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

Abstract

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1α and -1β result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1α and -1β, HNF-1β mutation carriers have hyperinsulinemia, whereas HNF-1α mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1β 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 [6,6-²H₂]glucose, in six subjects with HNF-1α mutations, six subjects with HNF-1β mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1β subjects but was suppressed by 89% in HNF-1α 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-1β mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1β in the liver and possibly the kidney. This may be mediated through regulation by HNF-1β of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.