Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1β and -1α mutations

TY - JOUR

T1 - Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1β and -1α mutations

AU - Brackenridge, Anna

AU - Pearson, Ewan R.

AU - Shojaee-Moradie, Fariba

AU - Hattersley, Andrew T.

AU - Russell-Jones, David

AU - Umpleby, A. Margot

N1 - dc.publisher: American Diabetes Association dc.description.sponsorship: Diabetes UK RD03/2613 Wellcome Trust 064571

PY - 2006/2

Y1 - 2006/2

N2 - 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.

AB - 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.

U2 - 10.2337/diabetes.55.02.06.db05-1019

DO - 10.2337/diabetes.55.02.06.db05-1019

M3 - Article

SN - 0012-1797

VL - 55

SP - 405

EP - 411

JO - Diabetes

JF - Diabetes

IS - 2

ER -