MODY 2

Abstract: Background and Methods Non-insulin-dependent diabetes mellitus (NIDDM) is a genetically heterogeneous disorder. Maturity-onset diabetes of the young, a form of NIDDM with an early age of onset and autosomal dominant inheritance, can result from mutations in glucokinase, a key enzyme of glucose metabolism in beta cells and the liver. We studied 32 French families with maturity-onset diabetes of the young as well as 21 families with late-onset NIDDM to determine the frequency and clinical features of mutations of glucokinase. Fasting plasma glucose concentrations and oral glucose-tolerance tests were used to determine metabolic status. DNA was isolated from lymphocytes, and DNA polymorphisms in the glucokinase gene were tested for linkage with diabetes. Individual exons of the glucokinase gene from one affected member in each family were amplified by the polymerase chain reaction and screened for mutations by analysis of the conformation-dependent polymorphisms of single-stranded DNA and by DNA sequencing. ...

Abstract: Aims/hypothesis Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence. Methods UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures. Results MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from 50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r=0.96, p 80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.

Abstract: This article reviews evidence for a pivotal role of glucokinase as glucose sensor of the pancreatic beta-cells. Glucokinase explains the capacity, hexose specificity, affinities, sigmoidicity, and anomeric preference of pancreatic islet glycolysis, and because stimulation of glucose metabolism is a prerequisite of glucose stimulation of insulin release, glucokinase also explains many characteristics of this beta-cell function. Glucokinase of the beta-cell is induced or activated by glucose in contrast to liver glucokinase, which is regulated by insulin. Tissue-specific regulation corresponds with observations that liver and pancreatic beta-cell glucokinase are structurally distinct. Glucokinase could play a glucose-sensor role in hepatocytes as well, and certain forms of diabetes mellitus might be due to glucokinase deficiencies in pancreatic beta-cells, hepatocytes, or both.

Abstract: Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.