Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By the term "insulin resistance" we understand the attenuation of insulin-stimulated glucose uptake, which is mainly due to attenuated glycogen synthesis in skeletal muscle and is partially compensated with regard to plasma glucose homeostasis by hyperinsulinemia. Other mechanisms of insulin are either not attenuated or are less so and may contribute via hyperinsulinemia to the prevalence of hypertension, obesity, dyslipoproteinemia and type-II diabetes. At the level of insulin receptors, resistance can be due to muscle-specific, preferential expression of the low-affinity B-isoform of the insulin receptors. In rare cases of extreme resistance, it can also be due to several mutations at the insulin receptor gene or due to insulin-receptor autoantibodies. At the postreceptor level, the translocation and or expression of the insulin-responsive glucose carrier GluT-4 can be down-regulated via the hexosamine pathway by hyperglycemia plus hyperinsulinemia. Furthermore, Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency, partially via c-AMP-dependent pathways. Additionally, the insulin-induced glycogen synthesis in skeletal muscle can be attenuated by the endogenous peptides amylin and calcitonin-gene-related peptide, and by modulations of endothelial function, perfusion and capillary recruitment in the microcirculation of skeletal muscle. Epidemiological data indicate a genetic predisposition for insulin resistance. However, among the many mechanisms potentially contributing to the complex syndrome of insulin resistance, no specific localization of that predisposition can be proposed at present.
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PMID:[The mechanisms of insulin resistance]. 153 3

Werner's syndrome is a genetic disease characterized by premature aging and is often associated with glucose intolerance due to insulin resistance. The clinical manifestations in this syndrome are preferentially expressed in the face and acral regions without apparent involvement of the trunk. We compared insulin receptor binding and amino acid uptake of fibroblasts derived from the forearm that had sclerodermoid features, and from the abdomen that was apparently normal in a patient with Werner's syndrome. In normal controls, specific insulin binding was not different in forearm and abdomen-derived fibroblasts (10.72 +/- 2.11%, 10.40 +/- 1.27%, respectively). In the patient, however, specific insulin binding was reduced in the fibroblasts derived from the forearm compared with those derived from the abdomen (3.55%, 8.16%, respectively). Scatchard analysis revealed that the reduction in insulin binding of the forearm fibroblasts from the patient was due to a reduction in receptor number with no change in receptor affinity. The dose-response curve for insulin of alpha-aminoisobutyric acid (AIB) uptake is shifted to the right in the fibroblasts derived from the acral area. The results show that in a patient with Werner's syndrome, regional differences occur in fibroblast insulin receptor binding and function. This suggests early phenotypic expression of the genetic abnormality of insulin receptor function in these patients.
Diabetes Res Clin Pract 1992 Feb
PMID:Regional differences in insulin receptor function in Werner's syndrome. 156 26

We analyzed single-stranded conformational polymorphisms to screen for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Using this new technique, we demonstrated the existence of mutations in the insulin receptor gene which we had identified previously. In addition, a new mutation was found in exon 20 of the insulin receptor gene in a patient with moderate insulin resistance associated with morbid obesity, acanthosis nigricans, and polycystic ovary syndrome. The patient was heterozygous for a mutation substituting Leu (CTG) for Pro (CCG) at codon 1178. Pro1178 is a part of a characteristic sequence motif (D1150 F1151 G1152---A1177 P1178 E1179) common to many protein kinases. Analysis of single-stranded conformational polymorphisms was also used to estimate the frequency of a polymorphism at codon 1058. The two codons CAC (1058 His) and CAT (1058 His) both had a prevalence of 50% in 30 Japanese subjects. These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance.
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PMID:Detection of mutations in the insulin receptor gene in patients with insulin resistance by analysis of single-stranded conformational polymorphisms. 156 82

Gliclazide is a second-generation sulfonylurea that is widely used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It has been recommended for use on the basis of both its metabolic and nonmetabolic effects. It has a clear beneficial effect on metabolic control in NIDDM. Blood glucose and lipid levels are lowered. The glucose-lowering effects are secondary to both enhanced insulin secretion and a decrease in insulin resistance. The former is due to closure of a K+ adenosine triphosphate (ATP) channel in the beta cell. The mechanism whereby insulin action on the liver and muscle are potentiated remains unknown. It does not appear to involve the insulin receptor, and although glycogen synthase activation is enhanced, this is probably not specific. It has proven difficult to separate the metabolic effects of gliclazide from the effects of improved control. The metabolic actions are probably also shared with other sulfonylureas. Gliclazide also has beneficial effects on platelet behavior and function and on the endothelium, in addition to improving free radical status. These effects should be beneficial for the prevention of diabetic microangiopathy and macroangiopathy. Some evidence has appeared for the prevention of deterioration of diabetic retinopathy, but results are variable and more convincing studies are required. Many of the nonmetabolic effects of gliclazide appear to be unique to this agent. Gliclazide thus appears to be a reasonable choice in the treatment of NIDDM with diet failure, both from the metabolic and nonmetabolic standpoint.
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PMID:Gliclazide: metabolic and vascular effects--a perspective. 157 15

Hyperglycemic emergencies are the most common endocrinopathies that require intensive care. It is estimated that between 10% and 15% of patients admitted to intensive care units experience complications of acute hyperglycemia. The common denominator of hyperglycemic emergencies is diabetes mellitus, a group of diseases in which, either because of beta-cell destruction of the pancreas or insulin receptor-site defects, there is a relative or absolute deficiency of insulin that results in hyperglycemia. In response to various precipitating factors, staggering hyperglycemia may develop in the form of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar nonketotic syndrome (HHNK). The existence of DKA has been known since ancient times, and critical care nurses are familiar with the diagnosis. The more lethal disorder of HHNK was "rediscovered" in the 1950s and is occurring with greater frequency as clinical awareness of the condition grows and the elderly (who are at greatest risk for the disorder) populate critical care units in increasing numbers. Prevention is instrumental in abating deadly hyperglycemic emergencies. A positive outcome can be realized but only with timely diagnosis and prompt hormonal and fluid replacement.
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PMID:Hyperglycemic emergencies. 157 33

To assess the mechanism of insulin resistance in sepsis, we investigated insulin receptor binding and glucose uptake in isolated rat epididymal adipocytes. Male Sprague-Dawley (SD) rats weighing 200-220 g were submitted to cecal ligation under chloral hydrate anesthesia, followed by double punctures with 18-G needle into the ligated portion to produce peritonitis. Age-matched SD rats without operation were used as the controls. After starvation for 16 h, blood samples were taken from the inferior vena cava for bacterial culture and assayed for plasma glucose and IRI levels, and then adipocytes were isolated from the dissected epididymal fat tissues. Plasma levels of both glucose and IRI in septic rats were higher than those in the controls. The [125I]-insulin binding rate of the adipocytes in septic rats was similar to that of the controls. However, [3H]-2-deoxy-D-glucose uptake by adipocytes was markedly decreased in the septic group (approximately 45% of the control group at the plateau). In conclusion, this study suggests that insulin resistance in the septic state results, at least partly, from impairment in the post-binding level of the insulin receptor.
Diabetes Res Clin Pract 1992 Mar
PMID:Sepsis inhibits insulin-stimulated glucose transport in isolated rat adipocytes. 157 21

Point mutation of mitochondrial DNA has been described in the blood from a MELAS patient. The 39-year-old patient developed progressive dementia, stroke-like episodes, heart conduction defect (Lown-Ganong-Levin syndrome) and cortical blindness. CT scan revealed brain atrophy and low density areas in the bilateral occipital lobes. Laboratory tests showed hyperglycemia and lactic acidosis. Muscle biopsy showed ragged red fibers on Gomori trichrome staining. He was clinically diagnosed as having MELAS and insulin-dependent diabetes mellitus. Onset of diabetes mellitus and MELAS was almost same. Family history showed his mother's brother and sisters had also insulin-dependent diabetes mellitus. We amplified the leucine (UUR) tRNA gene from the patient's blood with polymerase chain reaction (PCR) and analysed it by restriction enzyme analysis and sequencing. Genetic analysis showed A-to-G substitution at the nucleotide position 3243 in the leucine (UUR) tRNA gene. This substitution made a new restriction site Apa I. Mutant DNA coexisted with wild type DNA (heteroplasmy). It is shown that in some types of mitochondrial encephalomyopathies, especially patients of Kearns-Sayre syndrome (KSS), diabetes mellitus is often complicated. And in KSS patients insulin receptor in normal, but insulin secretion from beta cells of pancreas is decreased. In MELAS patients, however, has diabetes mellitus been reported to be rarely complicated and relationship between MELAS and diabetes mellitus is not done. As far as we know, two cases, including ours, with genetically diagnosed MELAS have been reported to have diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[MELAS associated with diabetes mellitus and point mutation in mitochondrial DNA]. 159 Nov 3

Two insulin receptor mRNA transcripts resulting from alternative splicing of exon 11 in the receptor gene are expressed in a highly regulated tissue-specific fashion. To date, there is no information about the relative abundance of the protein isoforms encoded by these mRNAs in tissues of normal or diabetic subjects. We employed an antibody raised against the peptide sequence encoded by exon 11 to develop a specific immunoprecipitation assay that is capable of determining the fraction of receptors that include this amino acid sequence. The assay is based on the relative ability of the exon 11 specific monoclonal antibody (alpha IR alpha) compared to a nonspecific anti-receptor antiserum (B-2) to immunoprecipitate solubilized receptors that are first labeled with 125I-insulin. The assay was validated using standard curves generated with samples composed of known ratios of the two receptor isoforms. Our results in general confirm observations regarding the relative abundance of the two mRNA species in human tissues, with marked predominance of the exon 11+ isoform in liver, and the exon 11- isoform in leukocytes. Similar amounts of both variants are present in placenta, skeletal muscle, and adipose tissue. In studies with this assay using skeletal muscle extracts from control and noninsulin-dependent diabetes mellitus (NIDDM) subjects, as well as in studies of the two mRNAs in control versus NIDDM muscle using a quantitative polymerase chain reaction assay, we could find no significant difference between control and diabetic subjects. This data contradicts a recent report claiming that normal individuals have only the exon 11- mRNA transcript in their skeletal muscle, whereas NIDDM subjects have similar expression of both mRNAs. Given the emerging evidence that functional differences exist between the two receptor isoforms, these studies are relevant to our understanding of insulin receptor function in health and disease.
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PMID:Alternatively spliced variants of the insulin receptor protein. Expression in normal and diabetic human tissues. 160 13

Denaturing gradient gel electrophoresis (DGGE) has been used to screen for mutations in the insulin receptor gene. Each of the 22 exons was amplified by the polymerase chain reaction (PCR). For each exon, one of the two PCR primers contained a guanine-cytosine (GC) clamp at its 5' end. The DNA was analyzed by electrophoresis through a polyacrylamide gel containing a gradient of denaturants. Two geometries for the gels were compared; the gradient of denaturants was oriented either parallel or perpendicular to the electric field. The sensitivity of the technique was evaluated by determining whether DGGE succeeded in detecting known mutations and polymorphisms in the insulin receptor gene. With parallel gels, 12 of 16 sequence variants were detected. The use of perpendicular gels increased the sensitivity of detection so that all 16 sequence variants were successfully detected when DNA was analyzed by a combination of perpendicular and parallel gels. Furthermore, DGGE was used to investigate a patient with leprechaunism whose insulin receptor genes had not previously been studied. Two mutant alleles were identified in this patient. The allele inherited from the father had a mutation substituting alanine for Val-28; in the allele inherited from the mother, arginine was substituted for Gly-366.
Diabetes 1992 Apr
PMID:Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis. 160 67

It has been shown that insulin associated with nanocapsules of isobutylcyanoacrylate retains biological activity after oral administration to diabetic rats from 6 to 21 days. Because part of this action is unexplained, we focused on the interaction of encapsulated insulin with the insulin receptor in vitro. We have shown that encapsulated insulin is able 1) to bind to insulin receptors both in rat liver plasma membranes and after solubilization from Chinese hamster ovary (CHO) cells transfected with the gene of human insulin receptor, 2) to accelerate 125I-labeled insulin dissociation from its receptor, and 3) to ensure transduction of a signal leading to stimulation of the beta-subunit phosphorylation, with parameters similar to those of native insulin. In addition, encapsulated 125I-insulin was rapidly internalized in transfected CHO cells. Analysis of cell-associated radioactivity showed that encapsulated insulin remained largely intact (greater than 80%) after 3 h, whereas native insulin was mostly degraded. These data indicate that encapsulated insulin fulfills all the earliest events at the receptor level leading to biological actions and suggests that encapsulation protects insulin against insulin degradation inside the cells.
Diabetes 1992 Apr
PMID:Encapsulation of insulin for oral administration preserves interaction of the hormone with its receptor in vitro. 160 72


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