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)

A new beta-chain hemoglobin variant, Hb Randwick [beta 15(A12)Trp----Gly] was detected in a 43-year-old female of Northern Italian parentage. During investigation for possible diabetes, mild red cell changes were noted and hemoglobin electrophoresis studies were requested. Independently, her sister's assessment had resulted in similar investigations. The most prominent findings were numerous "Hb H"-like inclusions and a positive isopropanol stability test. The hemoglobin variant separated poorly towards the anode at pH 9.2 and the level was estimated to be between 48-50% of the total hemoglobin. The variant beta-chain was partially purified by column chromatography, and its tryptic peptides fractionated by high performance liquid chromatography. Amino acid analysis and sequence data indicated that the tryptophan at residue 15 (A12) had been substituted by a glycine residue. Further study has indicated that eight other family members are heterozygous for the variant; they are clinically normal with no evidence of splenomegaly or history of jaundice, although four of them showed a mild reticulocytosis.
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PMID:Hemoglobin Randwick or beta 15 (A12)Trp----Gly: a new unstable beta-chain hemoglobin variant. 338 7

The present study was designed to determine the effect of alloxan-induced diabetes in rabbits on L-[15N]alanine and [15N]glycine kinetic parameters. This process was measured by single-dose administration of 15N-labeled amino acids to postabsorptive control rabbits and alloxan-induced diabetics and insulin-treated diabetic rabbits. Gas chromatography-mass spectrometry was used to determine the 15N enrichment of plasma glycine and alanine. Glycine and alanine pools and turnover rate constants were estimated from isotope enrichment time decay curves. The data from the present study indicate that plasma glycine and alanine turnover rate constants increased by 25-50% after alloxan administration but pool sizes showed only little changes, resulting in highly significant increases in fluxes and metabolic clearance rates of both alanine and glycine following alloxan administration; single-dose crystalline insulin or protamine zinc insulin treatment failed to restore the turnover rate constants of glycine or alanine toward control values and caused a depletion of 50% in glycine pool size; 7 days prolonged treatment with protamine zinc insulin restored alanine and glycine fluxes and metabolic clearance rates towards control postabsorptive values; and the reduction in flux values following insulin treatment is consistent with the reduction in the plasma glucose levels in rabbits. The data suggest that the regulatory mechanisms for uptake and metabolism of circulating glycogenic amino acids no longer are operative as a consequence of insulin deficiency following alloxan administration. Exogenous insulin restored the activity of the regulatory mechanism toward the postabsorptive control state.
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PMID:Dynamic aspects of amino acid metabolism in alloxan-induced diabetes and insulin-treated rabbits: in vivo studies with 15N and gas chromatography-mass spectrometry. 353 38

The relationships between changes in the plasma levels of immunoreactive insulin (IRI) and glucagon (IRG) in response to the postprandial increments of circulating amino acids were studied under normal physiological conditions in healthy dogs. In the presence of a unique postprandial physiological euglycemic "glucose clamp" which occurs in these dogs, plasma IRG rose to an earlier peak than IRI and both remained elevated for 16-19 hr. Amino acid (AA) profiles also showed postprandial incremental responses for up to 16 hr. Multiple correlation analyses indicated that only branched chain AAs were significantly correlated with IRI profiles and were devoid of a relationship to IRG. Similarly, only ornithine, lysine and glycine were significantly correlated with IRG profiles and devoid of a relationship to IRI. The significance of individual IRG stimulating effects of alanine and arginine were masked by other amino acid interactions, as significant intercorrelation was found among all 13 amino acids. Two equations were derived from the multiple regression analysis accounting for the postprandial time course of changes in IRI and IRG levels with only 5 amino acid concentrations: (1) (delta IRI) = 0.37 (delta Leu) -0.45(delta His), and (2) (delta IRG) = 0.55(delta Orn) + 0.37(delta Gly) -0.69 (delta Ser). These observations confirm the physiologic role in islet hormone secretion of the postprandial increments in circulating amino acids in the absence of glycemic change.
Diabetes Res 1985 Jan
PMID:Changes in blood amino acids account for the insulin and glucagon responses to mixed meals in dogs. 388 96

The hypothalamic tetradecapeptide, somatostatin (SRIF), inhibits the secretion of growth hormone (GH) and numerous other hormones, including insulin and glucagon. Attempts to use SRIF as an adjunct in the treatment of diabetes mellitus met with limited success due to its short biological half-life and the undesirable diabetogenic activity of its insulin-lowering properties. Efforts at synthesis have yielded SRIF derivatives with prolonged GH-lowering activity which did not suppress glucagon or had equivalent insulin-inhibiting activity as well as several short-acting compounds with the appropriate glucagon specificity. A dodecapeptide analogue [des-Ala, Gly] His-D-Trp-SRIF (Wy-41, 747) has been identified that combines selective inhibition of GH and glucagon release with prolonged activity. However, in routine pharmacological tests chronic treatment of mature rats with Wy-41, 747 produced anti-reproductive effects resembling those described for luteinising hormone (LH)-releasing hormone (RH) and its agonists. We report here that Wy-41, 747, unlike SRIF and other of its analogues tested, releases LH, induces ovulation and inhibits pregnancy when administered before or after implantation; these properties are traditionally associated with the separate LH-releasing class of peptides.
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PMID:Luteinising hormone-releasing and anti-fertility properties of a glucagon-selective somatostatin analogue. 698 34

A possible pathogenic mutation in the glucagon receptor gene causing a Gly to Ser change at codon 40 (Gly40Ser) was reported to be associated and linked with non-insulin-dependent diabetes mellitus (NIDDM), in France and Sardinia. Since the frequency of the mutation (Gly40Ser), about 5% in the French population of familial NIDDM and 8% in randomly chosen diabetic patients in Sardinia, was much higher than that of any of the previously reported mutations in candidate genes, it is important to clarify whether the contribution of this mutation to NIDDM is universal. In this study, we investigated the association of this mutation with diabetes mellitus in a large number of Japanese diabetic patients (383 NIDDM and 53 insulin-dependent diabetic patients) by polymerase chain reaction-restriction fragment length polymorphism analysis. None of the Japanese diabetic patients showed Gly40Ser mutation and the association of this mutation with NIDDM was significantly different (p < 4.10(-5) vs French, p < 3.10(-6) vs Sardinian by Fisher's exact test). The results not only indicate that the mutation plays little, if any, role in susceptibility to diabetes in Japan, but also indicate the genetic heterogeneity in NIDDM and further emphasize the importance of studies on genetic susceptibility to NIDDM and other complex traits in different ethnic groups.
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PMID:A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus. 863 82

We examined the locomotor-enhancing action of mu-opioid receptor agonists, such as morphine and [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), and physical dependence on morphine in diabetic and nondiabetic mice. Morphine (5-20 mg/kg, s.c.) and DAMGO (1-4 nmol, i.c.v.) had a dose-dependent locomotor-enhancing effect in both nondiabetic and diabetic mice. The locomotor-enhancing effects of morphine and DAMGO were significantly less in diabetic mice than in nondiabetic mice, and were significantly reduced after pretreatment with either beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist, or naloxonazine (35 mg/kg, s.c.), a selective mu1-opioid receptor antagonist. Both diabetic and nondiabetic mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. During this treatment, neither diabetic nor nondiabetic mice showed any signs of toxicity. After morphine treatment, withdrawal was precipitated by injection of naloxone (0.3-10 mg/kg, s.c.). Several withdrawal signs, such as weight loss, diarrhea, ptosis, jumping and body shakes, were observed after naloxone challenge in morphine-dependent nondiabetic mice. Although morphine-dependent diabetic mice showed greater weight loss than nondiabetic mice, the incidence of jumping and body shakes after naloxone challenge in diabetic mice were lower than that in nondiabetic mice. These results suggest that diabetic mice are selectively hyporesponsive to mu1-opioid receptor-mediated locomotor enhancement. Furthermore, diabetes may affect mu1-opioid receptor-mediated naloxone-precipitated signs of withdrawal from physical dependence on morphine.
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PMID:Modification of mu-opioid agonist-induced locomotor activity and development of morphine dependence by diabetes. 763 31

Non-insulin-dependent diabetes mellitus (NIDDM) affects about 5% of the world population. The disease presents a polygenic mode of inheritance, but mechanisms and genes involved in late-onset NIDDM are largely unknown. We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM. This mutation was highly associated with NIDDM in a pooled set of French and Sardinian patients (chi 2 = 14.4, P = 0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (chi 2 = 6.63, P < 0.01). Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor.
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PMID:A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. 777 93

We analyzed the structural correlates underlying the insulin-dependent selection of the specific anti-insulin IgG1 kappa mAb13-producing cell clone, derived from a patient with insulin-dependent diabetes mellitus treated with recombinant human insulin. First, we cloned the germ-line genes that putatively gave rise to the expressed VH and V kappa segments and used them to generate the full (unmutated) "germ-line revertant" of the "wild-type" (somatically mutated) mAb13, using recombinant PCR methods and an in vitro human C gamma 1 and C kappa expression system. The full "germ-line revertant" bound insulin specifically and in a dose-saturable fashion, but with a relative avidity (AVrel) more than three-fold lower than that of its wild-type counterpart (Avrel, 1.69 x 10(-8) vs 4.91 x 10(-9) g/microliters). Second, we established, by reassorting wild-type and germ-line revertant forms of the mAb13 VH and V kappa segments, that the increased Avrel for insulin of mAb13 when compared with its full "germ-line revertant" counterpart was entirely dependent on the mutations in the VH not those in the V kappa chain. Third, we determined, by site-directed mutagenesis experiments, that of the three mutations in the mAb13 VH segment (Ser-->Gly, Ser-->Thr, and Ser-->Arg at positions 31, 56, and 58, respectively), only Arg58 was crucial in increasing the mAb13 Avrel (from 1.44 x 10(-8) to 5.14 x 10(-9) g/microliters) and affinity (Kd, from 189 to 59 nM) for insulin. The affinity enhancement mediated by the VH segment Arg58 residue reflected about a threefold decrease in dissociation rate constant (Koff, from 4.92 x 10(-3) to 1.54 x 10(-3) s-1) but not an increase in association rate constant (Kon, from 2.60 x 10(4) to 2.61 x 10(4) M-1 s-1), and it contrasted with the complete loss of insulin binding resulting from the substitution of the VH segment Asn52 by Lys. The present findings suggest that human insulin, a self Ag, has the potential to recruit a natural autoantibody-producing cell precursor expressing a specific surface receptor for Ag in unmutated configuration, and drive it through affinity maturation. They also show that binding of insulin by such a receptor can be enhanced or completely abrogated by a single amino acid change.
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PMID:A human anti-insulin IgG autoantibody apparently arises through clonal selection from an insulin-specific "germ-line" natural antibody template. Analysis by V gene segment reassortment and site-directed mutagenesis. 799 43

We studied a simple tandem repeat DNA polymorphism in the glycogen synthase gene and polymorphisms at codon 513 (Ala-->Pro) and 972 (Gly-->Arg) in the insulin receptor substrate-1 (IRS-1) gene in 197 non-insulin-dependent diabetes mellitus (NIDDM) and 178 control subjects in Japan. Eight alleles (-3G, -2G, -1G, 0G, 1G, 2G, 3G, and 4G) were identified in the tandem repeat polymorphism in the glycogen synthase gene. No difference in the frequencies of these alleles was found between diabetics and controls. The codon 972 polymorphism of IRS-1 gene was observed in 7 diabetics (3.6%) and 8 controls (4.5%), whereas the codon 513 polymorphism was not found in either of the two groups. We conclude that the tandem repeat polymorphism in the glycogen synthase gene and the polymorphisms at codons 513 and 972 of the IRS-1 gene are not associated with a higher risk for the development of NIDDM in Japanese subjects.
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PMID:Molecular scanning of the glycogen synthase and insulin receptor substrate-1 genes in Japanese subjects with non-insulin-dependent diabetes mellitus. 803 48

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.
Diabetes 1993 Aug
PMID:Sequence variations of the glucokinase gene in Japanese subjects with NIDDM. 832 43


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