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)

The cytokine tumor necrosis factor alpha (TNF alpha) was proposed to mediate obesity related insulin resistance upon production in fat cells and to participate in tissue remodelling leading to vascular complications upon being released by macrophages. To assess its putative role in diabetes we determined plasma levels of TNF alpha in 105 adult humans. Male nondiabetic subjects had significantly lower TNF alpha levels than female controls (4.4 +/- 0.3, n = 17 vs. 6.6 +/- 1.0 pg/ml, n = 13; p = 0.049). Men with NIDDM had elevated TNF alpha (6.7 +/- 0.6 pg/ml, n = 34) compared to nondiabetic subjects (4.4 +/- 0.3 pg/ml, n = 17; p = 0.012). Such a difference was not apparent in women. Levels of TNF alpha were correlated with serum triglyceride levels in male controls (r2 = 0.64; p = 0.007) but not in NIDDM. Neither body mass index nor glycosylated hemoglobin correlated with TNF alpha in any of the groups. The presence of retinopathy (p = 0.046) but not of neuropathy or nephropathy or macroangiopathy was associated with significantly elevated plasma TNF alpha. We conclude that plasma levels of TNF alpha are sex-dependent and that increased TNF alpha occurs in male but not female NIDDM and may participate in the development of diabetic complications.
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PMID:Circulating tumor necrosis factor alpha is elevated in male but not in female patients with type II diabetes mellitus. 913 80

Segregation analysis of body-mass index (BMI) supported recessive inheritance of obesity, in pedigrees ascertained through siblings with non-insulin dependent diabetes mellitus (NIDDM). BMI was estimated as 39 kg/m2 for those subjects homozygous at the inferred locus. Two-locus segregation analysis provided weak support for a second recessive locus, with BMI estimated as 32 kg/m2 for homozygotes. NIDDM prevalence was increased among those subjects presumed to be homozygous at either locus. Using both parametric and nonparametric methods, we found no evidence of linkage of obesity to any of nine candidate genes/regions, including the Prader-Willi chromosomal region (PWS), the human homologue of the mouse agouti gene (ASP), and the genes for leptin (OB), the leptin receptor (OBR/DB), the beta3-adrenergic receptor (ADRB3), lipoprotein lipase (LPL), hepatic lipase (LIPC), glycogen synthase (GYS), and tumor necrosis factor alpha (TNFA).
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PMID:Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and lack of linkage to nine candidate genes. 932 33

Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.
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PMID:Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance. 956 47

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.
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PMID:Bezafibrate reduces blood glucose in type 2 diabetes mellitus. 1072 10

Recent data have suggested that certain growth factors and cytokines are involved in the development of diabetic nephropathy. The aim of this study was to investigate whether circulating transforming growth factor beta 1 (TGF-beta1) and tumor necrosis factor alpha (TNF-alpha) are associated with diabetic kidney disease. Serum levels of active and total TGF-beta1 and TNF-alpha were measured in type 2 diabetic patients with nephropathy (n = 23) or without (n = 35) and normoglycemic controls (n = 12). Serum levels of circulating active TGF-beta1 were significantly higher in patients with diabetic nephropathy (0.43 +/- 0.06 ng x mL(-1)) compared with diabetic patients without renal involvement (0.23 +/- 0.03 ng x mL(-1), P = .002) and healthy controls (0.24 +/- 0.03 ng x mL(-1), P= .001), whereas the levels of total (active + latent) TGF-beta1 were not different between the subgroups. Active TGF-beta1 concentrations were correlated with urinary albumin excretion (r = .49, P < .003) and serum creatinine (r= .55, P < .01). Sera from patients with type 2 diabetes contained significantly more TNF-alpha than sera from normoglycemic controls (3.07 +/- 0.24 v 1.65 +/- 0.20 pg x mL(-1), P = .001). However, the comparison of serum TNF-alpha concentrations between microalbuminuric and normoalbuminuric diabetic patients showed no significant difference (3.21 +/- 0.28 v 2.97 +/- 0.34 pg x mL(-1), P = .12). In conclusion, type 2 diabetic patients with diabetic nephropathy exhibit increased activation of TGF-beta1, in serum, suggesting an association between circulating TGF-beta1 activity and the development of renal disease.
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PMID:Activation of transforming growth factor-beta1 in diabetic kidney disease. 1072 14

In this chapter, we summarize our studies on plasminogen activator inhibitor 1 (PAI-1), tissue factor, and transforming growth factor beta (TGF-beta) expression in obesity, using genetically obese mice as a model. These studies emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also implicate multiple cytokines, hormones, and growth factors in the abnormal expression of these and perhaps other hemostatic genes by adipocytes in obesity/NIDDM. These studies demonstrate that tumor necrosis factor alpha (TNF-alpha) plays a central role in the expression of hemostatic genes in this disorder.
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PMID:The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM. 1086 47

The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.
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PMID:Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. 1099 30

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity. These include leptin, tumor necrosis factor alpha, Acrp30/adiponectin/adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor gamma, a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans.
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PMID:Resistin and obesity-associated insulin resistance. 1175 Aug 58

With the thiazolidinediones rosiglitazone and pioglitazone a novel treatment modality for type 2 diabetes has become available in many countries. As monotherapy, fasting blood glucose and glycosylated hemoglobin (HbA1c), on average, can be improved by approximately 40 mg/dl and almost 1%, respectively. In combination with other agents their efficacy is additive. Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPARgamma is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis factor alpha, resistin, adiponectin) in a way that results in net improvement of insulin sensitivity (i.e. in muscle and liver). Nevertheless, a direct molecular effect in skeletal muscle cannot be excluded. Interference with transcription entails a potential for side-effect risk, that cannot definitively be assessed yet. For example, the in-vitro stimulation of adipogenic differentiation may underlie the clinical observation of weight gain. Theoretically, this may turn out to be counterproductive in the long run. However, there is not sufficient evidence from humans at the moment, especially no long-term data, to allow a conclusive statement. The hepatotoxicity observed with troglitazone, on the other hand, does not seem to be PPARgamma-mediated but secondary to toxic metabolites. Based on differences in drug metabolism this problem is relatively unlikely to occur with rosiglitazone or pioglitazone. Unexplained but not unimportant is the propensity for fluid retention. In summary, with the thiazolidinediones a novel concept for the treatment of insulin resistance is available that in theory could also be used for prevention of type 2 diabetes. Long-term data are indispensable for a final risk-benefit assessment of these substances.
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PMID:Glitazones: clinical effects and molecular mechanisms. 1217 92

Type 2 diabetes and obesity are major risk factors for the development of coronary artery disease (CAD) and premature atherosclerosis. Both conditions are associated with insulin resistance, oxidative stress, and inflammation. Inflammatory mediators, including plasma interleukin 6, tumor necrosis factor alpha, and tumor necrosis factor R are elevated in these individuals. The elevations of inflammatory mediators may contribute to the pathogenesis of atherosclerosis, because atherosclerosis is an inflammation of the arterial wall. There is evidence that the thiazolidinedione (TZD) class of drugs may alleviate some of the adverse atherosclerotic effects common in patients with type 2 diabetes. Considerable recent data suggest that the TZDs possess anti-inflammatory properties and exert an effect on the atherogenic process, including effects on endothelial function, monocyte/macrophage function, lipid abnormalities, smooth muscle cell migration, and fibrinolysis, all functions that are abnormal in the presence of insulin resistance. These actions of TZDs are consistent with the recently described anti-inflammatory effects of insulin. The use of TZDs as potent anti-inflammatory agents in patients with type 2 diabetes is an approach that would normalize glucose levels, as well as potentially alleviate the long-term risk of atherosclerosis.
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PMID:A rational approach to pathogenesis and treatment of type 2 diabetes mellitus, insulin resistance, inflammation, and atherosclerosis. 1223 Oct 76


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