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

Insulin resistance in skeletal muscle plays a key role in the development of the metabolic-endocrine syndrome and its further progression to non-insulin-dependent diabetes mellitus (NIDDM). Available data suggest that insulin resistance is caused by impaired signalling from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase, which is found in NIDDM, appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutation of the receptor. Two potential mechanisms were investigated that might be relevant to the abnormal function of the insulin receptor in NIDDM. That is, changes of the receptor isoforms and the effect of hyperglycaemia. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). HIR-B expression in skeletal muscle is increased in NIDDM. Characterization of the functional properties of HIR-B, however, revealed that increased HIR-B expression did not cause impaired tyrosine kinase activity, but more probably represented a compensatory event. In contrast, hyperglycaemia is able to inhibit insulin receptor function. In a rat-1 fibroblast cell line overexpressing human insulin receptor, inhibition of the tyrosine kinase activity of the receptor can be induced by high glucose levels. This effect appears to be mediated through activation of certain protein kinase C isoforms, which are able to form stable complexes with the insulin receptor and modulate its tyrosine kinase activity through serine phosphorylation of the receptor beta-subunit. This mechanism might also be relevant in human skeletal muscle and thereby contribute to the pathogenesis of insulin resistance.
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PMID:Modulation of insulin signalling in non-insulin-dependent diabetes mellitus: significance of altered receptor isoform patterns and mechanisms of glucose-induced receptor modulation. 808 9

To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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PMID:Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. 810 37

The insulin receptor was evaluated at different disease stages in the sand rat (Psammomys obesus), a model for nutrition-induced diabetes. Nondiabetic sand rats showed markedly low receptor number in liver compared with albino rats. Their receptor had an intact tyrosine kinase activity but a higher Km for ATP in the phosphorylation reaction of exogenous substrates. The initial effects of overeating (i.e., development of hyperinsulinemia without hyperglycemia) were associated in the sand rat with a dramatic decrease in in vitro and in vivo insulin-induced receptor tyrosine kinase activity in both liver and muscle. In muscle, this coincided with a decrease in receptor number and an increase in basal tyrosine kinase activity. Similar changes were observed upon development of hyperinsulinemia with hyperglycemia. Upon recovery from the diabetic state by diet restriction, the impaired receptor kinase activation was corrected. Complete restoration occurred only in animals that fully recovered from the diabetic state and became normoinsulinemic. These observations indicate that loss and gain of receptor tyrosine kinase activity were dependent on insulin levels. Thus, overeating may lead to the development of hyperinsulinemia through ineffective extraction of excess insulin by the scarce liver receptors. Hyperinsulinemia, in turn, causes a reversible reduction in receptor kinase activity, leading to insulin resistance. This sequence of events may be relevant to diet-related changes in human non-insulin-dependent diabetes mellitus.
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PMID:Hyperinsulinemia induces a reversible impairment in insulin receptor function leading to diabetes in the sand rat model of non-insulin-dependent diabetes mellitus. 812 94

The insulin receptor is a member of the ligand-activated receptor and tyrosine kinase family of transmembrane signaling proteins that collectively are fundamentally important regulators of cell differentiation, growth, and metabolism. The insulin receptor has a number of unique physiological and biochemical properties that distinguish it from other members of this large well-studied receptor family. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor tyrosine kinases are engaged in regulating cell growth and/or differentiation. Receptor tyrosine kinases are allosterically regulated by their cognate ligands and function as dimers. In all cases but the insulin receptor (and 2 closely related receptors), these dimers are noncovalent, but insulin receptors are covalently maintained as functional dimers by disulfide bonds. The initial response to the ligand is receptor autophosphorylation for all receptor tyrosine kinases. In most cases, this results in receptor association of effector molecules that have unique recognition domains for phosphotyrosine residues and whose binding to these results in a biological response. For the insulin receptor, this does not occur; rather, it phosphorylates a large substrate protein that, in turn, engages effector molecules. Possible reasons for these differences are discussed in this review. The chemistry of insulin is very well characterized because of possible therapeutic interventions in diabetes using insulin derivatives. This has allowed the synthesis of many insulin derivatives, and we review our recent exploitation of one such derivative to understand the biochemistry of the interaction of this ligand with the receptor and to dissect the complicated steps of ligand-induced insulin receptor autophosphorylation. We note possible future directions in the study of the insulin receptor and its intracellular signaling pathway(s).
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PMID:The insulin receptor: structure, function, and signaling. 814 Dec 46

Hyperinsulinaemia due to pancreatic beta-cell tumours has been reported to lead to insulin resistance. A possible contribution of dysregulated insulin receptors to the impaired insulin action of insulinoma has not been explored. Therefore, we studied insulin receptor function in a patient with insulin-producing adenoma. This patient was rather unusual in that she was found to have a very large tumour and strikingly high circulating levels of insulin. In addition, her previous history included type 2 (non-insulin-dependent) diabetes mellitus. We confirmed decreased glucose utilization and metabolic clearance rate for glucose in presence of marked endogenous hyperinsulinaemia (approximately 2000 pM). 125I-labelled insulin binding capacity and receptor affinity for insulin were normal in her intact blood monocytes and erythrocytes. Insulin receptors were purified from the patient's tumour as well as from the pancreas, omental fat, liver and erythrocytes. All parameters of insulin binding to these receptors were normal. Thus, no evidence of receptor downregulation due to the marked hyperinsulinaemia was found. As expected, addition of insulin in vitro stimulated receptor autophosphorylation and tyrosine kinase activity of the receptors isolated from the liver, fat and erythrocytes. However, the basal tyrosine kinase activities of the tumour and pancreatic receptors were very high when isolated and further addition of insulin in vitro increased the protein kinase activity only slightly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin resistance in a case of coexisting insulinoma and type 2 diabetes. 818 Apr 17

The function of insulin receptor and IGF-1 receptor was investigated in placentas from 10 healthy control mothers, 8 diabetic mothers with appropriate-for-gestational-age babies (AGA group) and 9 diabetic mothers with large-for-gestational-age babies (LGA group). None of the diabetic mothers were obese before pregnancy; their blood glucose was well controlled during pregnancy and glycosylated HbA1c was 6.52 +/- 0.71% (M +/- S.E.). Insulin and IGF-1 receptors were partially purified from placentas using wheat germ agglutinin chromatography. The insulin-binding capacity was significantly increased in both the AGA and the LGA groups compared to the control, whereas the IGF-1 binding capacity was similar in the three groups. Autophosphorylation studies were performed with partially purified receptors equalized for similar binding capacity, then immunoprecipitated with anti-insulin receptor antibody or anti-IGF-1 receptor antibody. Insulin-stimulated 32P-incorporation into the insulin receptor beta-subunit was increased by 133% in the LGA group versus the control, whereas incorporation in the AGA group was equivalent to the control. Insulin-stimulated tyrosine kinase activity of the receptor preparation for histone H2B phosphorylation was also significantly increased in the LGA group compared to the control. 32P-incorporation into beta-subunit IGF-1 receptor and IGF-1-stimulated tyrosine kinase activity did not show any significant differences among the three groups. The data in the present study suggest that elevated insulin receptor kinase might be involved in fetal overgrowth in diabetic mothers.
Diabetes Res Clin Pract 1994 Jan
PMID:Insulin-receptor kinase is enhanced in placentas from non-insulin-dependent diabetic women with large-for-gestational-age babies. 820 Feb 91

A novel pathway for physiological "cross-talk" between the insulin receptor and the regulatory Gi-protein has been demonstrated. We tested the hypothesis that a coupling defect between Gi and the insulin receptor is present in the liver of obese patients with and without type II diabetes. Insulin 1 x 10(-9) M (approximately ED50) and 1 x 10(-7) M (Max) inhibited pertussis toxin-catalyzed ADP ribosylation of Gi in human liver plasma membranes from lean and obese nondiabetic patients. However, 1 x 10(-7) M insulin was without effect in membranes from patients with type II diabetes. This coupling defect was not intrinsic to Gi, since Mg2+ and GTP gamma S inhibited pertussis toxin-catalyzed ADP ribosylation in both diabetic and nondiabetic patients. Binding of insulin of the alpha-subunit and activation of the tyrosine kinase intrinsic to the beta-subunit of the insulin receptor are not responsible for the coupling defect. 125I insulin binding is the same in obese patients with or without diabetes. Tyrosine kinase of the insulin receptor is decreased in diabetes. However, a monoclonal antibody to the insulin receptor (MA-20) at equimolar concentrations with insulin equally inhibits pertussis toxin-catalyzed ADP ribosylation of Gi without activating tyrosine kinase or insulin receptor autophosphorylation. Immunodetection of G-proteins suggested that Gi3 alpha was normal in diabetes and Gi1-2 alpha was decreased by 40% in the diabetic group as compared to the obese nondiabetic group but was normal when compared to the lean non diabetic group. We conclude that the novel pathway of insulin signaling involving the regulatory Gi proteins via biochemical mechanisms not directly involving the tyrosine kinase of the insulin receptor is altered in obese type II diabetes and offers a new target for the search of the mechanism(s) of insulin resistance.
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PMID:Guanine nucleotide binding regulatory proteins in liver from obese humans with and without type II diabetes: evidence for altered "cross-talk" between the insulin receptor and Gi-proteins. 820 Sep 11

Hepatic insulin receptor tyrosine kinase activity (IR-TKA) correlates with plasma insulin levels in severely hyperinsulinemic Zucker rats (Diabetes 1990; 39: 619-625). We tested such a correlation in rat models of insulin resistance with plasma insulin concentrations in the physiologic range. Female Sprague Dawley rats drank either 10% glucose (G; n = 7) or 10% fructose (F; n = 5) in their water for two months and were compared to a control group (C; n = 6). The rats in both experimental groups developed hyperglycemia (G = 8.4 +/- 0.3, F = 8.5 +/- 1.1, C = 4.9 +/- 0.3 mM) but plasma insulin levels did not differ significantly (G = 144 +/- 30, F = 162 +/- 12, C = 108 +/- 6 pmol/L). There were no differences observed in any function of the hepatic insulin receptors between the rat groups. 125I-insulin binding to purified liver receptors was normal. However, for all groups, there was a significant correlation between in vivo plasma insulin levels and IR-TKA measured both in the absence (r = 0.47, p < 0.05) and presence (r = 0.57, p < 0.02) of added insulin in in vitro experiments. The same correlation was seen for the insulin/glucose ratio (as a measure of in vivo insulin resistance) vs. IR-TKA (r = 0.62, p < 0.01; r = 0.49, p < 0.05, in the basal and insulin-stimulated states, respectively). Thus, insulin in the physiologic range regulates TKA of rat liver IR. The TKA of hepatic IR isolated from such rats maintains the ability to be further stimulated by exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of hepatic insulin receptor tyrosine kinase in rat models of mild insulin resistance. 822 56

Endothelial cells are likely to play an important role in the development of diabetic vascular diseases, since they are exposed directly to the abnormal circulating metabolites of diabetes and may be easily damaged early in the natural course of vascular complications. In this study, aortic endothelial cells were cultured from diabetic BB rats. Their binding and internalization of insulin-like growth factor-I (IGF-I) were measured. IGF-I binding was higher in cells of diabetic rats than of control rats at both 37 degrees C (4.5% +/- 1.6% v 2.74% +/- 0.9% per mg protein, P < .05) and 4 degrees C (20.6% +/- 5.6% v 13.7% +/- 4.6% per mg protein, P < .01). Internalization of IGF-I also increased (1.62% +/- 0.2% v 0.74% +/- 0.15% of total count at 37 degrees C after 60 minutes, P < .05). Cross-linking studies showed that in cells from diabetic rats, the major band of 140 kd corresponding to the alpha-subunit of the IGF-I receptor increased in density by 50% compared with those from control rats. The IGF-I-stimulated tyrosine kinase activity (TKA) of partially purified receptor from cells of diabetic rats, measured using poly-glu-tyr as substrate, was normal. Since the biological effects of IGF-I are initiated by its binding to the IGF-I receptor, which is able to transduce mitogenic and metabolic signals, our results support the hypothesis that the IGF-I receptor is involved in the development of diabetic vascular complications.
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PMID:Insulin-like growth factor-I receptor increases in aortic endothelial cells from diabetic rats. 823 30

Due to alternative splicing of exon 11 of the receptor gene, the human insulin receptor exists in two forms, that have distinct tissue-specific expression and are functionally different. Needle biopsies obtained from vastus lateralis muscle from 20 patients with noninsulin-dependent diabetes mellitus (NIDDM) and 20 normal control subjects were analyzed for the relative expression of insulin receptor mRNA variants in a novel assay using fluorescence-labeled primers and subsequent analysis on an automated DNA sequencer. In subgroups of patients and control subjects, insulin binding and tyrosine kinase activity were examined in wheat germ agglutinin-purified insulin receptors isolated from muscle biopsies. Moreover, insulin-stimulated glucose disposal was studied by means of the euglycemic hyperinsulinemic clamp technique. No difference in the relative expression of spliced variants of the insulin receptor mRNA was observed (control subjects, 71.4 +/- 1.3% insulin receptor mRNA with exon 11; NIDDM patients, 71.5 +/- 1.3% insulin receptor mRNA with exon 11). No significant interrelationships were demonstrated among the relative expression of insulin receptor mRNA variants, insulin binding, and tyrosine kinase activity toward the exogenous substrate poly(Glu-Tyr(4:1)). Furthermore, no significant relationship was demonstrated between the glucose disposal rate and the relative expression of insulin receptor splice variants. In conclusion, in skeletal muscle from both normal control subjects and NIDDM patients, the proportion of insulin receptor mRNA with exon 11 is about 70%. In addition, no significant correlations exist among insulin binding, insulin receptor tyrosine kinase activity, glucose disposal rate, and expression of alternative spliced insulin receptors in human skeletal muscle.
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PMID:Expression of insulin receptor spliced variants and their functional correlates in muscle from patients with non-insulin-dependent diabetes mellitus. 826 33


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