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)

We compared the current prevalence of increased BMI and type 2 diabetes in a representative group of Tongan subjects with measurements made in 1973, and we determined the distribution and possible interrelations with the UCP2 insertion/deletion (ins/del) polymorphism of these variables. We documented the BMI, glucose tolerance, and standard lipid variables in 1012 Tongan subjects (429 men and 583 women, ages 15 to 85 years) during 1998 and 2000 and compared the BMI findings with those of the 1973 survey. We also genotyped for the UCP2 ins/del polymorphism, assessed its association with obesity and type 2 diabetes, and compared its prevalence with those reported for other ethnic populations. The mean BMI +/- SD was greatly increased in both men (30.2 +/- 5.4 kg/m(2)) and women (33.8 +/- 6.2 kg/m(2)), representing increases since 1973 of 11.9% and 19.4%, respectively. The genotype frequencies were 97% for the del/del genotype and 3% for the ins/del genotype; we found no ins/ins homozygotes. This distribution is strikingly different from those reported for white, South Indian, Pima Native-American, and Asian populations (49 to 77% for del/del genotype). We conclude that there is a marked prevalence of obesity in Tonga, a prevalence that has increased since 1973. We also conclude that there is a unique, near-uniform distribution of the UCP2 45-bp ins/del polymorphism in Tongans. This may be the result of a founder effect and may be relevant to the prevalence of obesity and type 2 diabetes in Tonga.
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PMID:A 45-bp insertion/deletion polymorphism of uncoupling protein 2 in relation to obesity in Tongans. 1269 79

Uncoupling proteins (UCP) are carriers expressed in the mitochondrial inner membrane that uncouple oxygen consumption by the respiratory chain from ATP synthesis. UCP2 is a member of the multigenic UCP family that is expressed in a wide range of tissues and organs. Possible functions of UCP2 include control of ATP synthesis, regulation of fatty acid metabolism and control of reactive oxygen species production. UCP2 expression in tissues involved in lipid and energy metabolism and mapping of the gene to a region linked to obesity and hyperinsulinemia prompted studies on the involvement of UCP2 in metabolic disorders, and especially in type 2 diabetes. In human adipose tissue and skeletal muscle, UCP2 expression is increased during fasting. The carrier was shown to be under the control of fatty acids and thyroid hormones in vivo. An upregulation has been observed in the liver during high-fat feeding and obesity. However, data in UCP2 gene knockout mice do not support a role for UCP2 in steatohepatitis. The most compelling metabolic role of UCP2 comes from studies in pancreatic beta cells. Overexpression in isolated pancreatic islets results in decreased ATP content and blunted glucose-stimulated insulin secretion. UCP2-deficient mice show an increased ATP level and an enhanced insulin secretion. Lack of UCP2 dramatically improves insulin secretion and decreases hyperglycemia in leptin-deficient mice. The role of UCP2 in the control of insulin secretion constitutes, to date, the most pertinent path to investigate in a therapeutic perspective.
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PMID:The role of uncoupling protein 2 in the development of type 2 diabetes. 1274 44

Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 129S6 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyperglycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes.
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PMID:Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance. 1276 67

The onset of type 2 diabetes (T2DM) is preceded by obesity, insulin resistance, and impaired beta-cell function. Uncoupling protein-2 (UCP2) is a widely expressed inner mitochondrial membrane protein. Common polymorphisms of the UCP2 gene have been implicated in diabetes, in obesity, and with changes in UCP2 mRNA levels. We tested the hypothesis that common UCP2 variants influence T2DM susceptibility in four parallel studies of separate populations. We typed the -866 promoter (G/A) variant, a nonsynonymous (Ala55Val or A55V) single-nucleotide polymorphism in exon 4, and a 45-nt insertion in the 3'-untranslated (3'UTR) region. Study populations included a case-control population study, a family-based association study, and a metabolic study of individuals who had been characterized for insulin sensitivity and secretion. To evaluate UCP2 mRNA levels, we examined a fourth population of subjects, who had undergone subcutaneous fat biopsy. All three variants showed a trend to an association with T2DM (P = 0.05 to 0.07) in the population but not the family-based association study. The 3' insertion/deletion (3'UTR I/D) variant was associated with body mass index (BMI, P = 0.035) among nondiabetic family members. Haplotype combinations were significantly associated with BMI (P = 0.028), triglyceride levels (P = 0.026), and fasting insulin (P = 0.029); highest values for the three traits were observed in individuals with the heterozygous combination GVI/AVD. In the metabolic study, all three variants were associated with an index of beta-cell compensation for insulin sensitivity (disposition index), particularly in interaction with family membership (P < 0.000001). Individuals homozygous for the -866 A allele had decreased adipose mRNA levels relative to GG homozygous individuals (P = 0.009), but the 3'UTR I/D variant had no impact on mRNA levels. We confirm modest effects of UCP2 variants on BMI and T2DM and show significant effects on insulin secretion in interaction with family-specific factors. However, the associated allele and the effects on gene expression are opposite to those reported previously.
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PMID:Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. 1291 97

Alterations in hepatic glucose metabolism play a key role in the development of the hyperglycemia observed in type 2 diabetes. Because the transcription factor c-Myc induces hepatic glucose uptake and utilization and blocks gluconeogenesis, we examined whether hepatic overexpression of c-myc counteracts the insulin resistance induced by a high-fat diet. After 3 months on this diet, control mice became obese, hyperglycemic, and hyperinsulinemic, indicating that they had developed insulin resistance. In contrast, transgenic mice remained lean and showed improved glucose disposal and normal levels of blood glucose and insulin, indicating that they had developed neither obesity nor insulin resistance. These findings were concomitant with normalization of hepatic glucokinase and pyruvate kinase gene expression and enzyme activity, which led to normalization of intrahepatic glucose-6-phosphate and glycogen content. In the liver of control mice fed a high-fat diet, the expression of genes encoding proteins that control energy metabolism, such as sterol receptor element binding protein 1-c, peroxisome proliferator activated receptor alpha, and uncoupling protein-2, was altered. In contrast, in the liver of transgenic mice fed a high-fat diet, the expression of these genes was normal. These results suggest that c-myc overexpression counteracted the obesity and insulin resistance induced by a high-fat diet by modulating the expression of genes that regulate hepatic metabolism.
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PMID:Overexpression of c-myc in the liver prevents obesity and insulin resistance. 1295 86

The development of type 2 diabetes requires impaired beta cell function. Hyperglycemia itself causes further decreases in glucose-stimulated insulin secretion. A new study demonstrates that hyperglycemia-induced mitochondrial superoxide production activates uncoupling protein 2, which decreases the ATP/ADP ratio and thus reduces the insulin-secretory response. These data suggest that pharmacologic inhibition of mitochondrial superoxide overproduction in beta cells exposed to hyperglycemia could prevent a positive feed-forward loop of glucotoxicity that drives impaired glucose tolerance toward frank type 2 diabetes.
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PMID:A radical explanation for glucose-induced beta cell dysfunction. 1467 78

The cloning of the uncoupling protein (UCP)1 homologs UCP2 and UCP3 has raised considerable interest in the mechanism. The expression of UCP3 mainly in skeletal muscle mitochondria and the potency of the skeletal muscle as a thermogenic organ made UCP3 an attractive target for studies toward manipulation of energy expenditure to fight disorders such as obesity and type 2 diabetes. Overexpressing UCP3 in mice resulted in lean, hyperphagic mice. However, the lack of an apparent phenotype in mice lacking UCP3 triggered the search for alternative functions of UCP3. The observation that fatty acid levels significantly affect UCP3 expression has given UCP3 a position in fatty acid handling and/or oxidation. Emerging data indicate that the primary physiological role of UCP3 may be the mitochondrial handling of fatty acids rather than the regulation of energy expenditure through thermogenesis. It has been proposed that UCP3 functions to export fatty acid anions away from the mitochondrial matrix. In doing so, fatty acids are exchanged with protons, explaining the uncoupling activity of UCP3. The exported fatty acid anions may originate from hydrolysis of fatty acid esters by a mitochondrial thioesterase, or they may have entered the mitochondria as nonesterified fatty acids by incorporating into and flip-flopping across the mitochondrial inner membrane. Regardless of the origin of the fatty acid anions, this putative function of UCP3 might be of great importance in protecting mitochondria against fatty acid accumulation and may help to maintain muscular fat oxidative capacity.
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PMID:Human uncoupling protein-3 and obesity: an update. 1469 6

Stressors such as chronic hyperglycemia or hyperlipidemia may lead to insufficient insulin secretion in susceptible individuals, contributing to type 2 diabetes. The molecules mediating this effect are just beginning to be identified. Uncoupling protein (UCP)-2 may be one such negative modulator of insulin secretion. Accumulating evidence shows that beta-cell UCP2 expression is upregulated by glucolipotoxic conditions and that increased activity of UCP2 decreases insulin secretion. Mitochondrial superoxide has been identified as a posttranslational regulator of UCP2 activity in islets; thus, UCP2 may provide protection to beta-cells at one level while simultaneously having detrimental effects on insulin secretion. Interestingly, the latter appears to be the dominant outcome, because UCP2 knockout mice display an increased beta-cell mass and retained insulin secretion capacity in the face of glucolipotoxicity.
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PMID:Uncoupling protein 2 and islet function. 1474 79

The metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes, and dyslipidemia) resembles Cushing's Syndrome, but without elevated circulating glucocorticoid levels. An emerging concept suggests that the aberrantly elevated levels of the intracellular glucocorticoid reamplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11 beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11 beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11 beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11 beta-HSD-1 nullizygous (11 beta-HSD-1(-/-)) mice. 11 beta-HSD-1(-/-) mice expressed lower resistin and tumor necrosis factor-alpha, but higher peroxisome proliferator-activated receptor-gamma, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11 beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11 beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11 beta-HSD-1(-/-) mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories. These data provide the first in vivo evidence that adipose 11 beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11 beta-HSD-1 deficiency or inhibition.
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PMID:Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. 1504 7

Uncoupling protein (UCP)-2 is a member of the mitochondrial inner membrane carriers that uncouple pro-ton entry in the mitochondrial matrix from ATP synthesis. The -866G/A polymorphism in the UCP2 gene, which enhances its transcriptional activity, was associated with enhanced risk for type 2 diabetes in obese subjects. We addressed the question of whether the -866G/A polymorphism contributes to variation in insulin sensitivity by genotyping 181 nondiabetic offspring of type 2 diabetic patients. Insulin sensitivity, assessed by the hyperinsulinemic-euglycemic clamp, was reduced in -866A/A carriers compared with -866A/G or -866G/G carriers (P = 0.01). To directly investigate the correlation between UCP2 expression and insulin resistance, UCP2 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from 100 obese subjects who underwent laparoscopic adjustable gastric banding. UCP2 mRNA expression was significantly correlated with insulin resistance as assessed by the homeostasis model assessment index (r = 0.27, P = 0.007). We examined the association of the -866A/A genotype in a case-control study including 483 type 2 diabetic subjects and 565 control subjects. The -866A/A genotype was associated with diabetes in women (odds ratio 1.84, 95% CI 1.03-3.28; P = 0.037), but not in men. These results indicate that the -866A/A genotype of the UCP2 gene may contribute to diabetes susceptibility by affecting insulin sensitivity.
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PMID:The -866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes. 1522 Feb 18


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