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

¹ Department of Diabetes and Endocrinology, Royal Surrey County Hospital, Guildford, U.K
² Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K
³ Department of Diabetes and Endocrinology, St. Thomas’ Hospital, Guy’s, King’s, and St. Thomas’ School of Medicine, Kings College, London, U.K

Address correspondence and reprint requests to Professor Margot Umpleby, Wolfson Centre for Translational Research, Department of Diabetes and Endocrinology, Postgraduate Medical School, University of Surrey, Daphne Jackson Road, Manor Park, Guildford, Surrey, GU2 7WG, U.K. E-mail: m.umpleby{at}surrey.ac.uk

Key Words: G6Pase, glucose-6-phosphatase • HNF, hepatocyte nuclear factor • HOMA, homeostasis model assessment • MCR, metabolic clearance rate • MODY, maturity-onset diabetes of the young • NEFA, nonesterified fatty acid

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 and -1ß result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1 and -1ß, HNF-1ß mutation carriers have hyperinsulinemia, whereas HNF-1 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-1 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-1 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.

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