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)

Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signalling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of glucose homeostasis. Brown adipocytes are target cells for insulin and IGF-I action, especially during late foetal development when insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K)/Akt. Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and protein kinase C zeta. Tumour necrosis factor (TNF-alpha) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS-2. Activation of stress kinases and phosphatases by this cytokine contribute to insulin resistance. Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor gamma, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. Rosiglitazone ameliorates insulin resistance provoked by TNF-alpha, completely restoring insulin-stimulated glucose uptake in parallel to the insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating insulin action, as well as for the mechanism by which rosiglitazone increase insulin sensitivity under situations that mimic insulin resistance.
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PMID:The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance. 1565 20

The inhibition of the renin-angiotensin system (RAS) with either angiotensin converting enzyme inhibitors (ACEIs) or AT1 angiotensin receptor blockers (ARBs) consistently and significantly reduces the incidence of type 2 diabetes in patients with hypertension or congestive heart failure. The mechanisms underlying this protective effect appear to be complex and may involve an improvement of both insulin sensitivity and insulin secretion. These two effects may result, at least in part, from the well known effects of these pharmacological agents on the vascular system on the one hand, on the ionic balance on the other hand. Indeed, the vasodilation induced by ACEIs or ARBs could improve the blood circulation in skeletal muscles, thus favouring peripheral insulin action, but also in the pancreas, thus promoting insulin secretion. Preserving cellular potassium and magnesium pools by blocking the aldosterone effects could also improve both cellular insulin action and insulin secretion. However, besides these classical effects, new mechanisms have been recently suggested. A direct effect of the inhibition of angiotensin and/or of the enhancement of bradykinin on various steps of the insulin cascade signalling has been described as well an increase in GLUT4 glucose transporters after RAS inhibition. Furthermore, it has been demonstrated that angiotensin II inhibits adipogenic differentiation of human adipocytes via A1 receptors and, therefore, it has been hypothesised that RAS blockade may prevent diabetes by promoting the recruitment and differentiation of adipocytes. Finally, some lipophilic ARBs appear to induce PPAR-gamma activity in the adipose tissue. Hence, the protection against type 2 diabetes observed after RAS inhibition may be partially linked to a thiazolidinedione-like effect. In conclusion, numerous physiological and biochemical mechanisms could explain the protective effect of RAS inhibition against the development of type 2 diabetes in individuals with arterial hypertension or congestive heart failure. What might be the main mechanism in the overall protection effect of ACEIs or ARBs remains an open question.
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PMID:Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. 1567 19

Defective uptake of glucose into muscle and fat cells, or insulin resistance, is a central feature of obesity and type 2 diabetes. As we brace ourselves for the diabetes epidemic, it is reassuring to know that real progress is being made in defining the molecular biology of how insulin stimulates glucose uptake and what goes awry in obesity and type 2 diabetes. An understanding of the molecular determinants of insulin-stimulated glucose transport has been one of the holy grails of hormone action research. A major breakthrough was the discovery that insulin stimulates the translocation of a specific glucose transport protein, GLUT4, from intracellular vesicles to the cell surface. Elucidating how this process is regulated has remained a challenge because it represents a convergence of 2 disparate and complex fields of research--namely, vesicle transport and signal transduction. A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle-trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling/trafficking intersection that controls insulin-stimulated GLUT4 movement.
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PMID:MUNC-ing around with insulin action. 1569 75

Because of recent studies showing linkage of type 2 diabetes with the calpain 10 gene, we investigated the ability of calpains to regulate GLUT4 expression in 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the calpain inhibitor ALLN significantly decreased the mRNA and protein expression of GLUT4. GLUT4 expression was not affected by treatment with the more selective calpain inhibitors PD150606, calpeptin, or a calpastatin peptide. In contrast, treatment with the proteasome inhibitors lactacystin or MG132 repressed GLUT4 mRNA level to 35% (10 microM lactacystin) and 12% (10 microM MG132) of control levels. Therefore, the expression of GLUT4 in 3T3-L1 adipocytes was repressed by proteasome inhibition, but not by inhibition of calpains; the effect of ALLN was due to its ability to inhibit proteasome function, rather than its action to inhibit calpains. Concomitant with the repression of GLUT4 mRNA levels, proteasome inhibition decreased GLUT4 protein levels in 3T3-L1 adipocytes. The decrease in GLUT4 expression occurred at the transcriptional level, as treatment with proteasome inhibitors decreased GLUT4 transcription measured by a nuclear run-on assay. Thus, these data demonstrate a new pathway for the regulation of GLUT4 expression that involves proteasomal degradation of factors that regulate GLUT4 expression.
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PMID:GLUT4 expression in 3T3-L1 adipocytes is repressed by proteasome inhibition, but not by inhibition of calpains. 1573 67

It is suggested that insulin resistance and metabolic maladaptation of the heart are causes of contractile dysfunction. We tested the hypothesis whether systemic PPARgamma activation, by changing the metabolic profile in a model of insulin resistance and type 2 diabetes (the ZDF rat) in vivo, improves contractile function of the heart in vitro. Male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats, at 53-56 days of age, were treated with either GI-262570 (a nonthiazolidinedione PPARgamma agonist; A) or vehicle (V) for 1 wk. Agonist treatment resulted in correction of hyperglycemia and dyslipidemia, as well as in reduced hyperinsulinemia. The accumulation of triacylglycerols in the myocardium, characteristic of the ZDF rat, disappeared with treatment. Cardiac power and rates of glucose oxidation in the isolated working heart were significantly reduced in ZDF-V rats, but both parameters increased to nondiabetic levels with agonist treatment. In ZDF-V hearts, transcript levels of PPARalpha-regulated genes and of myosin heavy chain-beta were upregulated, whereas GLUT4 was downregulated compared with ZL. Agonist treatment of ZDF rats reduced PPARalpha-regulated genes and increased transcripts of GLUT4 and GLUT1. In conclusion, by changing the metabolic profile, reducing myocardial lipid accumulation, and promoting the downregulation of PPARalpha-regulated genes, PPARgamma activation leads to an increased capacity of the myocardium to oxidize glucose and to a tighter coupling of oxidative metabolism and contraction in the setting of insulin resistance and type 2 diabetes.
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PMID:Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats. 1579 88

The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined. A euglycemic-hyperinsulinemic clamp, combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle, was performed before and after 26 weeks of metformin (n = 9), rosiglitazone (n = 10), or placebo (n = 11) treatment. Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32%, respectively, after rosiglitazone (P < 0.01) but not after metformin or placebo treatment. Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. These insulin signaling parameters were unaltered after metformin, rosiglitazone, or placebo treatment. Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups. Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling. In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes.
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PMID:Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. 1585 34

Calpain is a Ca(2+)-regulated cytosolic cysteine protease that exists mainly in two isoforms and mediates crucial cellular functions, including rearrangement of cytoskeletal proteins, transport of the glucose transporter GLUT4, and protein cleavage to activate various receptors and pro-enzymes. Unintentional activation or functional loss of intracellular calpain has been implicated in several pathologies, including neurodegenerative diseases, traumatic brain and spinal cord injuries, cataracts and ischemia-associated injuries. Furthermore, polymorphism in the gene encoding calpain-10 has been associated with increased risk of type 2 diabetes. Recent studies have revealed a novel role for calpain in the progression of toxicant-induced liver damage. Evidence suggests that calpain leaking out of necrotic hepatocytes is highly activated in the extracellular milieu and hydrolyzes proteins in the plasma membrane of neighboring cells leading to progression of injury. Experimental intervention with calpain inhibitors substantially mitigates progression of liver injury initiated by toxicants, thereby preventing acute liver failure, and toxicant-induced animal death, pointing to a new potential therapeutic strategy against acute toxicities.
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PMID:Calpain: a death protein that mediates progression of liver injury. 1586 Mar 69

A better understanding of the mechanism of adipose tissue differentiation is of paramount importance in the development of therapeutic strategies for the treatment and prevention of obesity and type 2 diabetes mellitus. Optimal results using tissue culture models can be expected only when the in vitro adipocyte resembles adipose tissue in vivo as closely as possible. In this study, we used tissue-engineering principles to develop a three-dimensional (3-D) culture system to mimic the geometry of adipose tissue in vivo. Mouse preadipocyte 3T3-L1 cells were seeded onto nonbiodegradable fibrous polyethylene terephthalate scaffolds and differentiated with a hormone cocktail consisting of insulin, dexamethasone, isobutylmethylxanthine, and fetal calf serum. Cell morphology, growth, differentiation, and function were studied by immunocytochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay, and oil red O staining. Cells grown on 3-D fibrous scaffolds were differentiated in situ by hormone induction with high efficiency (approximately 90%) as shown by scanning electron microscopy. Immunocytochemistry, immunoblot analysis, and RT-PCR revealed that the 3-D constructs expressed adipocyte-specific genes, including peroxisome proliferator-activated receptor gamma, leptin, adipsin, aP2, adiponectin, GLUT4, and resistin. Adipocytes matured on 3-D constructs secreted leptin at levels even greater than that of fully differentiated adipocytes in 2-D conventional cell cultures. Finally, adipocyte-specific phenotypic function was demonstrated by accumulation of neutral lipids in larger fat droplets. In conclusion, preadipocytes grown on 3-D matrices acquire morphology and biological features of mature adipocytes. This new culture model should have significant utility for in vitro studies of adipocyte cell biology and development.
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PMID:Adipose tissue model using three-dimensional cultivation of preadipocytes seeded onto fibrous polymer scaffolds. 1586 24

AS160 is a newly described substrate for the protein kinase Akt that links insulin signaling and GLUT4 trafficking. In this study, we determined the expression of and in vivo insulin action on AS160 in human skeletal muscle. In addition, we compared the effect of physiological hyperinsulinemia on AS160 phosphorylation in 10 lean-to-moderately obese type 2 diabetic and 9 healthy subjects. Insulin infusion increased the phosphorylation of several proteins reacting with a phospho-Akt substrate antibody. We focused on AS160, as this Akt substrate has been linked to glucose transport. A 160-kDa phosphorylated protein was identified as AS160 by immunoblot analysis with an AS160-specific antibody. Physiological hyperinsulinemia increased AS160 phosphorylation 2.9-fold in skeletal muscle of control subjects (P < 0.001). Insulin-stimulated AS160 phosphorylation was reduced 39% (P < 0.05) in type 2 diabetic patients. AS160 protein expression was similar in type 2 diabetic and control subjects. Impaired AS160 phosphorylation was related to aberrant Akt signaling; insulin action on Akt Ser(473) phosphorylation was not significantly reduced in type 2 diabetic compared with control subjects, whereas Thr(308) phosphorylation was impaired 51% (P < 0.05). In conclusion, physiological hyperinsulinemia increases AS160 phosphorylation in human skeletal muscle. Moreover, defects in insulin action on AS160 may impair GLUT4 trafficking in type 2 diabetes.
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PMID:Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. 1591 90

A relationship between cell metabolism and the expression of glucose transporters (GLUT) has been reported. On the other side, treatment with some antipsychotics has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. We here examined the effects of different concentrations of the conventional antipsychotic haloperidol (400 and 800 microg/ml), of the atypical antipsychotics clozapine (100 and 200 microg/ml) and olanzapine (100 and 200 microg/ml) as well as of the antidepressant mirtazapine (10(-7) mol) on the mRNA levels of GLUT1-5 in the human leukemic blood cell line U937 after incubation for 48 h. After experimental treatment, significant increases were detected by ANOVA and appropriate post-hoc tests for mirtazapine in GLUT4 mRNA levels as well as for haloperidol 400 and 800 microg/ml, olanzapine 200 microg/ml, and mirtazapine in GLUT5 mRNA levels. ANOVAs revealed no statistically significant changes in GLUT1-3 and beta-actin mRNA levels. These findings suggest that direct effects of psychotropic drugs on cellular GLUT4 and GLUT5 may be involved in the metabolic dysfunctions occurring during psychopharmacological treatment.
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PMID:Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter mRNA levels in human blood cells. 1600 93


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