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 and secretory defects seem to be present in Swedish obese elderly, NIDDM subjects. A defect in insulin secretion seems to dominate in lean elderly male Swedish subjects with NIDDM. Furthermore, TNF alpha expression and secretion are increased in adipose tissue from obese subjects and correlates with insulin resistance roughly measured as elevated fasting plasma insulin in spite of normal fasting blood glucose.
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PMID:Obesity and insulin resistance in Swedish subjects. 889 88

Obesity plays a central role in the development of skeletal muscle insulin resistance. The molecular mechanism causing skeletal muscle insulin resistance in obese people is still poorly understood. It has been speculated that circulating factors derived from adipose tissue impair insulin signalling in the skeletal muscle cell. TNF-alpha and leptin, which are overproduced in fat tissue of obese insulin resistant animal models and in obese humans, might mediate such an inhibitory effect on insulin signalling in skeletal muscle. The aim of the present study was to evaluate whether circulating TNF-alpha and leptin correlates to the individual skeletal muscle insulin sensitivity in individuals with different degrees of obesity and insulin resistance. We measured circulating TNF-alpha and leptin values in non diabetic offsprings of NIDDM patients. 36 German and 47 Finnish subjects participated in the study. The GDR of each participant was determined by the euglycemic hyperinsulinemic clamp technique, a range between 1.37 to 14.01 mg/kg LBM x min was observed. Percent of desirable body weight (PDW) covered also a wide range (87.58% to 197.06%). Although linear regression analysis suggested a dependence between TNF-alpha and GDR (Germany group: r = -0.37, p < 0.05, Finnish group: r = -0.32, p < 0.05) and a dependence between TNF and PDW (German group: r = 0.46, p < 0.05, Finnish group: r = 0.38, p < 0.05), in multiple linear regression analysis only the correlation with PDW was significant. Leptin levels were measured from 29 German and 36 Finnish subjects and a strong association was found between leptin and PDW (German group: r = 0.55, p < 0.05, Finnish group: r = 0.73, p < 0.05). In contrast, leptin levels did not correlate with GDR and TNF-alpha. In summary, even though, in a few insulin resistant subjects, higher circulating TNF-alpha or leptin levels with the individual insulin sensitivity can be demonstrated, the data suggest that the circulating pool of TNF-alpha and leptin in blood is unlikely to be a major contributing factor for obesity induced insulin resistance in the vast majority of individuals at high risk to develop NIDDM.
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PMID:Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity. 901 54

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

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 resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

The effects of tumor necrosis factor-alpha (TNF alpha) on glucose uptake and glycogen synthase (GS) activity were studied in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. In nondiabetic muscle cells, acute (90-min) exposure to TNF alpha (5 ng/ml) stimulated glucose uptake (73 +/- 14% increase) to a greater extent than insulin (37 +/- 4%; P < 0.02). The acute uptake response to TNF alpha in diabetic cells (51 +/- 6% increase) was also greater than that to insulin (31 +/- 3%; P < 0.05). Prolonged (24-h) exposure of nondiabetic muscle cells to TNF alpha resulted in a further stimulation of uptake (152 +/- 31%; P < 0.05), whereas the increase in cells from type 2 diabetics was not significant compared with that in cells receiving acute treatment. After TNF alpha treatment, the level of glucose transporter-1 protein was elevated in nondiabetic (4.6-fold increase) and type 2 (1.7-fold) cells. Acute TNF alpha treatment had no effect on the fractional velocity of GS in either nondiabetic or type 2 cells. Prolonged exposure reduced the GS fractional velocity in both nondiabetic and diabetic cells. In summary, both acute and prolonged treatment with TNF alpha up-regulate glucose uptake activity in cultured human muscle cells, but reduce GS activity. Increased skeletal muscle glucose uptake in conditions of TNF alpha excess may serve as a compensatory mechanism in the insulin resistance of type 2 diabetes.
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PMID:Effects of tumor necrosis factor-alpha on glucose metabolism in cultured human muscle cells from nondiabetic and type 2 diabetic subjects. 983 15

Recent research suggests that tumor necrosis factor-alpha (TNF alpha) may play an important role in obesity-associated insulin resistance and diabetes. We studied the relationship between TNF alpha and the anthropometric and physiological variables associated with insulin resistance and diabetes in an isolated Native Canadian population with very high rates of type 2 diabetes mellitus (DM). A stratified random sample (n = 80) of participants was selected from a population-based survey designed to determine the prevalence of type 2 DM and its associated risk factors. Fasting blood samples for glucose, insulin, triglyceride, leptin, and TNF alpha were collected; a 75-g oral glucose tolerance test was administered, and a second blood sample was drawn after 120 min. Insulin resistance was estimated using the homeostasis assessment (HOMA) model. Systolic and diastolic blood pressure (BP), height, weight, and waist and hip circumferences were determined, and percent body fat was estimated using biological impedance analysis. The relationship between circulating concentrations of TNF alpha and the other variables was assessed using Spearman correlation coefficients, analysis of covariance, and multiple linear regression. The mean TNF alpha concentration was 5.6 pg/mL (SD = 2.18) and ranged from 2.0-12.9 pg/mL, with no difference between men and women (P = 0.67). There were moderate, but statistically significant, correlations between TNF alpha and fasting insulin, HOMA insulin resistance (HOMA IR) waist circumference, fasting triglyceride, and systolic BP (r = 0.23-0.34; all P < 0.05); in all cases, coefficients for females were stronger than those for males. Individuals with normal glucose tolerance had lower log TNF alpha concentrations than those with impaired glucose tolerance or type 2 DM (both P = 0.03, adjusted for age and sex), although differences were not significant after adjustment for HOMA IR (both P > 0.25). Regression analysis indicated that log HOMA IR and log systolic BP were significant independent contributors to variations in log TNF alpha concentration (model r2 = 0.32). We conclude that in this homogeneous Native Canadian population, circulating TNF alpha concentrations are positively correlated with insulin resistance across a spectrum of glucose tolerance. The data suggest a possible role for TNF alpha in the pathophysiology of insulin resistance.
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PMID:Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus. 992 95

The human adipocyte-specific apM-1 gene encodes a secretory protein of the adipose tissue that has been suggested to play a role in the pathogenesis of obesity. The regulation of apM-1 was studied along adipocyte differentiation. While apM-1-mRNA and apM-1 protein were absent in preadipocytes and in 48 h differentiated adipocytes, they were found upregulated from day 4 to day 9 of adipocyte differentiation as shown by RNase protection assay and Western blot analysis. These data indicate that apM-1 may be a late marker of adipocyte differentiation. In human sera apM-1 protein is also detectable by Western blots using a polyclonal antibody raised against a synthetic peptide sequence of the human apM-1. The genomic structure of the human apM-1 gene together with a total of 2.7 kb of the 5'-flanking region with putative transcription factor binding sites is presented. Interestingly, sequence comparisons link the apM-1 gene to the family of TNF's and to genes expressed in activated T-cells. The chromosomal localization of apM-1 was investigated by FISH and mapped to human chromosome 1q21.3-1q23, a region that was identified as a susceptibility locus for Familial Combined Hyperlipidaemia (FCH) and polygenic NIDDM. These data and the chromosomal localization on chromosome 1q21.3-q23 raises the possibility that apM-1 as an adipocyte-specific secretory protein may play a role in the pathogenesis of FCH and associated insulin resistance. Exon- and intron-specific primer sequences are presented as a basis for mutation screening of patients affected with FCH.
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PMID:The human apM-1, an adipocyte-specific gene linked to the family of TNF's and to genes expressed in activated T cells, is mapped to chromosome 1q21.3-q23, a susceptibility locus identified for familial combined hyperlipidaemia (FCH). 1040 84

Non-insulin dependent diabetes mellitus (NIDDM) is connected with a higher incidence of macrovascular atherosclerotic disorders. The aim of the study was to detect any difference in levels of "cardiovascular risk factors"--fibrinogen, PAI-1 and inflammation response (documented by an increase of protein of acute phase orosomucoid) and of soluble cytoadhesive molecule sE-selectin and sICAM-1 (as markers of endothelial dysfunction) in blood plasma of 118 patients with NIDDM in comparison to the levels in blood plasma of 59 healthy persons as a control group. We observed higher levels of fibrinogen (fibrinogen level was 3.44 +/- 1.02 g/l in NIDDM pts versus 2.44 +/- 0.55 g/l in control group, p < 0.01) and PAI-1 Ag concentration was 159.7 +/- 110.3 ng/ml in NIDDM pts versus 51.43 +/- 24.64 ng/ml in control group, p < 0.01) together with an increase of acute phase protein orosomucoid as a "inflammatory response marker" (orosomucoid concentration was 0.85 +/- 0.23 g/l in NIDDM pts versus 0.54 +/- 0.18 g/l in control group, p < 0.01) in patients with NIDDM. The increase of these "cardiovascular risk factors" levels will be probably induced by higher activity of inflammatory cytokines IL-1 beta and/or TNF alpha in NIDDM patients, because both are inducers of orosomucoid fibrinogen and PAI-1 synthesis. This hypothesis is also supported by observation of higher levels of soluble cytoadhesive molecules sE-selectin (sE-selectin level was 64.25 +/- 26.8 ng/ml in NIDDM pts versus 46.64 +/- 29.57 ng/ml in control group, p < 0.01) and sICAM-1 (sICAM-1 level was 307.71 +/- 86.2 ng/ml in NIDDM pts versus 255.6 +/- 58.0 ng/ml in control group, p < 0.01) in patients with NIDDM. Both cytoadhesive molecules are produced by endothelial cells which are influenced by IL-1 beta and/or TNF alpha. According to these findings we suppose that an "inflammation" plays an important role in the evolution of atherosclerotic process at NIDDM together with the known influence of glucose and lipid metabolism pathology.
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PMID:Haemostasis, cytoadhesive molecules (sE-selectin and sICAM-1) and inflammatory markers in non-insulin dependent diabetes mellitus (NIDDM). 1053 88

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
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PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48


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