Meier J J, Nauck M A
Larry Hillblom Islet Research Center, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Horm Metab Res. 2004 Nov-Dec;36(11-12):859-66. doi: 10.1055/s-2004-826176.
Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity.
进食后，葡萄糖依赖性促胰岛素多肽（GIP）从肠道的K细胞释放出来，并与胰高血糖素样肽1（GLP-1）协同作用，增强葡萄糖刺激的胰岛素分泌。虽然GLP-1的衍生物正在积极研究用于治疗2型糖尿病，但GIP的情况却不同。事实上，2型糖尿病患者几乎不存在GIP的促胰岛素作用。此外，天然GIP不利的药代动力学特征使其无法用于临床。为了改善GIP的抗糖尿病特性，已制备出具有延长稳定性和增强生物活性的不同GIP类似物。然而，GIP及其衍生物尚未能像2型糖尿病患者静脉注射GLP-1时通常观察到的那样实现血糖正常化。由于GIP似乎在脂质生理学中起作用，且GIP水平升高与肥胖有关，因此有人提出拮抗GIP作用作为肥胖的治疗策略。最近，GIP受体基因敲除小鼠对高脂饮食诱导的肥胖具有抵抗力这一观察结果进一步强化了这一概念。然而，消除内源性GIP的作用可能同时损害餐后胰岛素分泌，从而严重扰乱葡萄糖稳态。因此，基于增强或拮抗GIP作用的治疗策略远未成为未来治疗2型糖尿病或肥胖的既定替代方案。
