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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. Such antibodies were defined by their ability to compete with insulin for binding to insulin receptors and by their capacity to behave like insulin in activating lipogenesis in adipocytes. We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM.
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PMID:Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. 634 2

A literature survey and hypothesis is presented in which it is concluded that an intracellular ventromedial hypothalamic (VMH) glucopenia results in a bibrachial response consisting of adenohypophysial release of growth hormone and ACTH as well as sympathetic discharge, both of which act to elevate plasma glucose and remove the VMH glucopenia. This glucopenia may occur as a result of either a deficiency of circulating insulin or alterations in the kinetic properties of the VMH cellular insulin receptor. Two mechanisms for the development of insulin dependent diabetes mellitus (IDDM) are presented: (1) a defect in VMH glucose transport and/or metabolism such that a VMH glucopenia occurs with a subsequent bibrachial response. The result of this is glucose overproduction and a chronic excess glucose stimulus will eventually cause B-cell exhaustion (primary hypothalamic involvement). (2) reduction of the B-cell population by chemical, genetic and/or viral interactions with a consequential insulopenia results in a VMH glucopenia (secondary to a reduced glucose transport into the VMH cells) and causes a bibrachial response. This VMH response may temporarily restore plasma glucose balance but a chronically enhanced counter-regulatory response to maintain this balance will eventually stress the remaining B-cell population and cause further reductions in B-cell numbers (secondary hypothalmic involvement).
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PMID:A mechanism by which primary or secondary hypothalamic involvement results in the development of insulin-dependent diabetes mellitus (IDDM). 639 50

The single intravenous injection to rats of 1 ml of serum from an insulin resistant patient without an excessive titre of insulin antibodies (total extractable insulin levels: 0.8 U/l, serum insulin binding capacity: 1.58 U/l) and no demonstrable insulin receptor antibodies, produced fasting hyperglycemia in the animals on the fourth day following the injection (FPG: 212 +/- 35 mg %). On the 7th day the FPG returned to normal but the IVGTT was still pathological. After 14 days there was complete normalisation of the IVGTT. Glucose intolerance did not occur when rats were injected with 1 ml of the following control sera: the patient's serum following 6 months of treatment with cyclophosphamide when her insulin resistance was in remission, pooled sera from IDD's without insulin resistance, serum from an insulin resistant IDD with a high titre of insulin binding capacity (greater than 40 U/l) or with serum from a normal human subject. There were no alterations on light microscopy of the pancreatic islets of rats sacrificed on the 4th or 21st days. The above data suggest that our patient carried an uncharacterised substance which was capable of inducing glucose intolerance in rats. Hypothetically, it may be postulated that it was an immunoglobulin or some other protein acting via downregulation of insulin receptors or interfering with a post-receptor event mediating insulin action.
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PMID:Transient glucose intolerance in rats after a single injection of serum from a diabetic patient with an unusual insulin resistance. 666 41

Once thought to be solely a disease of insulin deficiency, diabetes mellitus now is recognized as a disorder with multiple pathogenetic mechanisms. Newer terminology identifies those uncommon patients with true insulin deficiency as having insulin-dependent diabetes (IDDM), while the majority of patients with diabetes have some residual insulin secretion but may have a disorder of insulin receptor number or affinity. These patients have non-insulin dependent diabetes (NIDDM). Other patients may have gestational diabetes, impaired glucose tolerance, a potential for glucose intolerance, or a previous history of diabetes. A few patients will have diabetes secondary to a known cause, such as pancreatitis or Cushing's syndrome. Understanding this nosological approach to diabetes should enhance the clinician's decisions regarding therapy.
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PMID:Classification and pathogenesis of the diabetes syndrome: a historical perspective. 705 Feb 15

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal 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 mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation. 782 30

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

We have recently reported two non-insulin-dependent diabetic patients exhibiting a heterozygous point mutation (R1152-Q) next to the key tyrosine autophosphorylation sites (Y1146, Y1150, Y1151) of the insulin receptor. In the present study, we demonstrate that the Q1152 mutation alters a previously unrecognized consensus sequence in the insulin receptor family of tyrosine kinases. To define the effect of this alteration on insulin receptor function, the mutant insulin receptor (Q1152) was constructed and overexpressed in NIH-3T3 cells. In spite of normal insulin binding, "in vivo" and "in vitro" autophosphorylation as well as transphosphorylation by the wild-type receptor (WT) were deficient in Q1152 as compared with the transfected WT receptors. Insulin-stimulated kinase activity toward poly(Glu, Tyr) 4:1 and the endogenous substrates p120 and p175 were also impaired in Q1152. However, insulin-independent kinase activity of Q1152 was 2-5-fold higher than that of WT. While insulin stimulated 2-deoxyglucose uptake and glycogen synthase activity in WT-transfected cells with a sensitivity proportional to receptor number, no insulin stimulation was observed in Q1152 cells. Similar to the kinase, insulin-independent glycogen synthase activity and 2-deoxyglucose uptake were 2-fold higher in Q1152 than in either WT or parental cells. We conclude that the Q1152 mutation deregulates insulin receptor kinase and generates insulin insensitivity in cells. Alterations in this highly conserved region of the insulin receptor may contribute to non-insulin dependent diabetes mellitin pathogenesis in humans.
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PMID:Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action. 838 32

Non insulin dependent diabetes mellitus (Type 2) is a multifactorial disease, with a polygenic inheritance and environmental factors contributing to its clinical expression. The search for the genetic determinants of Type 2 diabetes began when several genes involved in the mechanisms of insulin secretion or action were cloned, localized in the human genome, and when informative polymorphisms were described within or in the vicinity of these genes. It then became possible to compare, in groups of patients and normoglycaemic controls from various populations, the frequency of the different alleles of polymorphic markers of various candidate genes (e.g. insulin, insulin receptor, glucose transporters). The conflicting results observed in these studies can be ascribed to the small size of the population samples, to the genetic heterogeneity of Type 2 diabetes mellitus, but also to the methodology used therein. Indeed, these studies searched for a correlation between the frequency of certain alleles or genotypes and the phenotype of diabetes (studies of associations in affected populations compared to healthy controls). However in order to attribute to a gene the responsibility for a disease it is necessary to demonstrate the cotransmission in affected kindreds of a morbid allele of the gene along with the disease (familial or linkage analysis). The aim of this review is to summarize the results of family studies of Type 2 diabetes and Maturity Onset Diabetes of the Young (MODY), particularly with concern to the mutations described in candidate genes, and the implication of glucokinase in these disorders.
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PMID:Genetic determinants of type 2 diabetes mellitus: lessons learned from family studies. 850 79

Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146-1158 sequence of the human insulin receptor, and shows a high affinity for it. This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes. The ACP1 genotype was also determined in 482 non-diabetic pregnant women. In diabetic women glycemic levels in the last trimester of pregnancy appear to be significantly associated with the ACP1 genotype, and correlate positively with ACP1 enzymatic activity. The data suggest that quantitative variations of ACP1 may influence the clinical manifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways.
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PMID:Phosphotyrosine protein phosphatases and diabetic pregnancy: an association between low molecular weight acid phosphatase and degree of glycemic control. 862 Sep 37

Biguanides are used for the treatment of non-insulin dependent diabetes mellitus but there is no evidence for an improving action of biguanide on the enhancement of peripheral glucose disposal in type 1 diabetes. It is known that biguanide agents reduce the oxidation of free fatty acids. Using alloxan and streptozotocin (STZ) induced diabetic rats as a model for type 1 diabetes mellitus, we measured insulin binding capacity and plasma lipid peroxidation levels before and after metformin induction. There was a significant increase in insulin binding capacity and lipid peroxidation levels in alloxan and STZ diabetes compared to controls. We examined the effect of metformin on alloxan and STZ-induced diabetic rats. In alloxan-induced diabetes metformin (Met) treatment led to an increase in insulin receptor number in liver plasma membranes (before Met: 46.50 +/- 2.69, after Met: 76.00 +/- 3.39 fmol/mg, p < 0.001) and a decrease in plasma lipid peroxidation levels compared to the non-treated group (before Met: 1.85 +/- 0.53, after Met: 1.10 +/- 0.09 nmol MDA/ml, p < 0.05). In STZ-induced diabetic rats metformin treatment did not change the lipid peroxidation levels (before Met: 1.26 +/- 0.31, after Met: 1.38 +/- 0.44 nmol MDA/ml, p > 0.05) whereas it did increase the receptor numbers (before Met: 41.60 +/- 4.33, after Met: 63.40 +/- 8.64 fmol/mg, p < 0.002).
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PMID:The effect of metformin on insulin receptors and lipid peroxidation in alloxan and streptozotocin induced diabetes. 885 72


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