(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.