A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1

Huopio, Hanna; Otonkoski, Timo; Vauhkonen, Ilkka; Reimann, Frank; Ashcroft, Frances M.; Laakso, Markku

doi:10.1016/s0140-6736(03)12325-2

Cited by 174 publications

(145 citation statements)

References 24 publications

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“…However, it is not known whether this is the case with GCKactivating mutations. We suggest that since the defect is in glucose sensing rather than excess insulin secretion, this is not likely to result in the "␤-cell exhaustion" seen in K ATP channel mutations (21). None of the mutation carriers in the two families presented in this study have developed diabetes; however, the oldest is only 47 years of age.…”

Section: Discussionmentioning

confidence: 62%

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Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

et al. 2003

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Glucokinase (GCK) is a key regulatory enzyme in the pancreatic ␤-cell and catalyzes the rate-limiting step for ␤-cell glucose metabolism. We report two novel GCK mutations (T65I and W99R) that have arisen de novo in two families with familial hypoglycemia. Insulin levels, although inappropriately high for the degree of hypoglycemia, remain regulated by fluctuations in glycemia, and pancreatic histology was normal. These mutations are within the recently identified heterotropic allosteric activator site in the theoretical model of human ␤-cell glucokinase. Functional analysis of the purified recombinant glutathionyl S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic changes result in a relative increased activity index (a measure of the enzyme's phosphorylating potential) of 9.81 and 6.36, respectively, compared with wild-type. The predicted thresholds for glucose-stimulated insulin release using mathematical modeling were 3.1 (T65I) and 2.8 (W99R) mmol/l, which were in line with the patients' fasting glucose. In conclusion, we have identified two novel spontaneous GCK-activating mutations whose clinical phenotype clearly differs from mutations in ATP-sensitive K ؉ channel genes. In vitro studies confirm the validity of structural and functional models of GCK and the putative allosteric activator site, which is a potential drug target for the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 62%

“…A recent study (21) carried out in an extended Finnish family has illustrated that mutations in the SUR1 (ABCC8) gene can present as hypoglycemia during infancy and diabetes in early adulthood. However, it is not known whether this is the case with GCKactivating mutations.…”

Section: Discussionmentioning

confidence: 99%

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

et al. 2003

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“…Hyperinsulinaemia can be a consequence of Abcc8 mutations, which is in contrast to our findings of defective glucose-mediated insulin secretion that arises from the NZO Abcc8 allele. Interestingly, some individuals in the families of those with PHHI may develop diabetes later in life, prompting suggestion of a new genetic sub-class of T2D with similar phenotypes of glucose intolerance, b-cell dysfunction and hyperglycaemia (Huopio et al 2003). There is evidence for an association between the Kcnj11 and Abcc8 genes with T2D (Barroso et al 2003, Gloyn et al 2003.…”

Section: Discussionmentioning

confidence: 99%

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

Andrikopoulos

Fam

Holdsworth

et al. 2015

Journal of Endocrinology

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Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with b-cell dysfunction. A genomewide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a w211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucosemediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving b-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to b-cell dysfunction in T2D.

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“…Diabetes has also been linked to another activating mutation in GCK that causes neonatal hyperinsulinaemic hypoglycaemia [12]. Furthermore, a mutation in HNF4A associated with macrosomia and mild hyperinsulinaemic hypoglycaemia in infancy also resulted in diabetes in five out of a total of eight mutant carriers by the age of 14 years [13] Similarly, nine out of eleven individuals of a large Finnish pedigree with a defect in SUR1 characterised by PHHI developed diabetes or impaired glucose tolerance in the face of normal insulin sensitivity [14]. In fact, in this latter study the authors suggested that this autosomal dominant mutation in SUR1 causing congenital hyperinsulinaemia followed by insulindeficient diabetes be considered as a new genetic subclass of type 2 diabetes with similar phenotypes of glucose intolerance, beta cell dysfunction and hyperglycaemia.…”

Section: Ermentioning

confidence: 99%

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

et al. 2008

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A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1

Cited by 174 publications

References 24 publications

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

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