CLINICAL CHARACTERISTICS OF SUBJECTS WITH A MISSENSE MUTATION IN GLUCOKINASE

The clinical characteristics of subjects with a missense glucokinase m utation, gly299 --> arg, were studied in a large pedigree, BX, initial ly characterized by some members having Maturity Onset Diabetes of the Young (MODY). Glucose tolerance, beta cell function and insulin sensi tivity were measured with Homeostasis Model Assessment (HOMA) and with a 'Continuous Infusion of Glucose with Model Assessment' (CIGMA) test . Diabetic complications were clinically assessed. Subjects with gluco kinase gly299 --> arg were the same age, height, and obesity as the su bjects without the mutation. Diabetes was usually asymptomatic at diag nosis and was treated with diet alone in 15 of the 18 subjects. Five o f the 11 adult females had been diagnosed when they developed gestatio nal diabetes. The fasting plasma glucose concentrations at the time of study were 4.3-12.6 mmol l(-1) with the higher levels being in the mo re obese (p < 0.05) and in the older subjects (p < 0.05). In subjects with the mutation, beta cell function was impaired, being geometric me an 63 % (normal-100 %) compared with 126 % in the subjects without the mutation (p < 0.001) measured by HOMA and in a subset assessed by CIG MA 59 % and 127 % (p < 0.01), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrat ions or blood pressure between the groups. The haemoglobin A(1c) was r aised (mean 6.5 % compared with 5.5 % in the subjects without the muta tion), but microvascular and macrovascular complications were uncommon . The subjects with the mutation did not have microalbuminuria but had an impaired vibration perception threshold compared with subjects wit hout the mutation. Subjects with the glucokinase missense mutation, gl y299 --> arg had mild fasting hyperglycaemia commensurate with approxi mately a 50 % decreased beta-cell funtion. Longevity with few diabetic or vascular complications in members with the mutation may reflect th e moderate hyperglycaemia and lack of dyslipidaemia and hypertension.