Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean±SD; BMI 27±2.6 kg/m2, HbA1c 7.1±1.4% (54±15 mmol/mol) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2(1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared to placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared to saline (ΔAUC%±SEM; +7.3±2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved beta cell function by 37±12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate / plasma glucose ratio. We calculated an estimate of the ‘absolute sitagliptin-mediated impact of GIP on beta cell function’ as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (= 100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin plus saline) and the physiological response minus any contribution by GIP (placebo treatment plus GIP(3-30)NH2). We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes, and that endogenous GIP contributes to the improved beta cell function observed during DPP-4 inhibition.

中文翻译：

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内源性葡萄糖依赖性促胰岛素多肽有助于西格列汀介导的 2 型糖尿病患者 β 细胞功能的改善

二肽基肽酶 4 (DPP-4) 可降解肠促胰岛素激素胰高血糖素样肽 1 (GLP-1) 和葡萄糖依赖性促胰岛素多肽 (GIP)。DPP-4 抑制剂可改善 2 型糖尿病的血糖控制，但保护 GIP 免受降解对其临床效果的重要性尚不清楚。我们在这项双盲、安慰剂对照、交叉研究中纳入了 12 名 2 型糖尿病患者（平均值±标准差；BMI 27±2.6 kg/m2，HbA1c 7.1±1.4% (54±15 mmol/mol)，以调查其贡献内源性 GIP 对 DPP-4 抑制剂西格列汀的影响。参与者分别接受了两个随机 13 天的西格列汀（100 毫克/天）和安慰剂疗程。在每个治疗期结束时，我们进行了两次混合膳食测试输注 GIP 受体拮抗剂 GIP(3-30)NH2(1,200 pmol/kg/min) 或生理盐水安慰剂。与安慰剂治疗相比，西格列汀可将平均空腹血糖降低 1.1 mmol/L。在安慰剂治疗期间，与生理盐水相比，GIP(3-30)NH2 期间的餐后血糖波动增加（ΔAUC%±SEM；+7.3±2.8%），但在西格列汀治疗期间没有变化。在西格列汀抑制 DPP-4 期间，内源性 GIP 将 β 细胞功能提高了 37±12%。这由胰岛素分泌率/血浆葡萄糖比率确定。我们计算了“西格列汀介导的 GIP 对 β 细胞功能的绝对影响”的估计值，即西格列汀治疗加盐水输注期间的胰岛素生成指数减去西格列汀加 GIP(3-30)NH2 期间的胰岛素生成指数。该估计值是相对于 GIP 对西格列汀作用的最大潜在贡献（= 100%）表示的，定义为完整的西格列汀治疗效果之间的差异，包括由 GIP 介导的作用（西格列汀加生理盐水）和生理反应减去 GIP 的任何贡献（安慰剂治疗加 GIP(3-30)NH2）。我们证明了内源性 GIP 对 2 型糖尿病患者的促胰岛素和降糖作用，并且内源性 GIP 有助于在 DPP-4 抑制期间观察到的β细胞功能改善。