Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1beta and -1alpha mutations.
Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1alpha and -1beta, HNF-1beta mutation carriers have hyperinsulinemia, whereas HNF-1alpha mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1beta 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-(2)H(2)]glucose, in six subjects with HNF-1alpha mutations, six subjects with HNF-1beta mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1beta subjects but was suppressed by 89% in HNF-1alpha 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-1beta mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1beta in the liver and possibly the kidney. This may be mediated through regulation by HNF-1beta of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.
Brackenridge
Anna
A
Department of Diabetes and Endocrinology, Royal Surrey County Hospital, Guildford, UK.
Pearson
Ewan R
ER
Shojaee-Moradie
Fariba
F
Hattersley
Andrew T
AT
Russell-Jones
David
D
Umpleby
A Margot
AM
D000328:Adult; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000096:biosynthesis*; D015309:Glucose Clamp Technique; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D009154:Mutation
D005230:Fatty Acids, Nonesterified; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D051539:Hepatocyte Nuclear Factor 1-beta; D005934:Glucagon; D005947:Glucose