Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1[beta] and -1[alpha] 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 x [kg.sup.-1] x [min.sup.-1]) and high-dose (1.5 mU x [kg.sup.-1] x [min.sup.-1]) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-[sup.2][H.sub.2]]glucose, in six subjects with HNF-1[alpha] 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 endogenous 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.
Heterozygous mutations in hepatocyte nuclear factor (HNF)-1[alpha] and -1[beta] can cause maturity-onset diabetes of the young (MODY) (1,2). HNF-1[alpha] and -1[beta] are homeodomain-containing transcription factors that share >90% sequence homology [...]