Mari Andrea, Gastaldelli Amalia, Natali Andrea, Ostergard Torben, Schmitz Ole, Ferrannini Ele
Consiglio Nazionale delle Ricerche Institute of Biomedical Engineering, Padua, Italy.
Am J Physiol Endocrinol Metab. 2005 Mar;288(3):E541-6. doi: 10.1152/ajpendo.00175.2004. Epub 2004 Nov 2.
To investigate early secretory defects in prediabetes, we evaluated beta-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. beta-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 +/- 6 vs. 87 +/- 6 pmol x min(-1) x m(-2), P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, rho = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 x M1.23), compensation for insulin resistance was impaired in FDR (10.8 +/- 1.0 vs. 13.4 +/- 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 +/- 0.08 vs. 1.62 +/- 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). beta-Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, beta-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a beta-cell defect in the amplifying pathway of insulin secretion.
为研究糖尿病前期的早期分泌缺陷，我们评估了26名2型糖尿病患者的糖耐量正常的一级亲属（FDR）以及17名年龄和体重匹配的对照者的β细胞功能和胰岛素敏感性（通过正常血糖钳夹法测定的M值）。通过对在标准化生活条件下24小时内测得的葡萄糖和C肽浓度进行模型分析来评估β细胞功能。FDR的空腹和总胰岛素分泌率（ISR）均升高，在参考葡萄糖水平5 mM时的ISR（ISR5）也升高（107±6 vs. 87±6 pmol·min⁻¹·m⁻²，P<0.05）。在对照组中，ISR5与M呈负相关（ISR5 = k/M¹.²³，ρ = -0.74，P<0.005），但在FDR中并非如此；当考虑M时（通过计算补偿指数ISR5×M¹.²³），FDR对胰岛素抵抗的补偿受损（10.8±1.0 vs. 13.4±0.6单位，P<0.05）。FDR中ISR的增强（表示进餐期间葡萄糖刺激的ISR的相对短暂增加）受损（第一餐期间为1.29±0.08 vs. 1.62±0.08，P<0.02）。此外，两组中增强的时间进程均与葡萄糖依赖性胰岛素释放多肽（GIP）浓度相关，并且FDR中源自这种关系的对GIP增强的敏感性往往受损。补偿指数、增强和对GIP的敏感性是相互关联的参数（P<0.05或更低）。β细胞功能参数也与24小时平均血糖水平相关（r² = 0.63，P<0.0001，多变量模型）。总之，尽管从绝对值来看，胰岛素抵抗的FDR中ISR增加，但β细胞功能显示出一系列相互关联的异常，包括对胰岛素抵抗的补偿、增强以及对GIP的敏感性，提示胰岛素分泌放大途径中的β细胞缺陷。
