(D-Ala2)-GIP (human) is an analog of glucose-dependent insulinotropic polypeptide that activates the GIP receptor (EC50=630pM) and is commonly used in research on type 2 diabetes treatment[1]. (D-Ala2)-GIP is resistant to degradation by dipeptidyl peptidase-4, thereby prolonging (D-Ala2)-GIP in vivo half-life and enhancing its insulin-secreting activity[2]. (D-Ala2)-GIP can modulate cellular energy metabolism, fat storage, and β-cell function[3]. (D-Ala2)-GIP also has the potential to ameliorate obesity-related insulin resistance and protect β-cells[4].
In vitro, pretreatment of mouse primary cardiomyocytes with (D-Ala2)-GIP (300nM) for 1 hour, followed by stimulation with 30mM high glucose for 24 hours, significantly suppressed NADPH oxidase-driven superoxide generation and reduced mRNA expression levels of the cardiac hypertrophy marker β-Mhc and the key fibrotic factor Tgf-β2[5]. Pretreatment of 3T3-L1 preadipocytes with (D-Ala2)-GIP (1μM) for 96 hours significantly promoted adipocyte differentiation and lipid accumulation, while upregulating gene expression of lipoprotein lipase (Lpl) and fatty acid synthase (Fasn)[6].
In vivo, daily intraperitoneal injection of (D-Ala2)-GIP (25nmol/kg) for 42 days in high-fat diet-induced obese, prediabetic Swiss NIH mice significantly reduced non-fasting blood glucose levels and improved glucose tolerance[7]. Daily intraperitoneal injection of (D-Ala2)-GIP (25nmol/kg) for 8 weeks in APPswe/PS1 Alzheimer's disease model mice significantly improved spatial memory and synaptic plasticity, increased synaptic density in the hippocampus, reduced amyloid plaque load and neuroinflammation, and enhanced neural progenitor cell proliferation in the dentate gyrus[8].
References:
[1] Hinke SA, Gelling RW, Pederson RA, et al. Dipeptidyl peptidase IV-resistant [D-Ala(2)]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats. Diabetes. 2002 Mar;51(3):652-61.
[2] Gault VA, Porter DW, Irwin N, Patel S, et al. Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high-fat fed mice. J Endocrinol. 2011 Mar;208(3):265-71.
[3] Mansur SA, Mieczkowska A, Bouvard B, et al. Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus. J Cell Physiol. 2015 Dec;230(12):3009-18.
[4] Porter DW, Irwin N, Flatt PR, et al. Prolonged GIP receptor activation improves cognitive function, hippocampal synaptic plasticity and glucose homeostasis in high-fat fed mice. Eur J Pharmacol. 2011 Jan 15;650(2-3):688-93.
[5] Hiromura M, Mori Y, Terasaki M, et al. Glucose-dependent insulinotropic polypeptide inhibits cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2. Diab Vasc Dis Res. 2021 Mar-Apr;18(2):1479164121999034.
[6] English A, Craig SL, Flatt PR, et al. Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes. Biol Chem. 2020 Oct 25;401(11):1293-1303.
[7] Vyavahare SS, Mieczkowska A, Flatt PR, et al. GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice. Peptides. 2020 Mar;125:170207.
[8] Hölscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimers Dement. 2014 Feb;10(1 Suppl):S47-54.
(D-Ala2)-GIP (human)是一种葡萄糖依赖性促胰岛素多肽的类似物，可激活GIP受体的活性（EC50=630pM），常用于研究II型糖尿病的治疗方法 [1]。(D-Ala2)-GIP可以抵抗二肽基肽酶-4的降解，从而延长在体内的作用时间，增强其促进胰岛素分泌的活性[2]。(D-Ala2)-GIP可调节细胞能量代谢、脂肪储存以及β细胞功能[3]。(D-Ala2)-GIP还具有改善肥胖相关胰岛素抵抗和保护β细胞的潜力[4]。
在体外，(D-Ala2)-GIP (300nM) 预处理小鼠原代心肌细胞1小时，随后以30mM高葡萄糖刺激24小时，显著抑制NADPH oxidase驱动的超氧化物生成，同时降低心肌肥厚标志物β-Mhc及纤维化关键因子Tgf-β2的mRNA表达水平[5]。(D-Ala2)-GIP（1μM）预处理3T3-L1前脂肪细胞96小时，显著促进脂肪细胞分化和脂质积累，同时上调脂蛋白脂肪酶（Lpl）和脂肪酸合酶（Fasn）的基因表达[6]。
在体内，(D-Ala2)-GIP（25nmol/kg）每日腹腔注射一次，持续42天，用于处理高脂饮食诱导的肥胖预糖尿病瑞士NIH小鼠。(D-Ala2)-GIP显著降低了非空腹血糖水平，并改善了葡萄糖耐量[7]。(D-Ala2)-GIP（25nmol/kg）每日一次腹腔注射，用于处理APPswe/PS1阿尔茨海默病模型小鼠，持续8周。(D-Ala2)-GIP显著改善了小鼠的空间记忆和突触可塑性，增加了海马区突触数量，减少了淀粉样斑块负荷和神经炎症反应，并增强了齿状回的神经祖细胞增殖[8]。