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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is a major feature of noninsulin-dependent diabetes mellitus. This resistance appears to involve molecules, apart from the insulin receptor, that are capable of altering its function. Previously, we reported that dermal fibroblasts from a female patient with insulin resistance and noninsulin-dependent diabetes produced an inhibitor of insulin receptor tyrosine kinase activity. We have now studied inhibitors in fibroblasts from four additional patients (one male and three females) with severe insulin resistance. Although clinical features were diverse, these patients had in common normal fasting glucose values, with fasting and postprandial hyperinsulinemia. The fibroblast insulin receptor content was within the normal range, but both basal and insulin-stimulated tyrosine kinase activity in fibroblast extracts were markedly decreased compared to those in extracts of fibroblasts from nondiabetic subjects. Studies revealed that these fibroblasts contained a glycoprotein inhibitor of insulin receptor tyrosine kinase activity. This inhibitor was not found in extracts of either similar insulin-resistant patients with normal insulin receptors or insulin-resistant patients with insulin receptor abnormalities. The inhibitor was not adsorbed with antiserum to either tyrosine phosphatases or fetuin. These studies thus suggest that one or more unique inhibitors of insulin receptor tyrosine kinase are present in fibroblasts of certain patients with severe insulin resistance. The presence of insulin receptor tyrosine kinase inhibitors in target cells, therefore, may constitute a novel mechanism of postreceptor insulin resistance.
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PMID:Inhibitors of insulin receptor tyrosine kinase in fibroblasts from diverse patients with impaired insulin action: evidence for a novel mechanism of postreceptor insulin resistance. 768 17

Recent studies indicate that oxyanions, such as vanadate (V) or vanadyl (IV), cause insulin-like effects on rats by stimulating the insulin receptor tyrosine kinase. Tungstate (VI) and molybdate (VI) show the same effects on rat adipocytes and hepatocytes. Results of uncontrolled trials on volunteers accumulated in Japan also suggest that tungstate effectively regulates diabetes mellitus without detectable side effects. Since these oxyanions naturally exist in organisms, oxyanion therapy, the oral administration of vanadate, vanadyl, molybdate, or tungstate, can be considered to be orthomolecular medicine. Therefore, these oxyanions may provide a viable alternative to chemotherapy. Many diseases in addition to diabetes mellitus might also be treated since the implication of these results is that tyrosine kinases are involved in a variety of diseases.
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PMID:Vanadate, molybdate and tungstate for orthomolecular medicine. 781 75

Most patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin. Insulin resistance precedes the onset of this disease, suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus, but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity. Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase. Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10, 11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin-dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non-insulin-dependent diabetes mellitus.
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PMID:Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. 783 Jul 88

The metalion vanadate has insulin-like effects and has been advocated for use in humans as a therapeutic modality for diabetes mellitus. However, since vanadate is a tyrosine phosphatase inhibitor, it may result in undesirable activation of target cells. We studied the effect of vanadate on human mesangial cells, an important target in diabetic nephropathy. Vanadate stimulated DNA synthesis and PDGF B chain gene expression. Vanadate also inhibited total tyrosine phosphatase activity and stimulated tyrosine phosphorylation of a set of cellular proteins. Two chemically and mechanistically dissimilar tyrosine kinase inhibitors, genistein and herbimycin A, blocked DNA synthesis induced by vanadate. Vanadate also stimulated phospholipase C and protein kinase C. Downregulation of protein kinase C abolished vanadate-induced DNA synthesis. Thus, vanadate-induced mitogenesis is dependent on tyrosine kinases and protein kinase C activation. The most likely mechanism for the effect of vanadate on these diverse processes involves the inhibition of cellular phosphotyrosine phosphatases. These studies demonstrating that vanadate activates mesangial cells may have major implications for the therapeutic potential of vanadate administration in diabetes. Although vanadate exerts beneficial insulin-like effects and potentiates the effect of insulin in sensitive tissue, it may result in undesirable activation of other target cells, such as mesangial cells.
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PMID:Activation of mesangial cells by the phosphatase inhibitor vanadate. Potential implications for diabetic nephropathy. 788 73

IRS-1 (insulin receptor substrate-1) is a major substrate for the insulin receptor tyrosine kinase. After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. However, IRS-1 protein level was differently regulated in muscle and liver. In muscle, IRS-1 protein decreased with dexamethasone treatment and in hypoinsulinemic states such as starvation and streptozotosine-induced diabetes and showed no change in hyperinsulinemic states such as obesity. In liver, IRS-1 protein increased with dexamethasone treatment and hypoinsulinemic states and decreased in hyperinsulinemic states. In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA.
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PMID:[The expression of the insulin receptor substrate-1 (IRS-1) and analysis of its mechanism]. 789 62

Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.
Diabetes 1994 Nov
PMID:Tumor necrosis factor alpha: a key component of the obesity-diabetes link. 792

We have developed and characterized a line of Madin-Darby canine kidney (MDCK) cells overexpressing the human insulin receptor. The expressed receptor was found to be processed normally, and its intrinsic tyrosine kinase was determined to be functional from both in vitro and in vivo phosphorylation studies. The expressed receptor was able to mediate an insulin-stimulated increase in both anti-phosphotyrosine-precipitable and anti-insulin receptor substrate 1-precipitable phosphatidylinositol 3-kinase activity. Moreover, insulin-induced glycogen synthase activity was greater and more sensitive to insulin in the transfected cells than in the parental cells. Interestingly, insulin promoted tubule-like growth in cells overexpressing the insulin receptor but not in the parental cells. Another advantage of this cell system lies in its ability to polarize into distinct basolateral and apical membrane compartments. With the use of biotinylation and Western analysis, the expressed insulin receptor was found to be preferentially expressed in the basolateral membrane (fivefold greater) in comparison with the apical membrane. Therefore, MDCK cells overexpressing the insulin receptor represent a novel system to study not only the pathway of insulin signaling, but also this pathway in the context of cell polarity.
Diabetes 1994 Nov
PMID:Insulin receptor signaling in Madin-Darby canine kidney cells overexpressing the human insulin receptor. 792 3

The human insulin receptor gene is composed of 22 exons and spans in excess of 130 kb, on chromosome 19. The basic structure of the insulin receptor is a disulfide-linked tetramer, composed of the alpha subunit (135 kDa), which is extracellular and provides the binding site for insulin, and the beta subunit (95 kDa), contains the transmembrane domain, tyrosine kinase domain and C-terminal domain. Insulin binding to the alpha subunit causes the activation of the receptor tyrosine kinase activity that plays a critical role in mediating insulin signal transduction. Site-directed mutagenesis or the gene analysis of the patients with insulin resistant diabetes mellitus has revealed the structure and functional relationship of the insulin receptor to some extent but further investigations required.
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PMID:[The structure function relationship in the human insulin receptor]. 798 87

Insulin stimulates glucose uptake and non-oxidative glucose metabolism (predominantly glycogen synthesis) in skeletal muscle. Among other things, insulin resistance is characterized by a subnormal insulin-stimulated glucose disposal, and it appears to be associated with an increased risk for development of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present investigation has been to elucidate the mechanism of action of insulin on non-oxidative glucose metabolism both during conditions of insulin resistance and during physiological modification of glucose metabolism. To do so, the effect of insulin was investigated both with respect to its initial activation of the insulin receptor kinase and the terminal step of the signal pathway, namely stimulation of the glycogen synthase. From needle biopsies of human skeletal muscle (vastus lateralis) cellular membranes were solubilized and the insulin receptors were partially purified by affinity chromatography using wheat germ agglutinin. Subsequently insulin binding and the insulin-stimulated tyrosine kinase activity were characterized. The insulin receptor kinase activity did not change during physiological modification of the glucose metabolism (exercise training, acute exercise, growth hormone exposure or experimental hyperglycemia). No specific abnormalities of the insulin receptor kinase activity were revealed in insulin-dependent diabetes (IDDM) or in common NIDDM. In addition, insulin receptor kinase activity did not change during dietary or sulphonylurea treatment of NIDDM. Glucose deposition as glycogen in muscle is regulated by glycogen synthase (GS), which during insulin stimulation undergoes dephosphorylation and becomes more active at physiological concentrations of glucose-6-phosphate. Recently, insulin was shown to stimulate a cascade of phosphorylation-dependent kinases which ultimately activate a glycogen-bound subunit of a phosphatase (G-subunit of phosphatase-1) which promotes dephosphorylation GS by the catalytic subunit. The quantity of the GS enzyme (GStot) in muscle may be reduced in the diabetes disease. However, it may increase during physical training of insulin-dependent diabetic patients. GStot is not altered during acute exposure to insulin, hyperglycemia or muscle contraction. The insulin stimulation of GS is reduced in insulin resistant NIDDM patients. However, once the hyperglycemia and the insulin resistance is ameliorated during treatment with diet or sulphonylurea drugs the activation of GS improves. Growth hormone-induced transient insulin resistance in non-diabetic subjects, is accompanied by a reduced insulin stimulation of GS. Experimentally induced hyperglycemia in normal subjects has no influence on GS activation by insulin. After an acute exercise bout the GS in muscle becomes activated. The mechanism of this post-exercise GS activation is still unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin receptor function and glycogen synthase activity in human skeletal muscle. Physiology and pathophysiology. 803 33

The insulin receptor tyrosine kinase is required for insulin to elicit subsequent biological signalling. Recent studies have identified several endogenous substrates of the insulin receptor kinase, including one called insulin receptor substrate 1 (IRS-1). Tyrosine phosphorylation of this substrate results in its being bound by various proteins containing src homology 2 (SH2) sites, including a phosphatidylinositol 3-kinase and a ras activator complex containing GRB2 and son of sevenless (SOS) 1. Decreases in the insulin receptor tyrosine kinase activity have been observed in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. A model of insulin resistance has recently been described in which the insulin receptor is expressed in Chinese hamster ovary cells along with the phospholipid- and calcium-activated serine/threonine kinase called protein kinase C. In this model system, activation of protein kinase C is shown to interfere with insulin receptor signalling by inhibiting tyrosine phosphorylation of IRS-1 and its subsequent binding by phosphatidylinositol 3-kinase. Such a model system may be further utilized to determine the detailed biochemical basis for insulin resistance.
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PMID:Biochemical mechanisms of insulin resistance. 808 4


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