Surmely J F, Guenat E, Philippe J, Dussoix P, Schneiter P, Temler E, Vaxillaire M, Froguel P, Jéquier E, Tappy L
Institute of Physiology, University of Lausanne, Switzerland.
Diabetes. 1998 Sep;47(9):1459-63. doi: 10.2337/diabetes.47.9.1459.
Mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause impaired insulin secretion and hyperglycemia in patients with maturity-onset diabetes of the young (MODY)3. Whether these mutations also affect glucose metabolism in tissues other than the beta-cell has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidative glucose disposal, and glucose production during a two-step hyperglycemic clamp and a euglycemic hyperinsulinemic (0.4 mU x kg(-1) x min(-1)) clamp. Compared with healthy control subjects, MODY3 patients had higher fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin secretion were virtually abolished during the hyperglycemic clamp, and glucose production was suppressed by only 43% in MODY3 patients vs. 100% in healthy control subjects. The rate of glucose infusion required to produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen deposition) was inhibited by 39%, and net carbohydrate oxidation during hyperglycemia was 25% lower in MODY3 patients compared with control subjects. Insulin-stimulated glucose utilization and oxidation measured during the hyperinsulinemic clamp (at approximately 200 pmol/l insulin) were identical in MODY3 patients and in healthy control subjects, indicating that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization, oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essentially secondary to insulinopenia, whereas insulin sensitivity remains intact.
肝细胞细胞核因子（HNF）-1α基因的突变会导致青年发病的成年型糖尿病（MODY）3患者胰岛素分泌受损和血糖升高。这些突变是否也会影响β细胞以外组织的葡萄糖代谢，目前尚无文献记载。因此，我们对5例MODY3患者和12名健康对照者进行了评估，在两步高血糖钳夹和正常血糖高胰岛素血症（0.4 mU·kg⁻¹·min⁻¹）钳夹期间，检测了胰岛素分泌、氧化和非氧化葡萄糖处置以及葡萄糖生成情况。与健康对照者相比，MODY3患者空腹血糖较高（升高100%），但空腹葡萄糖生成和氧化速率相似。在高血糖钳夹期间，胰岛素分泌的早期和晚期阶段实际上均被消除，MODY3患者的葡萄糖生成仅被抑制43%，而健康对照者为100%。使血糖比基础血糖升高5 mmol/l所需的葡萄糖输注速率降低了30%，净非氧化葡萄糖处置（等于净糖原沉积）受到39%的抑制，与对照者相比，MODY3患者高血糖期间的净碳水化合物氧化降低了25%。在高胰岛素血症钳夹期间（胰岛素浓度约为200 pmol/l）测量的胰岛素刺激的葡萄糖利用和氧化在MODY3患者和健康对照者中相同，表明外周胰岛素敏感性未改变。然而，内源性葡萄糖生成的抑制轻度受损。结论是，MODY3患者葡萄糖诱导的胰岛素分泌严重受损。这些患者高血糖的发生似乎是由于葡萄糖利用、氧化和非氧化葡萄糖处置的刺激减少以及内源性葡萄糖输出的抑制减弱所致。这些现象基本上继发于胰岛素缺乏，而胰岛素敏感性保持完整。
