Contrasting Insulin Sensitivity of Endogenous Glucose Production Rate in Subjects With Hepatocyte Nuclear Factor-1 and -1 Mutations

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 and -1 result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1 and -1 , HNF-1 mutation carriers have hyperinsulinemia, whereas HNF-1 mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1 mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU kg 1 min ) and high-dose (1.5 mU kg 1 min ) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-H2]glucose, in six subjects with HNF-1 mutations, six subjects with HNF-1 mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by lowdose insulin in HNF-1 subjects but was suppressed by 89% in HNF-1 subjects (P 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at lowand high-dose insulin. Subjects with HNF-1 mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1 in the liver and possibly the kidney. This may be mediated through regulation by HNF-1 of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK. Diabetes 55:405–411, 2006