GLUCOSE-UTILIZATION AND PRODUCTION IN PATIENTS WITH MATURITY-ONSET DIABETES OF THE YOUNG CAUSED BY A MUTATION OF THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE

Mutations of the hepatocyte nuclear factor (HNF)-1 alpha gene cause im paired insulin secretion and hyperglycemia in patients with maturity-o nset diabetes of the young (MODY)3. Whether these mutations also affec t glucose metabolism in tissues other than the P-cen has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidativ e glucose disposal, and glucose production during a two-step hyperglyc emic clamp and a euglycemic hyperinsulinemic (0.4 mU.kg(-1).min(-1)) c lamp. Compared with healthy control subjects, MODY3 patients had highe r fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin se cretion were virtually abolished during the hyperglycemic clamp, and g lucose production was suppressed by only 43% in MODY3 patients vs. 100 % in healthy control subjects. The rate of glucose infusion required t o produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen dep osition) was inhibited by 39%, and net carbohydrate oxidation during h yperglycemia was 25% lower in MODY3 patients compared with control sub jects. Insulin-stimulated glucose utilization and oxidation measured d uring the hyperinsulinemic clamp (at similar to 200 pmol/l insulin) we re identical in MODY3 patients and in healthy control subjects, indica ting that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization , oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essenti ally secondary to insulinopenia, whereas insulin sensitivity remains i ntact.