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)

Obesity, i.e. an excess of white adipose tissue (WAT), predisposes to the development of type 2 diabetes and cardiovascular disease. Brown adipose tissue is present in rodents but not in adult humans. It expresses uncoupling protein 1 (UCP1) that allows dissipation of energy as heat. Peroxisome proliferator-activated receptor gamma (PPAR gamma) and PPAR gamma coactivator 1 alpha (PGC-1 alpha) activate mouse UCP1 gene transcription. We show here that human PGC-1 alpha induced the activation of the human UCP1 promoter by PPAR gamma. Adenovirus-mediated expression of human PGC-1 alpha increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human subcutaneous white adipocytes. Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. PGC-1 alpha increased the palmitate oxidation rate by fat cells. Human white adipocytes can therefore acquire typical features of brown fat cells. The PPAR gamma agonist rosiglitazone potentiated the effect of PGC-1 alpha on UCP1 expression and fatty acid oxidation. Hence, PGC-1 alpha is able to direct human WAT PPAR gamma toward a transcriptional program linked to energy dissipation. However, the response of typical white adipocyte targets to rosiglitazone treatment was not altered by PGC-1 alpha. UCP1 mRNA induction was shown in vivo by injection of the PGC-1 alpha adenovirus in mouse white fat. Alteration of energy balance through an increased utilization of fat in WAT may be a conceivable strategy for the treatment of obesity.
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PMID:Acquirement of brown fat cell features by human white adipocytes. 1280 71

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.
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PMID:Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. 1283 13

The regulation of hepatic gluconeogenesis is an important process in the adjustment of the blood glucose level, and pathological changes in the glucose production of the liver are a central characteristic in type 2 diabetes. The pharmacological intervention in signaling events that regulate the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and the catalytic subunit glucose-6-phosphatase (G-6-Pase) is regarded as a potential strategy for the treatment of metabolic aberrations associated with this disease. However, such intervention requires a detailed understanding of the molecular mechanisms involved in the regulation of this process. Glucagon and glucocorticoids are known to increase hepatic gluconeogenesis by inducing the expression of PEPCK and G-6-Pase. The coactivator protein PGC-1 has been identified as an important mediator of this regulation. In contrast, insulin is known to suppress both PEPCK and G-6-Pase gene expression by the activation of PI 3-kinase. However, PI 3-kinase-independent pathways can also lead to the inhibition of gluconeogenic enzymes. This review focuses on signaling mechanisms and nuclear events that transduce the regulation of gluconeogenic enzymes.
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PMID:Novel concepts in insulin regulation of hepatic gluconeogenesis. 1295 35

Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-alpha. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.
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PMID:PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. 1510 44

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a beta(3)-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5 degrees C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary beta(3)-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes.
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PMID:Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity. 1516 32

The PGC-1 gene has been implicated in the regulation of several genes controlling energy metabolism. The prevalent Gly482Ser polymorphism of the PGC-1 gene has been shown to be associated with type 2 diabetes in some but not all studies. The aim of this study was to analyse whether the Gly482Ser variant is a risk factor for development of type 2 diabetes in Slovene population (Caucasians). Genotyping of the Gly482Ser polymorphism was performed for 545 subjects: 305 patients with type 2 diabetes and 240 non-diabetic controls. The Gly482Ser genotype distribution in patients with type 2 diabetes (AA = 11.5%, AG = 42.3%, GG = 46.2%) differed from genotype distribution in non-diabetic controls (AA = 6.3%, AG = 46.3%, GG = 47.5%), and the AA genotype was associated with 1.9-times increased risk of type 2 diabetes (95% confidence interval 1.0-3.6; P = 0.036). In conclusion, we suggest that the AA genotype of the Gly482Ser polymorphism of the PGC-1 gene should be considered as a risk factor for the development of type 2 diabetes in Caucasians.
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PMID:A Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with type 2 diabetes in Caucasians. 1558 Oct 67

Mitofusin 2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion and regulates mitochondrial metabolism in mammalian cells. Here, we show that Mfn2 gene expression is induced in skeletal muscle and brown adipose tissue by conditions associated with enhanced energy expenditure, such as cold exposure or beta(3)-adrenergic agonist treatment. In keeping with the role of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha on energy expenditure, we demonstrate a stimulatory effect of PGC-1 alpha on Mfn2 mRNA and protein expression in muscle cells. PGC-1 alpha also stimulated the activity of the Mfn2 promoter, which required the integrity of estrogen-related receptor-alpha (ERR alpha)-binding elements located at -413/-398. ERR alpha also activated the transcriptional activity of the Mfn2 promoter, and the effects were synergic with those of PGC-1 alpha. Mfn2 loss of function reduced the stimulatory effect of PGC-1 alpha on mitochondrial membrane potential. Exposure to cold substantially increased Mfn2 gene expression in skeletal muscle from heterozygous Mfn2 knock-out mice, which occurred in the presence of higher levels of PGC-1 alpha mRNA compared with control mice. Our results indicate the existence of a regulatory pathway involving PGC-1 alpha, ERR alpha, and Mfn2. Alterations in this regulatory pathway may participate in the pathophysiology of insulin-resistant conditions and type 2 diabetes.
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PMID:Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. 1673 43

Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclear-encoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 +/- 0.041 to 0.252 +/- 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 +/- 0.46 to 6.31 +/- 0.55 mg . kg(-1) . min(-1) (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 +/- 1.9 to 4.54 +/- 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1-and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III alpha-subunits (82- and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-beta1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear-encoded mitochondrial genes do not always correlate with changes in insulin sensitivity.
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PMID:Paradoxical changes in muscle gene expression in insulin-resistant subjects after sustained reduction in plasma free fatty acid concentration. 1732 45

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI approximately 25 kg/m(2)) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m(2)), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo(2max)) and moderate (70% Vo(2max)) intensities, with a 4-6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
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PMID:Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. 1732 55

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.
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PMID:Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism. 1748 46


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