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)

Skeletal muscle insulin resistance plays a key role in the pathogenesis of type 2 diabetes. It recently has been hypothesized that excessive activity of the inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IkappaB/NFkappaB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IkappaB/NFkappaB signaling in vastus lateralis muscle from six subjects with type 2 diabetes and eight matched control subjects. Muscle from type 2 diabetic subjects was characterized by a 60% decrease in IkappaB beta protein abundance, an indicator of increased activation of the IkappaB/NFkappaB pathway. IkappaB beta abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased IkappaB/NFkappaB pathway activity is associated with muscle insulin resistance. We also investigated whether reversal of this abnormality could be a mechanism by which training improves insulin sensitivity. In control subjects, 8 weeks of aerobic exercise training caused a 50% increase in both IkappaB alpha and IkappaB beta protein. In subjects with type 2 diabetes, training increased IkappaB alpha and IkappaB beta protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor alpha muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced IkappaB protein abundance in muscle, suggesting excessive activity of the IkappaB/NFkappaB pathway. Moreover, this abnormality is reversed by exercise training.
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PMID:Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. 1650 40

Inflammation is frequently present in the visceral fat and vasculature in certain patients with cardiovascular disease (CVD) and/or adult onset Diabetes Mellitus Type II (NIDDM). An hypothesis is presented which argues that repeated acute or chronic psychologically stressful states may cause this inflammatory process. The mediators are the major stress hormones norepinephrine (NE) and epinephrine (E) and cortisol together with components of the renin-angiotensin system (RAS), the proinflammatory cytokines (PIC), as well as free fatty acids (ffa), the latter as a result of lipolysis of neutral fat. NE/E commence this process by activation of NF(kappa)B in macrophages, visceral fat, and endothelial cells which induces the production of toll-like receptors which, when engaged, produce a cascade of inflammatory reactions comprising the acute phase response (APR) of the innate immune system (IIS). The inflammatory process is most marked in the visceral fat depot as well as the vasculature, and is involved in the metabolic events which culminate in the insulin resistance/metabolic syndromes (IRS/MS), the components of which precede and comprise the major risk factors for CVD and NIDDM. The visceral fat has both the proclivity and capacity to undergo inflammation. It contains a rich blood and nerve supply as well as proinflammatory molecules such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), leptin, and resistin, the adipocytokines, and acute phase proteins (APP) which are activated from adipocytes and/or macrophages by sympathetic signaling. The inflammation is linked to fat accumulation. Cortisol, IL-6, angiotensin II (angio II), the enzyme 11(beta) hydroxysteroid dehydrogenase-1 and positive energy balance, the latter due to increased appetite induced by the major stress hormones, are factors which promote fat accumulation and are linked to obesity. There is also the capacity of the host to limit fat expansion. Sympathetic signaling induces TNF which stimulates the production of IL-6 and leptin from adipocytes; these molecules promote lipolysis and ffa fluxes from adipocytes. Moreover, catecholamines and certain PIC inhibit lipoprotein lipase, a fat synthesizing enzyme. The brain also participates in the regulation of fat cell mass; it is informed of fat depot mass by molecules such as leptin and ffa. Leptin stimulates corticotrophin releasing hormone in the brain which stimulates the SNS and HPA axes, i.e. the stress response. Also, ffa through portal signaling from the liver evoke a similar stress response which, like the response to psychologic stress, evokes an innate immune response (IIR), tending to limit fat expansion, which culminates in inflammatory cascades, the IRS-MS, obesity and disease if prolonged. Thus, the brain also has the capacity to limit fat expansion. A competition apparently exists between fat expansion and fat loss. In "western" cultures, with excessive food ingestion, obesity frequently results. The linkage of inflammation to fat metabolism is apparent since weight loss diminishes the concentration of inflammatory mediators. The linkage of stress to inflammation is all the more apparent since the efferent pathways from the brain in response to fat signals, which results in inflammation to decrease and limit fat cell mass, is the same as the response to psychologic stress, which strengthens the hypothesis presented herein.
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PMID:The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II. 1678 Oct 84

To clarify whether polymorphisms of the lymphotoxin-alpha (LTA) gene and tumor necrosis factor alpha (TNF-alpha) gene were related to diabetic retinopathy (DR), we performed a case-control study in 251 Japanese patients with type 2 diabetes mellitus participating in a multicenter research protocol. Genetic analyses were performed by using a fluorescent allele-specific DNA primer assay system. Diabetic retinopathy was diagnosed in a masked manner by an independent ophthalmologist using fundus photographs and was classified as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), and proliferative retinopathy (PDR). The results showed that the genotype frequencies of 804C/A in exon 3 and 252A/G in intron 1 of the LTA gene were not significantly different among patients with NDR, NPDR, and PDR. A allelic frequency of the TNF-alpha gene (-302A/G in promoter) was also identical among NDR, NPDR, and PDR groups. Multivariate logistic regression analyses showed that significant associations with DR were glycosylated hemoglobin level and diabetes duration, but not polymorphisms of the LTA gene or TNF-alpha gene. In conclusion, the present study showed no association between polymorphisms 804C/A and 252A/G of the LTA gene and -302A/G of the TNF-alpha gene and DR in Japanese type 2 diabetic patients.
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PMID:Relationship between polymorphisms 804C/A and 252A/G of lymphotoxin-alpha gene and -308G/A of tumor necrosis factor alpha gene and diabetic retinopathy in Japanese patients with type 2 diabetes mellitus. 1697 13

The purpose of the study was to investigate the effects of dietotherapy on oxidative stress (OS) condition, the fl-cell functional activity (BCFA), insulin resistance index (IRI), and the serum tumor necrosis factor alpha (alpha-TNF) level in patients with type 2 diabetes mellitus (DM 2). The subjects, 30 patients with DM 2 (9 men, 21 women), aged 42 to 70 (mean age 58.77 +/- 8.86 years), were examined. The duration of DM 2 in the subjects was from 1 month to 5 years. OS parameters, IRI and BCFA, as well as serum alpha-TNF were measured before the study and after 3 months of observation. The tests performed after the end of the study showed that hydrocarbonate exchange remained compensated, and IRI and BCFA were moderately lowered in DM 2 patients on dietotherapy. There was an insignificant elevation of serum alpha-TNF, while the condition of hydrocarbonate exchange had bettered. Changes in OS parameters in patients on dietotherapy evidence that the reserve activity of anti-oxidative system enzymes decreases. Thus, the compensation of hydrocarbonate exchange in DM 2 patients on dietotherapy retains, which is accompanied by a decrease in IRI and BCFA, while serum alpha-TNFincreases insignificantly, and reserved anti-oxidative system enzyme activity decreases moderately.
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PMID:[Oxidative stress, the functional activity of beta-cells, and the content of tumor necrosis factor alpha in patients with type II diabetes mellitus]. 1708 90

The hepatitis C virus (HCV) core protein is a component of nucleocapsids and a pathogenic factor for hepatitis C. Several epidemiological and experimental studies have suggested that HCV infection is associated with insulin resistance, leading to type 2 diabetes. We have previously reported that HCV core gene-transgenic (PA28gamma(+/+)CoreTg) mice develop marked insulin resistance and that the HCV core protein is degraded in the nucleus through a PA28gamma-dependent pathway. In this study, we examined whether PA28gamma is required for HCV core-induced insulin resistance in vivo. HCV core gene-transgenic mice lacking the PA28gamma gene (PA28gamma(-/-)CoreTg) were prepared by mating of PA28gamma(+/+)CoreTg with PA28gamma-knockout mice. Although there was no significant difference in the glucose tolerance test results among the mice, the insulin sensitivity in PA28gamma(-/-)CoreTg mice was recovered to a normal level in the insulin tolerance test. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), production of IRS2, and phosphorylation of Akt were suppressed in the livers of PA28gamma(+/+)CoreTg mice in response to insulin stimulation, whereas they were restored in the livers of PA28gamma(-/-)CoreTg mice. Furthermore, activation of the tumor necrosis factor alpha promoter in human liver cell lines or mice by the HCV core protein was suppressed by the knockdown or knockout of the PA28gamma gene. These results suggest that the HCV core protein suppresses insulin signaling through a PA28gamma-dependent pathway.
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PMID:Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. 1713 26

Angiotensin II can influence adipocytokine levels in adipose tissue, but the association between aldosterone, which mediates the effect of angiotensin II, and adipocytokines has yet to be fully elucidated. This study was designed to investigate the effect of spironolactone, a representative aldosterone blocker, on adipocytokines such as adiponectin, visfatin, plasminogen activator inhibitor (PAI)-1 and tumor necrosis factor alpha in patients with type 2 diabetic nephropathy: the study included 33 patients, 22 of whom were randomly assigned to the spironolactone (50 mg/d) group and 11 to the amlodipine (2.5 mg/d) group. Data were collected at baseline and after 3 months of treatment and compared with baseline data for 25 age-matched healthy subjects. A significant decrease in plasminogen activator inhibitor 1 in the spironolactone group was observed (22.6 +/- 13.4 to 19.2 +/- 11.3 ng/mL, P =.0323), but this did not occur in the amlodipine group. Adiponectin and visfatin levels did not change in the spironolactone and amlodipine groups, but significant increases in these adipocytokines were found in a subgroup of patients in the spironolactone group with glycated hemoglobin A(1c) (HbA(1c)) 8.0% or greater (11.8 +/- 6.4 to 13.3 +/- 7.4 microg/mL, P = .0344; and 1.39 +/- 0.92 to 2.26 +/- 0.76 ng/mL, P =.0397, respectively). The tumor necrosis factor alpha level at baseline exceeded the lower detection limit of the assay in only 6 patients in the spironolactone group, and no change occurred in these patients. Moreover, neither spironolactone nor amlodipine therapy caused a change in high-sensitivity C-reactive protein or soluble CD40 ligand, but a significant decrease in the level of brain natriuretic peptide was found in the spironolactone group only. Furthermore, significant increases of HbA(1c), creatinine, potassium, and aldosterone levels and plasma renin activity, and a decrease in urinary albumin excretion were also observed only in the spironolactone group. The number of patients with HbA(1c) 8.0% or greater increased after spironolactone treatment. A significant decrease in systolic but not in diastolic blood pressure was observed in both treatment groups. In conclusion, our data suggest that in patients with type 2 diabetes mellitus complicated by diabetic nephropathy, spironolactone can decrease plasminogen activator inhibitor 1 and brain natriuretic peptide levels in addition to urinary albumin excretion, and systolic blood pressure, and that in patients with poor glycemic control, spironolactone can increase the levels of adiponectin and visfatin. However, the significant elevation of HbA(1c) levels by spironolactone should be emphasized.
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PMID:The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. 1714 38

Increased plasma concentrations of tumor necrosis factor alpha (TNFalpha) system components appear in type 2 diabetes patients with poor glycemic control. We have analyzed the expression of TNFalpha, TNFR1 and TNFR2 when monocytes and lymphocytes isolated from a group of recent onset type 2 diabetic patients, with fasting glucose levels below 7.0mM and glycated haemoglobin (Hb1Ac) in the normal range, were stimulated with high glucose or LPS endotoxin. We report, that cultured monocytes from these type 2 diabetic patients, in comparison to monocytes from non-diabetic individuals, had an enhanced response to LPS but did not respond to an acute glucose challenge (p<0.05). No differences were observed in the cultured lymphocyte fractions. These results indicate the existence of differences, elicited by LPS or high glucose related stimulus, between monocytes isolated from non-diabetic subjects or from type 2 diabetes patients.
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PMID:Different TNFalpha expression elicited by glucose in monocytes from type 2 diabetes mellitus patients. 1724 13

Endothelial dysfunction, insulin resistance, and elevated levels of circulating proinflammatory markers are among the earliest detectable abnormalities in people at risk for atherosclerosis. Accelerated atherosclerosis is a leading contributor to morbidity and mortality in type 2 diabetes mellitus, a complex genetic disorder. Therefore, we hypothesized that normoglycemic offspring of patients with type 2 diabetes mellitus (NOPD) may have impaired vascular and metabolic function related to an enhanced proinflammatory state. We compared NOPD (n = 51) with matched healthy control subjects without family history of diabetes (n = 35). Flow- and nitroglycerin-mediated brachial artery vasodilation were assessed by ultrasound to evaluate endothelium-dependent and -independent vascular function. Each subject also underwent an oral glucose tolerance test to evaluate metabolic function. Fasting levels of plasma adiponectin and circulating markers of inflammation (high-sensitivity C-reactive protein, CD40 ligand, interleukin 1beta, tumor necrosis factor alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule) were measured. Both NOPD and the control group had fasting glucose and insulin levels well within the reference range. However, results from oral glucose tolerance test and quantitative insulin sensitivity check index revealed that NOPD were insulin resistant with significantly impaired flow- and nitroglycerin-mediated dilation compared with the control group. Adiponectin levels were lower, whereas many circulating markers of inflammation were higher, in NOPD compared with the control group. Normoglycemic offspring of patients with type 2 diabetes mellitus have impaired vascular and metabolic function accompanied by an enhanced proinflammatory state that may contribute to their increased risk of diabetes and its vascular complications.
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PMID:Vascular, metabolic, and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus. 1729 32

Thiazolidinediones, also known as glitazones, represent a relatively new class of medication used for glycemic control in patients with type II diabetes mellitus. These drugs interact with the peroxisome proliferator-activated receptor gamma, a member of the nuclear receptor superfamily, which in turn heterodimerizes with retinoid X receptors to stimulate gene transcription. At a physiologic level, glitazones stimulate adipocyte differentiation, enhance insulin-sensitive glucose uptake by muscle and fat cells, suppress angiogenesis, inhibit tumor cell growth, and normalize keratinocyte differentiation. They have also demonstrated the capacity to diminish inflammatory cytokine production, most notably, that of tumor necrosis factor alpha. Patients with such disparate conditions as psoriasis, hirsutism, melanoma, angiosarcoma, lipodystrophy, and necrobiosis lipoidica have benefited from the administration of thiazolidinediones. Clinicians should become familiar with glitazones as they are experiencing a burgeoning use among patients with non-insulin-dependent diabetes mellitus and have demonstrated clinical efficacy in treating certain skin conditions.
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PMID:Thiazolidinediones in dermatology. 1755 May 51

Obesity is a major risk factor for hypertension, coronary artery disease and type 2 diabetes. Weight loss is associated with significant metabolic benefits. Our objective was to examine changes in adipocytokines and interleukin (IL) 10 in obese subjects before and after weight loss. We measured anthropometric parameters, adipocytokine and IL-10 in 78 obese people who had visited obesity clinics at five university hospitals (Ajou, Ulsan, Catholic, Hanyang and Yonsei) in Korea. They restricted their caloric intake to less than their usual intake (by 500 kcal), were administered sibutramine and were given a program of exercise for 12 weeks. After 12 weeks, weight, body mass index, waist circumference, hip circumference, waist-to-hip ratio, total body fat, total cholesterol, triglyceride, tumor necrosis factor alpha (TNF-alpha), IL-6, resistin and leptin had significantly decreased, while adiponectin and IL-10 had significantly increased. A bivariate correlation analysis found that increment in IL-10 and baseline IL-10 levels significantly correlated with decrement in TNF-alpha (P<.01) and baseline adiponectin (r=.52, P<.001), respectively. These results were confirmed in a multiple regression analysis. The results suggest that weight loss after caloric restriction and medical treatment in obesity can improve metabolic risk factors through changes in some cytokines.
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PMID:Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. 1761 71


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