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)

Insulin resistance is a pathophysiological component of type 2 diabetes and obesity and also occurs in states of stress, infection, and inflammation associated with an upregulation of cytokines. Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed. Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling.
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PMID:Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. 1516 5

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that regulates genes involved in lipid and glucose metabolism, may contribute to the onset of metabolic disorders such as diabetes and the accompanying dyslipidemia. Fat-derived tumor necrosis factor alpha (TNF-alpha) and the acute-phase response protein, C-reactive protein (CRP), may also have a role in the development of obesity-related insulin resistance and type 2 diabetes mellitus. In this study, a group of 14 naturally occurring, insulin-requiring, type 2 diabetic cynomolgus monkeys were used to evaluate the effects of the PPAR-gamma agonist, rosiglitazone, on glycemic and lipid parameters and serum levels of TNF-alpha and CRP. The animals were randomized into 2 groups of 7. One group was treated with 0.5 mg/kg rosiglitazone orally once a day for 7 weeks. Blood was collected for evaluation at baseline, at 2 and 7 weeks during the treatment period, and at 7 and 13 weeks after treatment. Daily insulin requirements were recorded during the entire study. Results showed daily exogenous insulin requirements were significantly reduced (P <.01) in those treated with rosiglitazone, while glycemic control was maintained. Plasma triglyceride concentrations were significantly lower (P <.01) whereas plasma cholesterol levels tended to be lower and high-density lipoprotein (HDL) concentrations tended to be higher after treatment. No significant differences were noted in TNF-alpha and CRP serum levels during the treatment period. Body weights remained steady in both groups during the study. These results suggest overall improvement in insulin regulation and lipid profiles during treatment with rosiglitazone.
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PMID:Rosiglitazone treatment improves insulin regulation and dyslipidemia in type 2 diabetic cynomolgus monkeys. 1533 71

The role of adipocytes as protein secreting cells has been known for almost 15 years. Most of these proteins have known biological activity and are called adipokines. However, only a few of the adipokines have been shown to regulate insulin sensitivity. The latter effects are direct or indirect. The adipokines regulating insulin sensitivity are tumor necrosis factor alpha, adiponectin, interleukin-6, resistin and leptin. This review examines the mechanism how these adipokines influence insulin sensitivity, how the adipocyte production of the adipokines is regulated and if genetic variance in the genes encoding for adipokines is important for the development of type 2 diabetes mellitus.
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PMID:Insulin resistance in type 2 diabetes -- role of the adipokines. 1589 52

This study examined the independent and combined effects of diet and exercise on adipocytokine and inflammatory cytokines in postmenopausal women with type 2 diabetes. Using a randomized, controlled design, 33 women (age, 50-70 years) were assigned to diet alone (D), exercise alone (EX), or diet + exercise (D + E) for 14 weeks. Before and after the interventions, blood samples for adipocytokines and inflammatory markers were drawn, a meal test was performed, and abdominal fat distribution was measured by magnetic resonance imaging (MRI). Body weight decreased approximately 4.5 +/- 0.6 kg ( P < .05) after the D and D + E interventions, whereas only small changes in body weight were found with the exercise-alone intervention. Plasma C-reactive protein levels were decreased by approximately 15% with all 3 interventions, whereas leptin levels were reduced with the D and D + E intervention (D: pre = 48.7 +/- 6.0, post = 38.9 +/- 5.0 ng/mL; D + E: pre = 38.5 +/- 6.0, post = 22.9 +/- 5.0 ng/mL; P < .05) with no differences between groups. There was a trend for leptin levels to decrease in the EX group ( P = .06). Plasma resistin levels were not altered by the 3 interventions from pre- to posttreatment (D: pre = 6.9 +/- 0.6, post = 6.2 +/- 0.4 ng/mL; D + E: pre = 5.6 +/- 0.6, post = 5.7 +/- 0.4 ng/mL; E: pre = 6.2 +/- 0.6, post = 5.9 +/- 0.6 ng/mL, P > .05), and no differences in adiponectin and tumor necrosis factor alpha (TNF- alpha ) levels were found. Visceral adipose tissue and tumor necrosis factor alpha were the only predictors of calculated insulin resistance ( P < .05), explaining 43% of the variability. A typically prescribed weight loss program with lifestyle changes resulted in few changes in adipocytokines and inflammatory cytokines in older women with type 2 diabetes, suggesting that dramatic weight loss or clinical interventions are needed.
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PMID:Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes. 1598 94

We investigated the clinical aspects and genetic background of 13 diabetic patients with high-titers (>10,000 U/ml) of anti-glutamic acid decarboxylase antibody (Group A) and compared these 28 middle-aged (35-51 years, Group B) and 13 elderly (66-79 years, Group C) patients with anti-GAD(+) (<1100 U/ml) who were diagnosed initially as having type 2 diabetes. The mean age and mean age at onset of Group A were 70.8 +/- 3.9 years (range, 64-78) and 50.4 +/- 5.4 years (range, 43-61), respectively. In Group A, the prevalence of insulin-deficient patients was significantly lower (30.8%, 4 of 13) than in Group C (96.3%, 27 of 28, P < 0.001). Patients in Group A had a significantly longer interval between the clinical onset of diabetes to initiation insulin therapy (21.8 +/- 2.3 years) compared to patients in both Group B (1.8+/-1.1 years, P < 0.001) and Group C (14.8 +/- 7.1 years, P = 0.049). The frequency of DRB1*0405-DQB1*0401/DRB1*1502-DQB1*0601 or DRB*1501-DQB*0602 heterozygous genotypes in Group A (53.8%, 7 of 13) was significantly higher than in both Group B (3.6%, 1 of 28, P < 0.01) and Group C (7.7%, 1 of 13, P < 0.05). Compared with Group B, Group A had an increased frequency of the TNFA-U01 haplotype and the IL-10 -592 C allele (TNFA-U01; 53.8% versus 30.4%, P = 0.05 and IL-10 -592 C; 57.7% versus 33.9 %, P = 0.042). All sera from Group A reacted with GAD(65) protein on Western blots. We conclude that adult-onset diabetic patients with a high-titer of anti-GDAab differ from patients with latent autoimmune diabetes mellitus in adult (LADA) with respect to beta-cell function, cellular autoimmunity and genetic background. Our study also showed that high-titers of antibodies to glutamic acid decarboxylase (anti-GADab) were not predictive of later development of insulin deficiency in adult and/or elderly patients with type 2 diabetes. Furthermore, our results suggest that HLA-DRB1*1502-DQB1*0601 or DRB1*1501-DQB1*0602/DRB1*0405-DQB1*0401 heterozygous genotypes may be associated with high production of anti-GADab that recognizes the linear epitope(s) on the GAD(65) protein.
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PMID:Clinical and genetic characteristics of diabetic patients with high-titer (>10,000 U/ml) of antibodies to glutamic acid decarboxylase. 1600 68

It has been recognized for some time that cardiovascular disease and type 2 diabetes are, to a major extent, inflammatory disorders associated with an environment characterized by a sedentary lifestyle together with abundant intakes of calories. Systemic low-level inflammation is suggested to be a cause as well as consequence of pathological processes with local tumor necrosis factor alpha production as an important biological driver. It is hypothesized that physical inactivity contributes to an enhanced proinflammatory burden independently of obesity, as regular muscle contractions mediate signals with myokines/cytokines as important messengers, which suppress proinflammatory activity at distant sites as well as within skeletal muscle. Muscle-derived interleukin (IL)-6 is considered to possess a central role in anti-inflammatory activities and health beneficial effects in relation to physical exercise. It is discussed how this fits the consistent observation that enhanced plasma levels of IL-6 represent a strong risk marker in chronic disorders associated with systemic low-level inflammation and all-cause mortality.
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PMID:Physical activity and modulation of systemic low-level inflammation. 1603 12

Streptozotocin administration in newborn rats (nSTZ-rats) leads to adults with mild insulin deficiency and normoglycemia, and is accepted as a model of type 2 diabetes. We examined possible differences in the production of inflammatory mediators between healthy and nSTZ-rats after ischemia-reperfusion (I-R). Two-month-old control and nSTZ-rats were randomly separated into control and intestinal I-R groups. After reperfusion, samples were obtained from the portal vein (PV) infrahepatic cava vein (ICV), suprahepatic cava vein (SCV), jejunal wall, and pancreas. Nitric oxide (NO), lipid hydroperoxides (LPO), tumor necrosis factor alpha (TNF-alpha), 60 kDa receptor (sTNF-R1), 80 kDa (sTNF-R2), and intercellular adhesion molecule-1 (ICAM-1), were determined. After I-R, nSTZ-rats showed increased plasma concentrations of LPO, NO, ICAM-1 (0.5141 +/- 0.083 vs 0.024 +/- 0.003, ICV; 0.574 +/- 0.075 vs 0.023 +/- 0.003, SCV; 0.528 +/- 0.067 vs 0.027 +/- 0.003 PV; ng/ml), TNF-alpha (42.4 +/- 5.7 ICV, 248.4 +/- 28.2 SCV, and 33.6 +/- 4.0 PV. In n STZ-rats, vs 4.36 +/- 0.57, 4.74 +/- 0.77, and 3.16 +/- 0.32, respectively, in control rats; pg/ml), and sTNF-R1. Both TNF-alpha and NO plasma levels were higher in SCV than in ICV and PV after I-R. In addition, after I-R, jejunal wall of nSTZ-rats showed an increase of TNF-alpha IL-1, and IL-10 levels. A pre-existing state of glucose intolerance intensifies the inflammatory response after intestinal I-R.
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PMID:Glucose intolerance modifies the inflammatory response after intestinal ischemia-reperfusion. 1608 24

The aim of the present study was to investigate the relationship between insulin resistance and tumor necrosis factor alpha (TNF-alpha) as well as soluble TNF receptors (sTNF-R), body mass index (BMI), leptin, adiponectin, and serum lipid profile including triglycerides in nonobese Japanese patients with type 2 diabetes. A total of 88 nonobese Japanese type 2 diabetic patients were studied. The duration of diabetes was 11.0 +/- 0.8 years. In conjunction with BMI, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, serum lipids (triglycerides, high-density lipoprotein cholesterol, and total cholesterol), serum leptin, serum adiponectin, serum TNF-alpha, and soluble TNF receptors (sTNF-R1 and sTNF-R2) were also measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Insulin resistance was positively correlated with BMI, triglycerides, leptin, and total cholesterol and negatively correlated with adiponectin and high-density lipoprotein cholesterol. In contrast, insulin resistance was not associated with TNF-alpha, nor sTNF-R (sTNF-R1 and sTNF-R2) in our diabetic patients. There was no significant relationship between the 3 measures of TNF-alpha system (TNF-alpha, sTNF-R1, and sTNF-R2) and BMI, serum triglycerides, leptin, or adiponectin in these patients. From these results, it can be concluded that peripheral levels of TNF-alpha system activity are not a major factor responsible for insulin resistance in nonobese Japanese type 2 diabetic patients.
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PMID:Three measures of tumor necrosis factor alpha activity and insulin resistance in nonobese Japanese type 2 diabetic patients. 1615 27

The aim of the present study was to analyze whether consumption of a fiber-supplemented diet containing 3.5% Plantago ovata husks prevented many of the abnormalities clustered in the metabolic syndrome, including obesity, dyslipidemia, hypertension and endothelial dysfunction. For this purpose, obese Zucker rats, a model of type 2 diabetes, and their lean littermates were studied. Rats consumed a standard control diet or that diet supplemented with 3.5% P. ovata husks for 25 wk. Body weights were measured weekly. Systolic blood pressure (SBP) was measured monthly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, FFAs, glucose, insulin, adiponectin, and tumor necrosis factor alpha (TNF-alpha) were determined, and studies on vascular function were performed using aortic rings. Rats fed the P. ovata husk-supplemented diet had a significantly reduced body weight gain compared with those fed the standard diet. Decreased endothelium-dependent relaxation in response to acetylcholine (ACh) by aortic rings from obese Zucker rats was improved in those fed the fiber-supplemented diet. The greater SBP, higher plasma concentrations of triglycerides, total cholesterol, FFA, glucose, insulin, and TNF-alpha, and the hypoadinectinemia that occurred in obese Zucker rats that consumed the control diet were significantly improved in those fed the fiber-supplemented diet. We conclude that intake of a P. ovata husk-supplemented diet prevents endothelial dysfunction, hypertension, and obesity development, and ameliorates dyslipidemia and abnormal plasma concentrations of adiponectin and TNF-alpha in obese Zucker rats.
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PMID:A diet supplemented with husks of Plantago ovata reduces the development of endothelial dysfunction, hypertension, and obesity by affecting adiponectin and TNF-alpha in obese Zucker rats. 1617 3

Reduced interleukin-10 (IL-10) production is associated with type 2 diabetes in elderly individuals. Antiviral therapy (ARV)-induced immune modulation results in diminished IL-10 production, and diabetes can be observed in ARV-treated human immunodeficiency virus (HIV)-infected individuals. We analyzed, in a cross-sectional pilot study, HIV-antigen-stimulated IL-10 and tumor necrosis factor alpha (TNFalpha) production, and intracellular concentration (ICC), as well as B7-H1 expression, a marker preferentially presented by IL-10-producing cells, in 20 ARV-treated individuals in whom diabetes did (n=10; diabetes mellitus, DM) or did not (n=10; controls) develop. Pre-ARV glucose, cholesterol, and triglycerides levels, duration of HIV infection and of therapy, exposure to protease inhibitors (PI), HIV plasma viremia, CD4 counts, and nadir were similar in DM and control patients. Results showed that: (1) IL-10 production was lower; (2) IL-10 ICC was reduced; (3) B7-H1-expressing CD19(+) cells were diminished; and (4) TNFalpha production and ICC by CD4(+) T cells was augmented in DM patients. Development of diabetes in HIV infected, ARV-treated individuals could be a response to therapy. Similar to what is observed in elderly individuals, low IL-10 production is associated with diabetes in antiviral-treated HIV infection. Further studies will be necessary to clarify whether low IL-10 is a risk factor for, or a consequence of, diabetes.
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PMID:Low interleukin-10 production is associated with diabetes in HIV-infected patients undergoing antiviral therapy. 1643 43


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