Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1β and -1α mutations

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 alpha and -1 beta result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1 alpha and -1 beta, HNF-1 beta mutation carriers have hyperinsulinemia, whereas HNF-1 alpha mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1 beta 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(-1)) and high-dose (1.5 mU . kg(-1) . min(-1)) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-H-2(2)]glucose, in six subjects with HNF-1 alpha infusion of mutations, six subjects with HNF-1 beta mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1 beta subjects but was suppressed by 89% in HNF-1 alpha 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 low- and high-dose insulin. Subjects with HNF-1 beta mutations have reduced insulin sensitivity of endogenons glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1 beta in the liver and possibly the kidney. This may be mediated through regulation by HNF-1 beta of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.