Here we report linkage between the glucokinase locus on chromosome 7p and diabetes in 16 French families with maturity-onset diabetes of the young, a form of NIDDM characterized by monogenic autosomal dominant transmission and early age of onset.
Glucokinase is thought to play a glucose-sensor role in the pancreas, and abnormalities in its structure, function, and regulation can induce diabetes.
DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes.
Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants.
This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period.
Significant associations between alleles at the GCK(3') marker and glucose tolerance were evident (p = 0.002), the frequency of the (z + 2) allele rising from zero in control subjects (n = 88 chromosomes) to 6.5% (n = 62) in subjects with impaired tolerance and 12.2% (n = 188) in subjects with diabetes.
Subsequently, we also sequenced each exon from an affected member of the single pedigree in which a glucokinase allele was most likely to segregate with diabetes.
The expression of genes involved in liver glucose metabolism, such as glucokinase, pyruvate kinase, and PEPCK, which is markedly altered by diabetes, was significantly recovered in transgenic mice treated with streptozotocin.
The glucokinase and mitochondrial tRNA(Leu(UUR)) genes were screened for mutations in at least one affected subject from each family in order to assess the contribution of mutations in these genes to the development of the diabetes.
This study was undertaken to test the hypothesis that the diabetes susceptibility gene on chromosome 20q12 responsible for maturity-onset diabetes of the young (MODY) in a large kindred, the RW family, results in characteristic alterations in the dose-response relationships between plasma glucose concentration and insulin secretion rate (ISR) that differentiate this form of MODY from MODY in subjects with glucokinase mutations.
In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes.
To assess the prevalence of diabetes complications and the severity of diabetes in kindreds with NIDDM linked to the MODY3 locus (chromosome 12q) and to compare these parameters with data obtained in glucokinase (GCK)-deficient and other-MODY (unlinked to any of the three known loci) families, as well as with data from families with a late age of onset of NIDDM.
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).
Pathophysiologically, there are at least two genetically different forms of diabetes linked to energy metabolism: the first example is one form of maturity-onset diabetes of the young (MODY2), an autosomal dominant disorder caused by point mutations of the glucokinase gene; the second example is several forms of mitochondrial diabetes caused by point and length mutations of the mitochondrial DNA (mtDNA) that encodes several subunits of the respiratory chain complexes.
Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro- and macro-vascular complications of diabetes.
In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree.