LINKAGE ANALYSIS OF THE GLUCOKINASE LOCUS IN FAMILIAL TYPE-2 (NON-INSULIN-DEPENDENT) DIABETIC PEDIGREES

Glucokinase is among the few genes which may play a key role in both insulin secretion and insulin action. Glucokinase is present in pancreatic beta cells where it may have a key role in the glucose sensing mechanism, and it is present in hepatocytes, where it may participate in glucose flux. Glucokinase defects have recently been implicated in maturity-onset diabetes of the young. To examine the hypothesis that glucokinase plays a key role in the predisposition to common familial Type 2 (non-insulin-dependent) diabetes mellitus, we typed 399 members of 18 Utah pedigrees with multiple Type 2 diabetic individuals for two markers in the 5' and 3' flanking regions of the glucokinase gene. Linkage analysis was performed under both dominant and recessive models. We also repeated these analyses with individuals with impaired glucose tolerance who were considered affected if their stimulated (2-h) glucose exceeded age-specific normal levels for 95 % of the population. Under several dominant models, linkage was significantly excluded, and under recessive models log of the odds (LOD) score was less than - 1. We were also unable to demonstrate statistical support for the hypothesis that a small subgroup of pedigrees had glucokinase defects, but the most suggestive pedigree (individual pedigree LOD 1.8-1.9) ranked among the youngest and leanest in our cohort. We can exclude a major role for glucokinase in familial Type 2 diabetes, but our data cannot exclude a role for this locus in a minority of pedigrees. Further testing of the hypothesis that glucokinase defects contribute to diabetes in a small proportion of Type 2 diabetic pedigrees must await thorough sequence analysis of the glucokinase gene, including regulatory regions, particularly from pedigrees with positive LOD scores.