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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperinsulinaemia and insulin resistance have been hypothesized to be the common pathophysiological factor of hypertension, NIDDM and obesity. To evaluate the possible role of hyperinsulinaemia and insulin resistance on hypertension, we studied a group of 37 patients with insulinoma who were admitted to our department in the period from 1966 to 1990. We recorded blood pressure and assayed blood glucose, plasma insulin, plasma triglycerides and serum uric acid levels, before and after surgery, in these patients and in a 37-subject control group. No significant increase in blood pressure and triglyceride plasma levels was recorded in the chronic hyperinsulinaemic hypoglycaemic patients, suggesting the lack of a direct role of hyperinsulinaemia on hypertension.
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PMID:Effect of endogenous organic hyperinsulinaemia on blood pressure and serum triglycerides. 808 12

During the period between January 1981 and December 1992, a total of ten patients with pathologically confirmed insulinoma were studied. All patients presented with variable degrees of neuroglycopenic symptoms and Whipple's triad. The ratio of insulin to glucose after an overnight fast was greater than 0.3 in 90% (9/10) of patients. Eight patients who received supervised fasting developed neuroglycopenia with relative hyperinsulinemia within 48 hours of fasting. Four of 8 patients developed hypoglycemia during a 5-hour oral glucose tolerance test (OGTT). Calcium infusion test was more sensitive in patients with an initially higher plasma glucose. The detection rates of various localization studies were 12.5% (1/8) by abdominal ultrasonography, 37.5% (3/8) by abdominal CT scan, 50% (5/10) by selective superior mesenteric and celiac arteriography. Transhepatic portal venous sampling (THPVS) detected insulinomas in 4 of 4 cases. Endoscopic ultrasonography and intraoperative ultrasonography were performed on 1 and 2 cases respectively, and were able to localize the lesions successfully. All patients received surgical treatment including enucleation (n = 2), subtotal pancreatectomy (n = 3) and distal pancreatectomy (n = 5). All patients had single tumors which were all benign islet cell adenomas. The mean size of the tumors was 15.5 +/- 2.0 mm in diameter (range: 8 to 30 mm) and mainly located in the body (50%) and tail (40%), only 1 in the pancreatic head. All symptoms of hypoglycemia subsided after operation. Hyperglycemia was observed in all patients immediately after operation, and most of them resumed normoglycemia within 8 days. However, the 2 patients who had impaired OGTT preoperatively had persistent hyperglycemia after operation and therefore were diagnosed as having diabetes (NIDDM).
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PMID:Insulinoma--clinical experience in ten cases. 820 95

Physiologically, a postprandial glucose rise induces metabolic signal sequences that use several steps in common in both the pancreas and peripheral tissues but result in different events due to specialized tissue functions. Glucose transport performed by tissue-specific glucose transporters is, in general, not rate limiting. The next step is phosphorylation of glucose by cell-specific hexokinases. In the beta-cell, glucokinase (or hexokinase IV) is activated upon binding to a pore protein in the outer mitochondrial membrane at contact sites between outer and inner membranes. The same mechanism applies for hexokinase II in skeletal muscle and adipose tissue. The activation of hexokinases depends on a contact site-specific structure of the pore, which is voltage-dependent and influenced by the electric potential of the inner mitochondrial membrane. Mitochondria lacking a membrane potential because of defects in the respiratory chain would thus not be able to increase the glucose-phosphorylating enzyme activity over basal state. Binding and activation of hexokinases to mitochondrial contact sites lead to an acceleration of the formation of both ADP and glucose-6-phosphate (G-6-P). ADP directly enters the mitochondrion and stimulates mitochondrial oxidative phosphorylation. G-6-P is an important intermediate of energy metabolism at the switch position between glycolysis, glycogen synthesis, and the pentose-phosphate shunt. Initiated by blood glucose elevation, mitochondrial oxidative phosphorylation is accelerated in a concerted action coupling glycolysis to mitochondrial metabolism at three different points: first, through NADH transfer to the respiratory chain complex I via the malate/aspartate shuttle; second, by providing FADH2 to complex II through the glycerol-phosphate/dihydroxy-acetone-phosphate cycle; and third, by the action of hexo(gluco)kinases providing ADP for complex V, the ATP synthetase. As cytosolic and mitochondrial isozymes of creatine kinase (CK) are observed in insulinoma cells, the phosphocreatine (CrP) shuttle, working in brain and muscle, may also be involved in signaling glucose-induced insulin secretion in beta-cells. An interplay between the plasma membrane-bound CK and the mitochondrial CK could provide a mechanism to increase ATP locally at the KATP channels, coordinated to the activity of mitochondrial CrP production. Closure of the KATP channels by ATP would lead to an increase of cytosolic and, even more, mitochondrial calcium and finally to insulin secretion. Thus in beta-cells, glucose, via bound glucokinase, stimulates mitochondrial CrP synthesis. The same signaling sequence is used in the opposite direction in muscle during exercise when high ATP turnover increases the creatine level that stimulates mitochondrial ATP synthesis and glucose phosphorylation via hexokinase. Furthermore, this cytosolic/mitochondrial cross-talk is also involved in activation of muscle glycogen synthesis by glucose. The activity of mitochondrially bound hexokinase provides G-6-P and stimulates UTP production through mitochondrial nucleoside diphosphate kinase. Pathophysiologically, there are at least two genetically different forms of diabetes linked to energy metabolism: the first example is one form of maturity-onset diabetes of the young (MODY2), an autosomal dominant disorder caused by point mutations of the glucokinase gene; the second example is several forms of mitochondrial diabetes caused by point and length mutations of the mitochondrial DNA (mtDNA) that encodes several subunits of the respiratory chain complexes. Because the mtDNA is vulnerable and accumulates point and length mutations during aging, it is likely to contribute to the manifestation of some forms of NIDDM.(ABSTRACT TRUNCATED)
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PMID:Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. 854 53

Pancreatic beta-cell mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) plays a major role in glucose-induced insulin secretion. Decreased activity of this enzyme has thus been proposed to play a role in the pathogenesis of NIDDM. Cloning of human insulinoma mGPDH cDNAs disclosed the existence of two variant transcripts with different 5' ends. Reverse transcription polymerase chain reaction (PCR) confirmed the presence of both mGPDH mRNAs in purified native human pancreatic islets and other tissues. A major 6.5-Kb mGPDH transcript was detected by Northern blot analysis in RNA from human and rat pancreatic islets, with distinctly lower levels in other human tissues, indicating that previously reported high mGPDH enzymatic activity in beta-cells is determined by high transcript levels. The mGPDH gene was mapped to chromosome 2 by PCR analysis of genomic DNA from human/rodent somatic cell hybrids, and five independent overlapping yeast artificial chromosome (YAC) clones containing the mGPDH sequence were identified from the Centre d'Etude du Polymorphisme Humain YAC library. Analysis of these YAC clones identified a highly polymorphic chromosome 2q21-q33 dinucleotide repeat genetic marker (D2S141) physically linked to the mGPDH gene. These studies provide the means to investigate the role of the human mGPDH gene in the pathogenesis of NIDDM and illustrate the value of a novel strategy to identify genetic markers for diabetes candidate genes.
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PMID:Mitochondrial glycerol-3-phosphate dehydrogenase. Cloning of an alternatively spliced human islet-cell cDNA, tissue distribution, physical mapping, and identification of a polymorphic genetic marker. 854 72

The pancreatic islet hormone, glucagon, stimulates hepatic glucose production and has also been shown to potentiate glucose-induced insulin secretion. Because glucagon is a key regulator of glucose homeostasis, its receptor, which mediates the actions of glucagon, was considered a candidate gene involved in the pathogenesis of NIDDM. We have previously reported that a single heterozygous missense mutation in exon 2 of the glucagon receptor gene, which changes a glycine to a serine (Gly40Ser), is associated with NIDDM in a French population. In the present study, the signaling properties of this mutant receptor were examined in baby hamster kidney cells and rat insulinoma cells (RIN-5AH) stably transfected with either the wild type or Gly40Ser mutant human glucagon receptor cDNAs. Competition assays using (125)I-labeled glucagon were performed, and in both cell types, the Gly40Ser mutant receptor was found to bind glucagon with an approximately threefold lower affinity compared with the wild type receptor. In both cell types, the production of cAMP in response to glucagon was decreased in cells expressing the mutant receptor compared with those expressing the wild type. Finally, glucagon-stimulated insulin secretion by RIN cells expressing the mutant receptor was decreased such that the dose-response curve was shifted to the right in comparison to that obtained with cells expressing the wild type receptor. These results indicate that this single-point mutation located in the extracellular region of the glucagon receptor decreases the sensitivity of target tissues to glucagon.
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PMID:The Gly40Ser mutation in the human glucagon receptor gene associated with NIDDM results in a receptor with reduced sensitivity to glucagon. 863 44

cDNA of mitochondrial glycerophosphate dehydrogenase (mGPDH), a defect of which is a possible cause of non-insulin dependent diabetes mellitus, was cloned from a human insulinoma cDNA library. The deduced amino acid sequence showed 91% and 92% homology with those of rat and mouse mGPDH, respectively. The mGPDH gene was mapped to chromosome 2q23 by FISH analysis. Genomic clones for mGPDH were then isolated using mouse mGPDH cDNA and PCR products of human mGPDH cDNA as probes. Genomic structure was studied by sequencing the exon-intron boundaries and by PCR amplification of intronic regions using genomic clones as templates. The human mGPDH gene was shown to be composed of 15 coding exons, containing a (CA)n repeat region inside the gene, which was not polymorphic in the Japanese population. Genomic cloning also identified a pseudogene located on chromosome 19q13.4. These results provide information useful for analyzing the mGPDH gene in patients with non-insulin dependent diabetes mellitus.
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PMID:Molecular cloning of human mitochondrial glycerophosphate dehydrogenase gene: genomic structure, chromosomal localization, and existence of a pseudogene. 868 21

By an indirect immunofluorescence method with In-111 cells (hamster insulinoma cell line), circulating islet cell surface antibodies (ICSA) were detected in 7 (20%) out of 36 patients with non-insulin dependent diabetes mellitus (NIDDM), 9% of 68 chronic thyroiditis (CT) patients, or 16% of 19 NIDDM patients associated with CT, but not in 18 normal subjects. Sera from five out of nine ICSA-positive patients examined further also showed cell-surface immunofluorescence on TPC-1 cells (human thyroid papillary adenocarcinoma cell line), and prior absorption of the sera with In-111 cells abolished the immunofluorescence. The 64 kDa protein from In-111 cells or human thyroid follicular cells was immunoprecipitated with ICSA-positive sera. In one case of NIDDM associated with CT, 64 kDa protein was detected in both cells. The results indicate that some ICSA in NIDDM patients recognize the same or a very closely-related autoantigen(s) in both islet beta-cells and thyroid follicular cells, suggesting an explanation, at least in part, for the autoimmune mechanism(s) in clinical association of NIDDM and CT.
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PMID:A possible common cell surface autoantigen in islet beta-cells and thyroid follicular cells in patients with non-insulin dependent diabetes mellitus and chronic thyroiditis. 888 24

The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (MODY3), with MODY2 and MODY3 being allelic with the genes encoding glucokinase, a key regulator of insulin secretion, and hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression.
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PMID:Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) 894 61

Insulin sensitivity was evaluated in 16 insulinoma patients and in 15 obese persons with Type 2 diabetes mellitus by using hyperinsulinaemic clamps and analysis of insulin receptor characteristics on erythrocytes. Significantly decreased insulin sensitivity index (M/l) was found in both insulinoma and obese Type 2 diabetic patients as compared with healthy non-obese controls (21.2 +/- 2.2 and 19.5 +/- 2.6 vs 40.3 +/- 3.7 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.001). No difference was observed between both groups of patients. Metabolic clearance rate of glucose was strongly reduced in obese diabetic patients but it was normal in insulinoma patients in comparison with healthy persons (2.7 +/- 0.4 vs 8.7 +/- 0.6 or 7.9 +/- 0.7 ml.kg-1.min-1, p < 0.001). A decreased insulin binding on specific receptors caused by reduced binding capacity was observed only in insulinoma patients but not in obese Type 2 diabetic patients. A significant negative correlation was proved between body mass index (BMI) and insulin sensitivity index (r = -0.82, p < 0.001) indicating that BMI is the main determining factor of insulin resistance in the total cohort of examined patients. We conclude that insulin resistance was caused by postreceptor changes in obese Type 2 diabetes, whereas a decreased insulin binding capacity together with post-receptor defect was present in insulinoma patients.
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PMID:Comparison of insulin sensitivity in patients with insulinoma and obese Type 2 diabetes mellitus. 896 Sep

The C-peptide suppression test employing the euglycemic hyperinsulinemic clamp technique has been proposed as a useful diagnostic measure for insulinoma. To examine the specificity of the C-peptide suppression, we applied this test to subjects with symptoms suggesting reactive hypoglycemia. Five subjects studied had never experienced fasting hypoglycemia, and were negative in ultrasound, CT and MRI of the pancreas. Plasma C-peptide was not suppressed by physiological (50-100 microU/ml) and supraphysiological (200-500 microU/ml) hyperinsulinemia (% of baseline: 97.3 +/- 8.6% and 90.6 +/- 10.4%, +/- SEM, respectively, both NS). Three subjects were re-examined one year later, when their hypoglycemic episodes were noticeably attenuated. No significant suppression was found. Significant suppression was observed when plasma glucose was clamped at 50-60 mg/dl in four of five subjects (61.7 +/- 11.5%, P < 0.05), but one subject responded to neither higher plasma insulin nor low-normal glucose. In contrast, normal glucose tolerance (n = 13), IGT (n = 12) and obese NIDDM (n = 31) subjects showed highly significant suppression during euglycemic and physiological hyperinsulinemia (37.1 +/- 3.8%, 46.3 +/- 5.6%, 39.9 +/- 2.6%, respectively, all P < 0.001). In conclusion, the results of the present study indicate that a failure of hyperinsulinemic suppression of C-peptide in euglycemia is not specific for insulinoma, and that suppression of C-peptide by insulin at lower plasma glucose levels (50-60 mg/dl) would be a better diagnostic test.
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PMID:Lack of C-peptide suppression by exogenous hyperinsulinemia in subjects with symptoms suggesting reactive hypoglycemia. 907 3


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