Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1a and -1ß result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1a and -1ß, HNF-1ß mutation carriers have hyperinsulinemia, whereas HNF-1a mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1ß 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-1a mutations, six subjects with HNF-1ß mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1ß subjects but was suppressed by 89% in HNF-1a 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-1ß mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1ß in the liver and possibly the kidney. This may be mediated through regulation by HNF-1ß of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.
|Number of pages||7|
|Publication status||Published - Feb 2006|