majority of these complexes. gamma3 was only associated with alpha2 and beta2 subunits, and accounted for approximately 20% of all alpha2/beta2 complexes. The remaining alpha2/beta2 and the alpha1/beta2 complexes were associated with gamma1. The trimer composition was unaffected by T2DM, whereas training induced a shift from gamma3- to gamma1-containing trimers. The data question muscular AMPK as a primary cause of T2DM whereas the maintained function in patients with T2DM makes muscular AMPK an obvious therapeutic target. In human skeletal muscle only three of 12 possible AMPK trimer combinations exist, and the expression of the subunit isoforms is susceptible to moderate strength training, which may influence metabolism and improve energy homeostasis in trained muscle.
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PMID:5'AMP activated protein kinase expression in human skeletal muscle: effects of strength training and type 2 diabetes. 1571 61


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