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

Insulin regulation of hepatic glucose production (HGP) is altered in non-insulin-dependent diabetes mellitus (NIDDM), resulting in increased glucose output by the liver; this contributes to the elevation in plasma glucose concentration observed both in the basal state and postprandially. Therefore, restoration of normal insulin action in the liver must be a goal of hypoglycemic therapy. Sulfonylureas have been widely used for treatment of NIDDM over the past 30 years. In addition to their stimulatory effect on insulin secretion, these compounds seem to possess extrapancreatic effects. Early in vitro studies showed that addition of sulfonylureas to the perfusion medium of liver preparations could exert a significant suppressive effect on HGP. Subsequent experience suggested that these compounds could act at the level of the insulin receptor as well as at various postreceptor sites. These studies showed that sulfonylureas may inhibit glycogenolysis and gluconeogenesis while stimulating glycogen synthesis. Results obtained in vivo in NIDDM patients are in agreement with the in vitro studies. Long-term treatment with sulfonylureas is associated with a decline in fasting plasma glucose concentration and a parallel reduction in HGP. Nevertheless, the direct effect of sulfonylurea administration on the liver remains unclear, since the reduction in HGP that occurs during sulfonylurea treatment may be secondary to an overall improvement in insulin secretion. It is also of interest that in insulin-dependent diabetic patients, sulfonylurea administration in combination with insulin injections is not followed by a significant change in HGP. Possible effects of sulfonylureas on glucagon secretion and on the metabolism of free fatty acids (FFAs) may also contribute to improved sensitivity of the liver to the suppressive action of insulin, since these agents appear to reduce plasma glucagon and FFA concentrations. Thus, present data support an extrapancreatic action of sulfonylureas on the liver. However, it does appear that a certain degree of residual insulin secretion is required for sulfonylurea agents to elicit their hepatic effect.
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PMID:Hepatic sensitivity to insulin: effects of sulfonylurea drugs. 187 1

A homeomorphic mathematical model of cell surface insulin receptor regulation is developed. The overall structure of the model is based on molecular mechanisms suggested by in vivo and in vitro experimental evidence from many different cell types. Model parameters correspond to cellular processes which are constrained by known boundry value conditions. As an example, computer simulation results are compared with published data from BC3H-1 myocytes in culture. With appropriate parameter choice, this model is able to simulate data from other cell types. Cellular processes which are explicitly represented in the model include: bound and unbound receptor endocytosis, receptor recycling, intracellular receptor degradation, and state-dependent receptor synthesis. Most of these processes are represented as first-order events. Using more complex representations of the model structure with higher order rate constants or saturable pathways does not qualitatively improve simulation results. Simulations are able to reproduce ligand-induced down and up regulation of receptors as well as the initial spontaneous display of surface insulin receptors. To demonstrate the behavior of our model and illustrate its utility for explaining insulin receptor regulation for a variety of conditions, simulations for which experimental data is unavailable for direct comparison are also shown. We believe the structure of our model is sufficient to explain insulin receptor regulation in a wide variety of cell types. In addition our model may aid in understanding the receptor component of insulin resistance (decreased sensitivity or responsiveness to insulin) seen in pathological states such as obesity and diabetes mellitus. Finally, this model may be applicable to the study of the regulation of other polypeptide hormone receptors.
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PMID:A mathematical model and computer simulation study of insulin receptor regulation. 189 Aug 48

Family studies suggest a strong genetic component in the aetiology of non-insulin dependent diabetes (NIDDM), with evidence for a major gene of co-dominant or dominant effect. A gene-dosage effect, whereby diabetes develops earlier in people with two susceptibility genes than in those with one susceptibility gene is likely. The search for the diabetes gene has led to the cloning and characterization of many genes involved in controlling glucose homeostasis. These include the insulin, insulin receptor, glucose transporter, amylin and glucokinase genes. Molecular techniques have permitted rapid screening of these genes in NIDDM patients and controls. There is now a rather contradictory genetic literature for NIDDM, with weak disease associations reported and refuted for most candidate genes. However, pedigree analyses and DNA sequencing of available candidate genes and their regulatory regions have failed to implicate any of these in the common form of diabetes, NIDDM. Methodical application of random clones in well-defined NIDDM families may be the strategy of choice in finding the NIDDM genes, given the wide range of genes potentially involved in the glucose and lipoprotein metabolic disturbances seen in NIDDM.
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PMID:Genetics of non-insulin dependent diabetes mellitus in 1990. 189 73

Proposed mechanisms by which insulin exerts its effects are discussed. Evidence for a role for the tyrosine kinase activity of the insulin receptor and of a phosphorylation/dephosphorylation cascade is presented. The possible roles of phospholipid breakdown, diacylglycerol, and protein kinase C are discussed. The hypothesis that insulin elicits the hydrolysis of a glycosyl phosphatidylinositol to form a mediator of certain of its actions is considered in detail. The evidence that a G protein is involved in insulin action is analyzed.
Diabetes 1991 May
PMID:Some thoughts on the mechanism of action of insulin. 190 25

The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period, mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L, p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L, p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast, insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover, gliclazide had no impact on maximal glycogen synthase activity. However, under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). In conclusion, sulfonylurea treatment of NIDDM enhances insulin-stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase.
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PMID:Effects of sulfonylureas on adipocyte and skeletal muscle insulin action in patients with non-insulin-dependent diabetes mellitus. 190 82

Insulin resistance is a common feature of non-insulin-dependent diabetes mellitus (NIDDM) and "diabetes susceptibility genes" may be involved in this abnormality. Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. Since binding properties of the IRs from NIDDM subjects are normal, we also analyzed the sequence of exons 16-22 (encoding the entire cytoplasmic domain of the IR) of the IR gene from the same six patients. When compared with the normal IR sequence, no difference was found in the predicted amino acid sequence of the IR cytoplasmic domain derived from the NIDDM patients. Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383. Consequently, the GLUT-4 sequence at position 383 was determined in 24 additional NIDDM patients and 30 nondiabetic controls and all showed only the normal sequence. From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. Possibly, a subpopulation of NIDDM patients exists displaying variation in the GLUT-4 gene.
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PMID:Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. 191 82

Hepatic insulin proreceptors and receptors were studied in control and in ketotic diabetic rats 2-4 wk after streptozotocin treatment. Solubilized preparations were partially purified by wheat germ agglutinin-agarose (WGA) and lentil lectin agarose (LLA) chromatography to enrich eluates in insulin receptors and proreceptors, respectively. After phosphorylation with [gamma-32P]ATP, an approximately 190-kDa glycoprotein was identified in LLA eluates as the insulin proreceptor, based on insulin dose-dependent tyrosine autophosphorylation, immunoprecipitation with insulin receptor-specific antibodies, and high-mannose glycosylation. Mature approximately 95 kDa phosphorylated beta-subunits were present in both LLA and WGA eluates. LLA also showed phosphorylated partially processed beta-subunits (approximately 85 kDa) and proreceptors (approximately 190 kDa). Proreceptors comprised less than 1% of the total yield of hepatic insulin receptors. The incorporation of 32P into proreceptors (per gram liver or DNA) was 4.7- or 4.5-fold greater in diabetic vs. control rats, whereas receptor labeling increased only 1.8- or 1.5-fold in diabetic rats. beta-Subunit autophosphorylation per receptor was identical in control and diabetic rats. The phosphorylation data suggested a diabetes-associated 2.6-fold increase in proreceptor-to-receptor ratios. When assessed by cross-linking with 125I-labeled insulin or by immunoblotting, proreceptor-to-receptor ratios were increased 1.5- and 3.1-fold, respectively, in diabetic rats. The data suggest that uncontrolled diabetes may alter insulin receptor processing.
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PMID:Increased hepatic insulin proreceptor-to-receptor ratio in diabetes: a possible processing defect. 195 80

The syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the beta-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 mumol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.
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PMID:Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. 195 1

To elucidate the mechanism responsible for the decreased insulin binding to erythrocytes in uremic patients, the effects of incubation with sera obtained from uremic patients or with methylguanidine, respectively, on insulin binding were examined. Insulin binding to erythrocytes from uremic patients was lower than that from normal subjects (3.1 +/- 0.19% vs 6.6 +/- 0.33%, Mean +/- SEM, P less than .005), being due mainly to decreased binding affinity (58% of control). Incubation of erythrocytes with 1:5 diluted sera of uremic patients resulted in decreased insulin binding (65 +/- 5% of control) and this decrease was restored to the level of 78 +/- 3% of the controls after incubation with buffer for 12 h. Methylguanidine inhibited insulin binding to erythrocytes in a dose-dependent manner. Post-dialyzed serum with 100 ng/ml of methylguanidine (as seen in pre-dialyzed uremic patients) inhibited insulin binding to erythrocytes as much as pre-dialyzed serum (54.3 +/- 3% vs 47 +/- 1% of control). Incubation of IM-9 lymphocytes with 100 ng/ml of methylguanidine did not alter the insulin receptor mRNA level. These results suggest that methylguanidine inhibits insulin binding to its receptor, resulting in decreased insulin binding to erythrocytes.
Diabetes Res Clin Pract 1991 Sep
PMID:Inhibitory effect of methylguanidine on insulin binding to its receptor. Mechanism underlying insulin resistance in uremia. 195 80

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. Recently, we have demonstrated a decrease of insulin binding and autophosphorylation of the insulin receptor in cultured capillary endothelial cells of diabetic rats. In this study, similar defects in insulin receptor of aortic endothelial cells cultured from diabetic BB rats were found. The specific insulin binding was 45% lower in cells from diabetic than from non-diabetic rats (3.9 +/- 1.3 vs 7.3 +/- 1.2% per mg protein, p less than 0.05), which was due to a decrease of cell surface binding sites. In contrast to the decrease in insulin binding, insulin-like growth factor-I binding was higher in cells of diabetic than control rats (20.6 +/- 5.6 vs 13.7 +/- 4.6% per mg protein). The decrease in insulin binding could not be induced by the two-week treatment of endothelial cells from non-diabetic rats with medium containing high concentration of glucose (400 mg/dl). Insulin-induced tyrosine kinase activity of partially purified insulin receptor measured using poly-glutyr as substrate was also lower in cells from diabetic rats (normal:1.4 +/- 0.6-fold; diabetic 0.5 +/- 0.3-fold above baseline; (p less than 0.05). These data suggest that the diabetic milieu in vivo can induce persistent defects in insulin receptor of aortic endothelial cells. Further studies are warranted to understand the potential pathophysiological role of these defects.
Diabetes Res 1990 May
PMID:Changes of insulin receptor in aortic endothelial cells from diabetic rats. 196 86


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