Neonatal Diabetes Mellitus Due to Complete Glucokinase Deficiency

Njølstad, Pål R.; Søvik, Oddmund; Cuesta-Muñoz, Antonio L.; Bjørkhaug, Lise; Massa, Ornella; Barbetti, Fabrizio; Undlien, Dag E.; Shiota, Chiyo; Magnuson, Mark A.; Molven, Anders; Matschinsky, Franz M.; Bell, Graeme I.

doi:10.1056/nejm200105243442104

Cited by 393 publications

(263 citation statements)

References 14 publications

Supporting

Mentioning

246

Contrasting

Unclassified

Order By: Relevance

“…Childhood-onset diabetes may also result from uncommon forms of monogenic diabetes [4] (estimated to represent less than 2% of cases) and less well characterised forms such as ketosis-prone/ 'Flatbush diabetes', type 1.5 diabetes and type 2 diabetes [5]. In addition, neonatal-onset diabetes often results from mutations of the genes associated with beta cell signalling and proinsulin [6]. The Barbara Davis Center for Childhood Diabetes cares for approximately 80% of children with newonset diabetes in the US state of Colorado.…”

Section: Introductionmentioning

confidence: 99%

Dimorphic histopathology of long-standing childhood-onset diabetes

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis Childhood diabetes is thought to usually result from autoimmune beta cell destruction (type 1A) with eventual total loss of beta cells. Analysis of C-peptide in children characterised at diabetes onset for autoantibodies shows heterogeneous preservation of insulin secretion in long-standing diabetes. The aim of this study was to characterise the pancreases of childhood-onset diabetes in order to define the pathological basis of this heterogeneity. Methods We evaluated 20 cadaveric organ donor pancreases of childhood-onset long-term patients for disease heterogeneity and obtained corresponding C-peptide measurements.Results Pancreases from the majority of cadaveric donors contained only insulin-deficient islets (14 of 20). The remaining six patients (30%) had numerous insulinpositive cells within at least some islets, with two different histological patterns. Pattern A (which we would associate with type 1A diabetes) had lobular retention of areas with 'abnormal' beta cells producing the apoptosis inhibitor survivin and HLA class I. In pattern B, 100% of all islets contained normal-appearing but quantitatively reduced beta cells without survivin or HLA class I. Conclusions/interpretation Our data demonstrate that C-peptide secretion in long-standing diabetic patients can be explained by two different patterns of beta cell survival, possibly reflecting different subsets of type 1 diabetes.

show abstract

Section: Introductionmentioning

confidence: 99%

Dimorphic histopathology of long-standing childhood-onset diabetes

et al. 2010

View full text Add to dashboard Cite

show abstract

“…This is a high K M hexokinase that is rate-limiting for glycolysis and is strongly expressed in beta cells and liver. Its importance in insulin secretion is exemplified by the fact that homozygous mutations cause permanent neonatal diabetes in man [36] and heterozygous mutations cause an early-onset form of diabetes (MODY2) [32][33][34][35][36][37]. Previous work [6] has suggested that C57BL/6J mice secrete less insulin during an intravenous glucose tolerance test and have lower in vitro Gck protein activity (but similar protein levels) than DBA/2 mice.…”

Section: Discussionmentioning

confidence: 99%

“…We sequenced the entire coding sequence of CamK2B and found no mutations capable of disrupting protein function. Given the crucial role of glucokinase in glucose homeostasis [32][33][34][35][36][37], we compared in vitro glucokinase function in liver of 12-week-old male C57BL/6J and C3H/HeH mice. C57BL/6J mice had significantly (p<0.01) lower glucokinase activity despite similar hexokinase activity: glucokinase activity was 16.61±2.144 (SD) mU/mg protein (n=5) for C57BL/6J compared to 22.73±2.09 mU/mg protein (n=4) for C3H/ HeH (enzyme activity level was measured using triplicate V max assays).…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. Methods: Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. Results: C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close K ATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. Conclusions/interpretation: The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.

show abstract

“…To detect the ±174G/C polymorphism, we carried out a PCR-RFLP with Sfa NI restriction enzyme and primers or a direct sequence [5]. Informed consent was obtained from all subjects.…”

mentioning

confidence: 99%

“…The association between TNDM and abnormalities of chromosome 6, either paternal isodisomy or partial trisomy with duplication of the paternal genome in the 6q24 region or methylation defect in the same region, has raised the possibility that an imprinted, paternally expressed gene is involved in its pathogenesis [3,4]. A recent study has described two patients in whom complete deficiency of the glycolytic enzyme glucokinase (GCK), a key regulator of glucose metabolism in pancreatic beta cells that couples extracellular glucose to insulin secretion, caused permanent neonatal-onset diabetes mellitus (PNDM) [5]. One patient was homozygous for an M210K mutation which was inherited from each parent heterozygous for this mutation in a context of consanguinity and cosegregated with diabetes or hyperglycaemia in other family members; the other was homozygous for a T228M mutation that has been found previously in an heterozygous state in a family with glucokinase-related MODY [6].…”

mentioning

confidence: 99%