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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both genetic and environmental factors contribute to the etiology of non-insulin-dependent diabetes. The genetic component is heterogeneous and in some patients is probably complex, involving multiple genes. Specific genetic defects have been identified for rate monogenic forms of NIDDM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40% of families), syndromes of extreme insulin resistance (which often involve the insulin receptor), and diabetes-deafness syndromes (with defects in mitochondrial genes). In contrast, the genes involved in common forms of NIDDM are still uncertain. Mutations have been extensively searched in genes regulating insulin signaling and secretion. Some evidence of involvement has been produced for insulin-receptor substrate-1, glycogen synthase, the glucagon receptor, a ras-related protein (Rad), histocompatibility antigens, PC-1, and fatty acid binding protein, but the contributions of these genes to NIDDM is probably small. Other candidate genes (e.g. insulin, insulin receptor, glucose transporters) have been excluded as major diabetogenes. New insights are expected in the near future from the systematic scanning of the genome for linkage with NIDDM.
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PMID:Genetics of non-insulin-dependent (type-II) diabetes mellitus. 871

Recently, subtypes of typical NIDDM were suggested based on missense mutations of mitochondrial DNA [tRNALeu(UUR)] and the glucagon receptor gene (Gly40Ser). Together these mutations might explain NIDDM in 5--8% of patients. To test the hypothesis that these mutations play an important role in a Northern European population with a strong family history of diabetes, we screened members of 45 families selected for having two or more diabetic siblings and 62 additional unrelated diabetic individuals for both mutations. We also examined 74 nondiabetic control subjects. Mitochondrial DNA mutations were not detected despite our ability to detect as little as 3% heteroplasmy in a sample from an individual known to carry the mutation. Likewise, the glucagon receptor Gly40Ser mutation was present in a single diabetic patient who on subsequent investigation was of Italian descent. Thus, neither subtype of NIDDM is present in the Utah diabetic population, which is reflective of other Northern European populations.
Diabetes Care 1996 May
PMID:Role of mitochondrial DNA tRNA leucine and glucagon receptor missense mutations in Utah white diabetic patients. 873 19

A mutation within the glucagon receptor gene (GRG) at codon 40 (Gly40Ser) was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM) in France and Sardinia. Since the frequency of the mutation, about 5% in the French and 8% in the Sardinian group was higher than that of any of the candidate gene mutations described so far, it appeared to be relevant to determine the prevalence within different populations. While a single mutation has not been found recently either in a Japanese, a Finnish or a Dutch cohort, but only in a British study in 2.2% of NIDDM patients, in this study we investigated the association of this mutation with NIDDM in 104 German patients by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). None of the German NIDDM patients had a Gly40Ser mutation. The results indicate that the mutation plays little role in susceptibility to NIDDM in this German region, and also indicate the genetic heterogeneity in NIDDM, and further emphasize the importance of studies in different ethnic groups.
Diabetes Res Clin Pract 1996 May
PMID:Restricted geographical extension of the association of a glucagon receptor gene mutation (Gly40Ser) with non-insulin-dependent diabetes mellitus. 885 7

Recent studies have shown both association and linkage between a Gly40-Ser mutation in the glucagon receptor gene and NIDDM in French patients with familial NIDDM. This mutation was present in heterozygous form in 4.6% of diabetic probands but only 1% of the French population, suggesting that it was an important risk factor in the development of NIDDM. A total of 348 unrelated Japanese subjects (220 with NIDDM, 53 with impaired glucose tolerance (IGT) and 75 normal subjects) were screened for the presence of the Gly40-Ser mutation. Seventy-two percent of the NIDDM patients and 52% of IGT subjects had a positive family history of NIDDM. The Gly40-Ser mutation, which could be readily detected in a positive control subject, was not found in any of the 348 Japanese subjects studied. Thus, the Gly40-Ser mutation does not play an important role in the pathogenesis of NIDDM in Japanese patients.
Diabetes Res Clin Pract 1996 Jul
PMID:Absence of the Gly40-ser mutation in the glucagon receptor gene in Japanese subjects with NIDDM. 887 60

We investigated whether a G123-->A mutation causing a Gly40-->Ser substitution in exon 2 of the human glucagon receptor gene, which has been reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in France and Sardinia with a prevalences as high as 4.6% and 8.3%, respectively, is associated with Japanese patients with glucose intolerance. This mutation was not found in 242 unrelated Japanese patients with NIDDM or 23 with IGT by screening by the polymerase chain reaction-restriction fragment length polymorphism method. We also performed single-stranded conformational polymorphism analysis to search for new mutations in this gene associated with glucose intolerance. We found no mutations by examining all the 13 exons from 30 selected patients with NIDDM who had at least 2 diabetic first-degree relatives. These patients were also screened for the common polymorphism at codon 155 reported previously, but none were found to carry it. The absence of the mutation and polymorphism, which are common in French and Sardinian NIDDM or IGT patients, in Japanese indicates the existence of marked ethnic differences.
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PMID:Absence of association between the Gly40-->Ser mutation in the human glucagon receptor and Japanese patients with non-insulin-dependent diabetes mellitus or impaired glucose tolerance. 893 90

The role of glucagon in eliciting hyperglycaemia has been studied extensively for more than 20 years. However, little has been learned about the specific targeted tissues and intracellular effects of glucagon since no specific causal interactions have been established between glucagon and the so called "glucagon-binding site". Indeed, glucagon and related hormones, such as glucagon-like peptide, glucoin-sulinotropic hormone and vasoactive intestinal peptide acting through different receptors, have similar effects in hyperglycaemic syndromes. The recent cloning of the glucagon receptor (GR) encoding sequences has clarified many aspects of its structure as well as its integrated role in the cell and the entire body. The GR contains seven transmembrane domains and is characterised by a conserved G-protein binding site and a large amino-terminal domain containing the amino-acid residues mainly involved in ligand binding. The GR is expressed in liver, pancreatic beta cells, kidney, adipose tissues, heart, and vascular tissues, as well as in some region of brain, stomach, and adrenal glands. The precise role of the GR in most of these tissues is still unclear. However, with the cloning of the coding sequences, genetic manipulations of the GR should provide specific indications of the normal metabolic effects of the GR system on these tissues and how altered glucagon signalling might contribute to the development of diabetes.
Diabetes Metab 1996 Dec
PMID:Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism. 898 46

A Gly40Ser amino acid substitution in the glucagon receptor gene has been associated with non-insulin-dependent diabetes mellitus (NIDDM), but the questions raised about its physiological implications have not been resolved. The aim of this study was to determine the frequency of the Gly40Ser mutation in different regions of Sardinia and to investigate the physiological implications of the mutation in glucose and insulin homeostasis. We studied a population of 691 subjects selected on the basis of their Sardinian origin. Only heterozygous subjects were found, 21 of 574 (3.6%) in NIDDM patients and 5 of 117 in non-diabetic subjects (4.2%). In northern Sardinia 3.4% of the NIDDM patients were carriers of the Gly40Ser substitution, 1.4% in central Sardinia, while 7.6% carried the substitution in the Southern part. No significant differences were found between hypertensive and normotensive subjects with respect to the presence of Gly40Ser. Ten subjects with Gly40Ser were carefully matched for diabetic state, BMI, age, sex, and geographical origin with 10 patients with Gly40, and a glucagon infusion test was performed using 1, 3, 9 and 27 ng glucagon kg-1.min-1 for 30 min. Blood for determination of glucose, glucagon, and insulin concentrations was drawn at 15-min intervals from the Controlateral arm. Plasma glucagon increased dose-dependently during the infusion with no significant difference between the two groups. Carriers of Gly40Ser had a significantly lower (p < 0.02) increase in plasma glucose concentration in response to glucagon infusion compared to Gly40 homozygous subjects at all times, while the plasma insulin increase was not significantly different at any time. In conclusion, our results indicate that the Gly40Ser variation is not associated with NIDDM in the Sardinian population and that its frequency varies in different parts of Sardinia. Moreover in vivo Gly40Ser plays a physiological role in the glucose homeostasis under glucagon control both in NIDDM and non-diabetic subjects. This latter result suggests that this amino acid substitution in the glucagon receptor may lead to a decreased blood glucose concentration because of the reduced stimulation of liver glucose output via the glucagon receptor.
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PMID:Physiological and genetic characterization of the Gly40Ser mutation in the glucagon receptor gene in the Sardinian population. The Sardinian Diabetes Genetic Study Group. 902 23

Non-insulin-dependent diabetes mellitus (NIDDM) is a clinically and genetically heterogeneous disorder. Recent advances in molecular genetics have allowed recognition of the genes involved in some subtypes of NIDDM with a well-defined mode of inheritance and a strong association with genetic factors. Thus, maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM, was shown to be caused by, or associated with, mutations in at least four genes. A maternally transmitted form of diabetes, often associated with deafness, was shown to be due to mutations in mitochondrial DNA. Despite these successes, little is known about susceptibility genes to the common polygenic forms of NIDDM. Studies of genes involved in insulin secretion or insulin action have been successful to a certain extent by showing the implication of the IRS-1 gene, the Rad gene, the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (among others) in a low percentage of cases of NIDDM in particular populations. However, the majority of susceptibility genes to NIDDM are still to be described. The aim of this review was to consider the strategies that can be used to identify the genetic determinants of NIDDM, and to summarise the significant results of recent literature.
Diabetes Metab 1997 Feb
PMID:Genetic determinants of non-insulin-dependent diabetes mellitus: strategies and recent results. 905 62

Recently, a missense mutation in the glucagon receptor (GCG-R) gene causing a Gly to Ser change at codon 40 (Gly40Ser) has been associated and linked with non-insulin-dependent diabetes mellitus (NIDDM). We screened 150 unrelated NIDDM patients and 109 non-diabetic subjects for the presence of the Gly40Ser polymorphism by use of polymerase chain reaction-restriction fragment length polymorphism in the Russian population. None of the NIDDM patients showed this polymorphism. In contrast, two of the control subjects were heterozygous carriers of the polymorphism. Both were healthy females without a family history of diabetes. The body mass index, age, and 2-h blood glucose levels of the two subjects with the polymorphism were similar to those of the control subjects homozygous for the wild-type. Our results suggest that Gly40Ser polymorphism of the GCG-R gene is not associated with NIDDM in the Russian population and point to the genetic heterogeneity of NIDDM in different ethnic groups.
Exp Clin Endocrinol Diabetes 1997
PMID:Polymorphism of the glucagon receptor gene and non-insulin-dependent diabetes mellitus in the Russian population. 928 10

The binding of glucagon to its hepatic receptor is known to result in a number of effects, including the intracellular accumulation of cAMP, the mobilization of intracellular Ca2+, and the endocytosis of glucagon and its receptor into intracellular vesicles. In this study, we begin to define the functional role of the COOH-terminal tail of the human glucagon receptor in glucagon-stimulated signal transduction and receptor internalization. We have created and expressed in Chinese hamster ovary (CHO) cells five truncation mutants in which the COOH-terminal 24, 56, 62, 67, and 73 amino acids have been removed. Cells expressing relevant truncated receptors were assayed for cell surface expression by immunofluorescence, for ligand-binding properties, for cAMP and Ca2+-mediated signal transduction properties, and for receptor endocytosis. In addition, a mutant receptor containing seven serine-to-alanine mutations in the COOH-terminal tail was studied. Our results reveal the following: 1) a region of the COOH-terminal tail that is required for proper cell surface expression, 2) the COOH-terminal 62 amino acids, which comprise the majority of the tail, are not required for ligand binding, cAMP accumulation, or Ca2+ mobilization, and 3) phosphorylation of the COOH-terminal tail is crucial for glucagon-stimulated receptor endocytosis.
Diabetes 1997 Sep
PMID:Role of the glucagon receptor COOH-terminal domain in glucagon-mediated signaling and receptor internalization. 928 38


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