Department of Endocrinology I, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
Diabetes Obes Metab. 2015 Jan;17(1):74-81. doi: 10.1111/dom.12395. Epub 2014 Oct 26.
To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM).
A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n = 12): mean ± standard error of the mean (s.e.m.) age 54 ± 2.5 years, mean ± s.e.m. HbA1c 7.8 ± 0.2%; placebo group (n = 13): mean ± s.e.m. age: 57 ± 3.0 years, mean ± s.e.m. HbA1c 7.9 ± 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. β-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses.
In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p = 0.01). The total β-cell response during GIP infusion improved significantly from week 1 to week 12, both within the sitagliptin group (p = 0.004) and when compared with the placebo group (p = 0.04). The total β-cell response during GLP-1 infusion was significantly higher (p = 0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in β-cell function occurred in the placebo group.
Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.
研究在 2 型糖尿病（T2DM）患者中，12 周的二肽基肽酶-4（DPP-4）抑制剂西他列汀治疗是否会影响高血糖钳夹过程中葡萄糖、葡萄糖依赖性胰岛素释放肽（GIP）和胰高血糖素样肽-1（GLP-1）诱导的胰岛素分泌。
进行了一项为期 12 周的随机、双盲、安慰剂对照研究，在此期间，25 例 T2DM 患者接受了西他列汀（100mg 每日一次）或安慰剂作为二甲双胍的附加治疗（西他列汀组（n=12）：平均±标准误差均值（SEM）年龄 54±2.5 岁，平均±SEM HbA1c 7.8±0.2%；安慰剂组（n=13）：平均±SEM 年龄：57±3.0 岁，平均±SEM HbA1c 7.9±0.2%）。在第 1 周和第 12 周，患者接受了 3 次 2 小时 15mM 的高血糖钳夹实验，分别输注生理盐水、GLP-1 或 GIP。根据第一相、第二相、增量和总胰岛素和 C 肽反应评估β细胞功能。
在西他列汀组，平均 HbA1c 浓度显著降低 0.9%（p=0.01）。GIP 输注期间的总β细胞反应在第 1 周到第 12 周显著改善，无论是在西他列汀组内（p=0.004）还是与安慰剂组相比（p=0.04）。GLP-1 输注时的总β细胞反应明显高于生理盐水和 GIP 输注时，但从第 1 周到第 12 周没有改善。安慰剂组β细胞功能无明显变化。
在 T2DM 患者中，12 周的 DPP-4 抑制剂西他列汀治疗部分恢复了 GIP 的丢失的胰岛素分泌作用，而 GLP-1 的保留的胰岛素分泌作用没有进一步改善。因此，GIP 的胰岛素分泌作用的逐渐增强可能有助于 DPP-4 抑制剂的抗糖尿病作用。
