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)

Activating transcription factor 6 (ATF6) is important for protective cell response to accumulation of unfolded and misfolded proteins in endoplasmic reticulum, and disturbances of this process can contribute to beta-cell apoptosis. We analyzed the structural gene located within a region on 1q21-q23 linked with type 2 diabetes in several populations for variants in the Pima Indians. Functionally important segments of ATF6 were sequenced in 15 diabetic and 15 nondiabetic Pimas and representative single nucleotide polymorphisms (SNPs) tested for association with type 2 diabetes in 900-1,000 subjects. We identified 20 variants including three amino acid substitutions [Met(67)Val, Pro(145)Ala, and Ser(157)Pro]. Pro(145)Ala and Ser(157)Pro were in a complete linkage disequilibrium and showed a nominal association with type 2 diabetes (P = 0.05; odds ratio 2.3 [95% CI 1.0-5.2]) and with 30-min plasma insulin during oral glucose tolerance test in 287 nondiabetic individuals (P = 0.045). Although the associations with type 2 diabetes and plasma insulin levels are marginal and their functional consequences are yet unknown, all three amino acid substitutions are located in a functionally important part of ATF6. Because these variants are not unique to the Pimas, it will be feasible to investigate their association with type 2 diabetes in other populations to better evaluate their significance for a predisposition to the disease.
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PMID:Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. 1650 52

To search for common variants etiological for type 2 diabetes, we screened 15 genes involved in fat assimilation for sequence variants. Approximately 55 kb in promoter and coding regions, and intron/splice sites were sequenced by cycle sequencing. In the set of 15 genes, 71 single nucleotide polymorphisms (SNPs) were detected. 33 SNPs were presumed to be functionally significant and were genotyped in 192 incident type 2 diabetes subjects and 384 matched controls from the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort. A total of 27 SNPs out of 15 genes showed no statistical association with type 2 diabetes in our study. Six SNPs demonstrated nominal association with type 2 diabetes, with the most significant marker (FABP6 Thr79Met) having an adjusted odds ratio of 0.45 (95% CI 0.22-0.92) in homozygous Met allele carriers. Evidence for an association with disease status was also found for a novel Arg109Cys (g.2129C > T) variant of colipase, 5'UTR (rs2084202) and Met71Val (rs8192506) variants of diazepam-binding inhibitor, Arg298His (rs13283456) of PTGES2, and a novel promoter variant (g.-1324G > A) of SLC27A5. The results presented here provide preliminary evidence for the association of common variants in genes involved in fat assimilation with the genetic susceptibility of type 2 diabetes. However, they definitely need further verification.
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PMID:Candidate gene association study of type 2 diabetes in a nested case-control study of the EPIC-Potsdam cohort - role of fat assimilation. 1726 79

Diabetic patients with metabolic syndrome (MetS) have higher lifetime risks for cardiovascular disease, especially in early-onset type 2 diabetes mellitus (EODM). Increased insulin resistance (IR) and impaired insulin secretion are important pathophysiologies in diabetic patients. Therefore, the effects of MetS on IR and insulin secretion in EODM were investigated. Forty-eight EODM (mean age, 22.8 +/- 0.6 years) patients were enrolled in this study. Two grouping criteria were used: the first was whether the patient had MetS or not (MetS+ or Met-, with 31 and 17 patients, respectively); and the second was the number of MetS components each group had, that is, MetS (1,2) with 1 to 2, MetS (3) with 3, and MetS (4,5) with 4 to 5 components (17, 17, and 14 patients in each group, respectively). A frequently sampled intravenous glucose tolerance test was performed to measure insulin sensitivity, glucose sensitivity, acute insulin response after glucose load, and disposal index. Severe IR was noted with both homeostasis model assessment and frequently sampled intravenous glucose tolerance test both in MetS+ and MetS-. However, significantly higher acute insulin response after glucose load and disposal index were noted in MetS+ and MetS (4,5) than in Met-, MetS (1,2), and MetS (3), respectively. Early-onset type 2 diabetes mellitus patients with MetS had similar IR to those without MetS. This may be due to early deterioration of insulin action in these subjects. In addition, insulin secretion was higher in subjects with more MetS components, suggesting that EODM patients with MetS had better preserved ability of beta-cell compensation for IR than those without MetS.
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PMID:The impact of metabolic syndrome on insulin sensitivity, glucose sensitivity, and acute insulin response after glucose load in early-onset type 2 diabetes mellitus: Taiwan Early-Onset Type 2 Diabetes Cohort Study. 1894 Apr 2

The ileal fatty acid binding protein (FABP6) is known to be involved in enterohepatic bile acid metabolism. We have previously found a significant association between the rare allele of the FABP6 Thr79Met polymorphism and lower type 2 diabetes risk in a small case-control study (192 cases and 384 controls) embedded in the large EPIC-Potsdam cohort. A priori functional implication of the amino acid change was gained from in-silico analysis. In this study, we analysed an independent nested case-cohort including 543 incident type 2 diabetes cases from the EPIC-Potsdam cohort and a case-control study including 939 type 2 diabetes cases from KORA to confirm the association with type 2 diabetes and performed association analyses with quantitative disease-related measures in 2112 non-diabetic individuals. Homozygosity for the Met-allele was associated with lower risk of type 2 diabetes (EPIC-Potsdam: 0.70, P=0.04; KORA: 0.79, P=0.06) if adjusted for age, sex, body mass index (BMI), and waist circumference. The homozygous rare variant showed a significant interaction (P=0.006) with BMI. Relative risks in different categories (BMI <25, 25-30, and >30 kg/m(2)) showed an association exclusively in obese (BMI >30 kg/m(2)) individuals (combined risk ratio: 0.62, 95% CI 0.45-0.86). In non-diabetic individuals from the general adult population, no significant associations were observed with plasma total cholesterol, LDL-, and HDL-cholesterol, triglyceride, insulin and glucose concentration. In summary, we found evidence that the-putative functional-Thr79Met substitution of FABP6 confers a protective effect on type 2 diabetes in obese individuals.
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PMID:Evidence for the Thr79Met polymorphism of the ileal fatty acid binding protein (FABP6) to be associated with type 2 diabetes in obese individuals. 1974 71

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects (n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2-3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% Vo(2peak) (MET + Ex). A second group (n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex (group 1), or immediately after Ex (group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU.m(2).min(-1)) clamp enriched with [6,6-(2)H]glucose. Insulin sensitivity was 54% higher after Ex (P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKalpha2 activity was elevated threefold (P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.
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PMID:Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals. 2007 60

Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNA(Leu(UUR)) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNA(Leu(UUR)). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders.
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PMID:Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. 2884 73

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.
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PMID:Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. 2080 51

Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.
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PMID:Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. 2181 93

Women with type 2 diabetes mellitus (T2DM) are at a greater risk of developing and dying from breast cancer than women without T2DM. Insulin resistance and hyperinsulinemia underlie the pathogenesis of T2DM. In the MKR mouse model of insulin resistance, we have previously shown increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in association with accelerated mammary tumor growth. In this study, we demonstrate that inhibiting PI3K with the oral pan-class I PI3K inhibitor, NVP-BKM120 reduced the growth of Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse. NVP-BKM120 treatment decreased phosphorylation of Akt and S6 ribosomal protein (S6rp); no change in Erk1/2 phosphorylation was seen. Hyperglycemia, hypertriglyceridemia and greater hyperinsulinemia developed in the MKR mice treated with NVP-BKM120. We previously reported reduced tumor growth using intraperitoneal rapamycin in the MKR mouse, with the development of hyperglycemia and hypertriglyceridemia. Therefore, we examined whether the oral PI3K/mTOR inhibitor NVP-BEZ235 augmented the tumor suppressing effects of PI3K inhibition. We also investigated the effect of targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the potential effects on glycemia. NVP-BEZ235 suppressed the growth of Met-1 and MCNeuA tumor orthografts, and decreased Akt and S6rp phosphorylation, despite increased Erk1/2 phosphorylation in Met-1 orthografts of MKR mice. Less marked hyperglycemia and hyperinsulinemia developed with NVP-BEZ235 than NVP-BKM120. Overall, the results of this study demonstrated that inhibiting PI3K/Akt/mTOR signaling with the oral agents NVP-BKM120 and NVP-BEZ235 decreased mammary tumor growth in the hyperinsulinemic MKR mouse. Inhibiting PI3K alone led to more severe metabolic derangement than inhibiting both PI3K and mTOR. Therefore, PI3K may be an important target for the treatment of breast cancer in women with insulin resistance. Monitoring for hyperglycemia and dyslipidemia should be considered when using these agents in humans, given the metabolic changes detected in this study.
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PMID:Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. 2203 15

Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. Here we report that the HGF-Met axis regulates metabolism by stimulating hepatic glucose uptake and suppressing hepatic glucose output. We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. We also found that the HGF-Met system restores insulin responsiveness in a mouse model of insulin refractoriness. These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting.
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PMID:A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. 2208 Oct 23


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