Brackenridge Anna, Pearson Ewan R, Shojaee-Moradie Fariba, Hattersley Andrew T, Russell-Jones David, Umpleby A Margot
Department of Diabetes and Endocrinology, Royal Surrey County Hospital, Guildford, UK.
Diabetes. 2006 Feb;55(2):405-11. doi: 10.2337/diabetes.55.02.06.db05-1019.
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.
转录因子肝细胞核因子（HNF）-1α和-1β的杂合突变会导致青年发病的成年型糖尿病（MODY）。尽管HNF-1α和-1β在结构上相似，但携带HNF-1β突变的个体有高胰岛素血症，而携带HNF-1α突变的个体胰岛素浓度正常或降低。我们研究了携带HNF-1β突变的个体是否存在胰岛素抵抗。对6名携带HNF-1α突变的受试者、6名携带HNF-1β突变的受试者和6名年龄、性别及体重指数相匹配的对照受试者，通过两步法、低剂量（0.3 mU·kg⁻¹·min⁻¹）和高剂量（1.5 mU·kg⁻¹·min⁻¹）的高胰岛素-正糖钳夹技术，并输注[6,6-(²)H₂]葡萄糖，来测量内源性葡萄糖生成率和葡萄糖摄取率。在携带HNF-1β突变的受试者中，低剂量胰岛素不能抑制内源性葡萄糖生成率，但在携带HNF-1α突变的受试者中内源性葡萄糖生成率被抑制了89%（P = 0.004），在对照受试者中被抑制了80%（P < 0.001）。在低剂量和高剂量胰岛素时，所有组中胰岛素刺激的葡萄糖摄取和脂肪分解抑制情况相似。携带HNF-1β突变的受试者内源性葡萄糖生成的胰岛素敏感性降低，但外周胰岛素敏感性正常。这可能反映了HNF-1β在肝脏以及可能在肾脏中的作用减弱。这可能是通过HNF-1β对关键的糖异生酶葡萄糖-6-磷酸酶或磷酸烯醇式丙酮酸羧激酶的调控来介导的。
