Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.
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PMID:Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. 808 55

To better understand abnormal insulin production (IP) in states of carbohydrate intolerance, insulin release was quantified following equimolar (2.4 mmol/kg) infusions of glucose, arginine, and valine in healthy subjects ([HS] age, 45 +/- 3 years; body mass index [BMI, kg/m2], 26.3 +/- 2.4; means +/- SEM), obese subjects with impaired glucose tolerance ([IGT] age, 43 +/- 5 years; BMI, 35.4 +/- 2.4), and non-obese patients with chronic non-insulin-dependent diabetes mellitus ([NIDDM] age, 55 +/- 3 years; BMI, 26.4 +/- 1.4; duration of disease, 13 +/- 3 years). There were eight subjects per group. Incremental IP (metabolic clearance rate of C-peptide [MCRCP] x total incremental area under the curve of plasma C-peptide [AUCCP], pmol/kg) following substrate infusion was as follows: glucose: HS, 227 +/- 14; IGT, 1,050 +/- 184 (P < .001 v HS); NIDDM, 114 +/- 27 (P < .001 v HS); arginine: HS, 139 +/- 23; IGT, 488 +/- 106 (P < .01 v HS); NIDDM, 206 +/- 47; and valine: HS, 21 +/- 7; IGT, 32 +/- 10; NIDDM, 54 +/- 12 (P < .01 v HS). The fractional clearance rate ([FCR] k, %/min) was impaired in IGT and NIDDM for glucose (HS, 3.9 +/- 0.4; IGT, 2.3 +/- 0.3 [P < .01 v HS]; NIDDM, 1.4 +/- 0.1 [P < .001 v HS]), arginine (2.4 +/- 0.1; 1.9 +/- 0.2 [P < .01 v HS]; 1.9 +/- 0.2 [P < .01 v HS]), and valine (0.95 +/- 0.06; 0.65 +/- 0.09 [P < .05 v HS]; 0.74 +/- 0.1 [P < .05 v HS]).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin production following intravenous glucose, arginine, and valine: different pattern in patients with impaired glucose tolerance and non-insulin-dependent diabetes mellitus. 813 89

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol.kg-1) or orally (5.0 mmol.kg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol.kg-1) and oral administration of either delapril or enalapril (5.0 mmol.kg-1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-alpha-adamantane-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-b bradykinin) (0.5 nmol.kg-1 x min-1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol.kg-1 x min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol.kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans. 817 45

Mutations in the glucokinase gene have been identified recently in patients with maturity-onset diabetes of the young, a subtype of NIDDM. The proposed role of glucokinase as a glucose sensor, combined with the low insulin response to glucose found in most Japanese with NIDDM, prompted us to speculate that mutations in the glucokinase gene might be one of the major causes of NIDDM in Japanese subjects. To determine the prevalence of mutations and sequence variations in the glucokinase gene, we screened all 12 exons of the glucokinase gene, including exon/intron junctions, by polymerase chain reaction followed by single-strand conformation polymorphism in 209 Japanese NIDDM subjects. In addition to the mutation in exon 7, which substituted Arg (AGG) for Gly (GGG) at codon 261 (10), a silent mutation of Pro (CCC-->CCG) in exon 4 at codon 145 and several new sequence variations in intervening sequences and the 5'-untranslated region of exon 1 beta (beta-cell-specific exon 1) were identified. Because we identified only one subject who had a structurally abnormal glucokinase molecule, we conclude that the prevalence of structural mutations in the glucokinase gene responsible for NIDDM appears to be rare among Japanese patients. To our knowledge, this is the first thorough study describing the ethnic prevalence of mutations and sequence variations in the glucokinase gene in NIDDM.
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PMID:Sequence variations of the glucokinase gene in Japanese subjects with NIDDM. 832 43

Deferoxamine has been proposed as a potentially important therapy for individuals with NIDDM and mild elevations in serum ferritin. Previously, iron chelation therapy with intravenous deferoxamine over a 5-13-wk period has been reported to normalize serum ferritin and markedly improve glycemic control. To confirm these results and to study potential beneficial effects of deferoxamine on insulin secretion, 9 individuals with NIDDM and elevated serum ferritin levels were treated twice weekly with deferoxamine infusion, following a previously described protocol. Although 8 of 9 subjects achieved normal or near-normal serum ferritin values after deferoxamine therapy, we found little evidence that it produced beneficial effects on glycemic control. Fasting glucose levels pre- and post-deferoxamine therapy were unchanged (11.6 +/- 1.2 and 11.3 +/- 1.5 mM, respectively, P = 0.80). GHb levels declined slightly after deferoxamine therapy (9.3 +/- 0.7 vs. 8.8 +/- 0.7%, P < 0.05); however, this effect was small and was not associated with elimination of or even substantial reduction in insulin or oral hypoglycemic therapy. Deferoxamine therapy did not significantly alter fasting insulin or C-peptide levels, nor stimulated insulin or C-peptide responses to intravenous arginine or glucose. During follow-up studies 1.5-8 mo after deferoxamine therapy, serum ferritin levels again were elevated in 5 of 8 subjects who showed an initial response. Thus, although deferoxamine therapy reduced serum ferritin levels in our subjects, we were unable to confirm a previous report that this effect was associated with any meaningful improvement in glycemic control or insulin secretion.
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PMID:No effect of deferoxamine therapy on glucose homeostasis and insulin secretion in individuals with NIDDM and elevated serum ferritin. 845 4

Islet amyloid polypeptide (IAPP) is a 37-amino acid residue polypeptide, originally isolated from the pancreatic amyloid deposits of patients with type II diabetes mellitus. Subsequently, IAPP was found to be colocalised with insulin in beta-cell secretory granules of the normal mammalian pancreas. Recently, IAPP has been reported to inhibit glucose-stimulated insulin release from isolated rat islets and to be released in response to glucose and arginine. To investigate further the regulation of IAPP release from the islet, we used a previously developed specific radioimmunoassay for IAPP and measured IAPP secretion from isolated rat islets of Langerhans. Release of IAPP-like immunoreactivity (-LI) was stimulated by glucose: 3.3 +/- 0.3, 3.9 +/- 0.3, and 11.1 +/- 1.5 (n = 5, mean +/- SEM) fmol/islet/60 min at 2, 7, and 20 mM, respectively. Carbachol (0.1 mM) increased the release of IAPP-LI at the lower glucose concentrations: 8.1 +/- 0.9, 8.7 +/- 0.6, and 11.7 +/- 1.8 fmol/islet/60 m in at 2, 7, and 20 mM glucose. Somatostatin (1 microM) suppressed glucose-stimulated IAPP-LI release (17.5 +/- 1.5 vs. 5.1 +/- 0.5 fmol/islet/60 min). Chromatographic characterisation of the IAPP-LI released into the incubation medium revealed two immunoreactive forms: The major peak (74% of the total IAPP-LI) corresponded to synthetic IAPP-37, while a smaller form, comprising 26% IAPP-LI, eluted later. In acid extracts of islets, all (> 95%) immunoreactivity co-eluted with the synthetic IAPP.
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PMID:Molecular form of islet amyloid polypeptide (amylin) released from isolated rat islets of Langerhans. 846 Jan

Morphological changes of the pancreas and impairment of pancreatic B-cell function in a model rat (Otsuka Long Evans Tokushima Fatty [OLETF]) with non-insulin dependent diabetes mellitus might be the result of over-activity of B-cells to compensate for insulin insensitivity. To test this possibility, we studied whether the histological and functional alterations in the pancreas of male OLETF rats were improved by treatment with insulin for a certain period, which might reduce the burden to B-cells. Groups of 6 male OLETF rats and 5 or 4 male non-diabetic control Long Evans Tokushima Otsuka (LETO) rats received injections of insulin (Ultralente MC; 10 U/kg/day to OLETF rats, 5 U/kg/day to LETO rats) or saline subcutaneously, once a day for 3 weeks from 24 weeks of age. Then their insulin responses to glucose (200 mg/dl) and arginine (10 mmol/l) were examined by perfusion of the pancreas. The morphological features of their pancreata were also examined. The insulin response to glucose in OLETF rats treated with insulin was significantly higher than that of OLETF rats treated with saline (sigma IRI 142.5 +/- 27.0 vs. 37.4 +/- 6.3 ng/ml.20 min, p < 0.05) and unlike in the latter showed the normal two phases. The morphological changes of the pancreas in the insulin-treated OLETF rats were remarkably ameliorated, animals showing no enlargement and only slight fibrosis of islets. Thus treatment with insulin was effective for preventing B-cell dysfunction and morphological changes of the pancreas in NIDDM model rats.
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PMID:Effect of timely insulin administration on pancreatic B-cells of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) strain rats. An animal model of non-insulin dependent diabetes mellitus (NIDDM). 855 37

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.
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PMID:Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation. 860 70

After an intravenous infusion Of L-arginine to inhibit tubular reabsorption of albumin, glomerular clearance, renal clearance, and tubular reabsorption of unmodified albumin (UMA) and glycated albumin (GA) were determined in 72 patients with NIDDM without (NIDDM-I; n = 47) or with microalbuminuria (NIDDM-II; n = 25) and in 24 healthy control subjects. Samples of serum albumin and dialyzed urine obtained 60 min before and during L-arginine infusion were applied to an affinity column to separate GA from UMA, and their albumin contents were assayed. The serum level of GA in NIDDM patients was higher than that in control subjects (P < 0.0001). Both UMA and GA were excreted in excess in NIDDM-II as compared with the other two groups (P < 0.0001), and UMA comprised 80% of total albumin excretion. In NIDDM-II, the glomerular clearance of UMA (2.5 +/- 0.16 > NIDDM-I [1.8 +/- 0.1] > control subjects [1.3 +/- 0.1 microliter/min], P < 0.001) and of GA (1.7 +/- 0.13 > NIDDM-I = control subjects [1.1 +/- 0.1 microliter/min], P < 0.001) were enhanced, as compared with the other two groups. Renal clearance of UMA (1.3 +/- 0.13 microliter/min) and GA (0.89 +/- 0.09 microliter/min) in NIDDM-II was greater than that in control subjects (0.27 +/- 0.03, 0.19 +/- 0.02 microliter/min) or in NIDDM-I (0.30 +/- 0.03, 0.11 +/- 0.01 microliter/min). Tubular reabsorption of UMA, as assessed by the difference between glomerular and renal clearances of albumin, in NIDDM-II (1.1 +/- 0.1 microliter/min) was less than in NIDDM-I (1.50 +/- 0.09 microliter/min), and that of GA in NIDDM-II was lower than that in the other two groups, despite exaggerated glomerular clearance of GA and UMA in NIDDM-II. In summary, microalbuminuria in NIDDM is caused by increased excretion of UMA resulting from the decompensated ability of tubular reabsorption, which is exceeded by increased glomerular clearance of UMA.
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PMID:Microalbuminuria in NIDDM is caused by increased excretion of unmodified albumin. 863 45

Selective impairment of glucose-induced insulin secretion and hyper-responsiveness to arginine are known features of GK rats, a genetic model of NIDDM. We focus on the ionic mechanism underlying these phenomena using patch-clamp techniques. Pancreatic islets were isolated from male GK rats and age-matched control Wistar rats and were subjected to dispersion and culture. Single channel recordings of KATP channels were performed using either on-cell mode or inside-out patch mode. Ca2+ channel currents were recorded under conventional whole-cell mode. In GK beta cells, ATP sensitivity of KATP channels itself was not altered, although glucose-induced closure of KATP channels was severely impaired. Among substrates for fuel metabolism, only dehydroxyacetone (DHA) reproduced this anomaly. On the other hand, current densities of L-type Ca2+ channels were increased in GK beta cells. Since DHA is a known substrate for glycerol phosphate shuttle, current data suggest that major metabolic deficit of GK beta cells resides in this shuttle. On the other hand, increased L-type Ca2+ channel activities might be an ionic basis for augmented insulin response to nonglucose depolarizing stimuli in GK beta cells.
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PMID:Altered functions of ion channels in diabetic beta cells. 865 42


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