Familial Hyperglycemia Due to Mutations in Glucokinase -- Definition of a Subtype of Diabetes Mellitus

Froguel, Philippe; Zouali, Habib; Vionnet, Nathalie; Velho, Gilberto; Vaxillaire, Martine; Sun, Fang; Lesage, Suzanne; Stoffel, Markus; Takeda, Jun; Passa, P; Permutt, M. A.; Beckmann, Jacques S.; Bell, Graeme I.; Cohen, Daniel

doi:10.1056/nejm199303113281005

Cited by 700 publications

(382 citation statements)

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“…Secondly, glucose phosphorylation to glucose-6-phosphate is catalysed by high K M hexokinase IV called glucokinase (GK) which constitutes the flux determining step for glycolysis [17±20]. This enzyme was early proposed to be the ªglucose sensorº [18] and it is now known that mutations in glucokinase underlie the impaired insulin secretion in MODY2 patients [21]. Thirdly, pyruvate generated by glycolysis is channelled to the mitochondria.…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

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Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

175

148

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In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ concentration in the mitochondrial matrix activating Ca 2+ -sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca 2+ -stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca 2+ -induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1a (HNF-1a) also displayed deletion of glucose-induced but not Ca 2+ -induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease. [Diabetologia (2000) 43: 265±277]

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Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

“…The genes for additional MODY sub-types are now being described [80]. The MODY2 subform is less severe [21] than the others [74,75], many of which can eventually require insulin therapy [81,82]. Except in MODY2, microvascular complications are generally present [81,82].…”

Section: Maturity-onset Diabetes Of the Youngmentioning

confidence: 99%

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

175

148

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“…Although commonly thought to be a relatively rare form of NIDDM, recent studies suggest that it may not be that uncommon and 2-5 % of patients with NIDDM may in fact have MODY [2]. Mutations in genes on chromosomes 20, 7 and 12, designated MODY1, MODY2/glucokinase (GCK) and MODY3, respectively, can cause this form of diabetes [3][4][5]. Moreover, there are likely to be additional MODY genes since there are families in which MODY does not cosegregate with markers tightly linked to the three known MODY loci [5].…”

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confidence: 99%

“…Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50 % of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro-and macro-vascular complicaMutations in the glucokinase gene are the most common cause of MODY in France with approximately 50 % of subjects with MODY having mutations in this gene [4]. These subjects are often characterized by mild persistent fasting and postprandial hyperglycaemia.…”

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Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

et al. 1997

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Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by early onset, usually before 25 years of age and often in adolescence, and by autosomal dominant inheritance [1]. Although commonly thought to be a relatively rare form of NIDDM, recent studies suggest that it may not be that uncommon and 2-5 % of patients with NIDDM may in fact have MODY [2]. Mutations in genes on chromosomes 20, 7 and 12, designated MODY1, MODY2/glucokinase (GCK) and MODY3, respectively, can cause this form of diabetes [3][4][5]. Moreover, there are likely to be additional MODY genes since there are families in which MODY does not cosegregate with markers tightly linked to the three known MODY loci [5]. Diabetologia (1997) Summary Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G → T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50 % of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro-and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM. [Diabetologia (1997) 40: 217-224]

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“…MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8)(9)(10), families linked to chromosome 12q are the most frequently described. The glucokinase defects in MODY2 interfere with glucose uptake, resulting in hyperglycemia (5).…”

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Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

Glucksmann

Lehto²,

Tayber³

et al. 1997

Diabetes

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Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF-la) located on chromosome 12q. We have identified four novel HNF-la missense mutations in M0DY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in M0DY3. We observed no HNFla mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes. Diabetes 46:1081-1086,1997MODY. The MODY1 locus, on chromosome 20q, was shown to be linked in a single extended family (2). M0DY1 was recently shown to be caused by mutations in the transcription factor hepatocyte nuclear factor-la (HNF4a) (3). MODY2, located on chromosome 7p (4), is caused by mutations in the glucokinase gene (5). MODY3 was mapped to chromosome 12q (6) and is known to be caused by mutations in another transcription factor, HNF-la (7). Although the relative prevalence of these MODY subtypes varies regionally (8-10), families linked to chromosome 12q are the most frequently described. The glucokinase defects in MODY2 interfere with glucose uptake, resulting in hyperglycemia (5). Although the mechanism of hyperglycemia in MODY1 and MODY3 is not yet understood, phenotypic characterization of these families has shown a deficient insulin secretion response to glucose (11-13).We report here the characterization of the MODY3 gene M region and the results of mutation analysis in eight different aturity-onset diabetes of the young (MODY) is a MODY3 families. We show that MODY3 can be caused by a form of NIDDM with a strong genetic basis, number of different mutations in HNF-la including a mutaDiagnostic criteria for MODY include 1) age of tional hotspot. onset <25 years, 2) correction of fasting hyperglycemia without insulin for at least 2 years, 3) nonketotic RESEARCH DESIGN AND METHODS disease, and 4) autOSOmal dominant mode Of inheritance (1). Family ascertainment and linkage analysis. Families were ascertained based It is therefore expected that a Significant proportion Of MODY on the criteria described by Lehto et al. (13). Genomic DNA was isolated from is caused by Single-gene defects. To date, linkage analysis has P eri P heral blood lymphocytes using standard protocols. Genotyping was pershown that three different, dominant-acting loci can cause fo ™ ed t^^ flu0

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Familial Hyperglycemia Due to Mutations in Glucokinase -- Definition of a Subtype of Diabetes Mellitus

Abstract: Mutations in glucokinase are the primary cause of hyperglycemia in a substantial fraction of French patients with maturity-onset diabetes of the young and result in a relatively mild form of NIDDM that can be diagnosed in childhood.

Cited by 700 publications

References 24 publications

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families

Novel Mutations and a Mutational Hotspot in the M0DY3 Gene

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