GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that are secreted from enteroendocrine L cells and K cells in response to digested nutrients, respectively. They are also referred to incretin for their ability to stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. Furthermore, GLP-1 exerts anorexic effects via its actions in the central nervous system. Since native incretin is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), DPP-resistant GLP-1 receptor agonists (GLP-1RAs), and DPP-4 inhibitors are currently used for the treatment of type 2 diabetes as incretin-based therapy. These new-class agents have superiority to classical oral hypoglycemic agents such as sulfonylureas because of their low risks for hypoglycemia and body weight gain. In addition, a number of preclinical studies have shown the cardioprotective properties of incretin-based therapy, whose findings are further supported by several randomized clinical trials. Indeed, GLP-1RA has been significantly shown to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes. However, the role of GIP in cardiovascular disease remains to be elucidated. Recently, pharmacological doses of GIP receptor agonists (GIPRAs) have been found to exert anti-obesity effects in animal models. These observations suggest that combination therapy of GLP-1R and GIPR may induce superior metabolic and anti-diabetic effects compared with each agonist individually. Clinical trials with GLP-1R/GIPR dual agonists are ongoing in diabetic patients. Therefore, in this review, we summarize the cardiovascular effects of GIP and GIPRAs in cell culture systems, animal models, and humans.

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

“…Currently, there are no clinical therapies using GIPR agonists [ 93 ]. Experimental results of GLP1R/GIPR dual co-agonists derived from intermixed incretin sequence have shown augmented antihyperglycemic and insulinotropic effect compared with specific GLP1 agonist in db/db mice, ZDF diabetic rats, monkeys and humans [ 94 , 95 ].…”

“…GIP has been related to different signalling pathways in vascular cells with both anti-atherogenic via NO production, or pro-atherogenic effects through increased endothelin-1 and VSMCs osteopontin expression [ 93 ]. In HUVECs cultures GIP/GIPR and GLP1/GLP1R interactions reduce the advanced glycation end products (AGEs) receptor (RAGE) expression, blocking the signalling pathways associated with diabetes-associated vascular damage [ 97 ].…”

“…On the other hand, as shown in Table 1 , GIPR levels are diminished in diabetic experimental models and consequently, administration of GIP in Apoe-/- and db/db diabetic mice reduced atherosclerotic plaque lesions and foam cell formation [ 37 , 98 ]. Furthermore, the administration of GIP active forms to Apoe-/- mice increased atherosclerotic collagen content [ 36 ], suppressed VSMCs proliferation and reduced aortic endothelial expression of MCP1, VCAM1, ICAM1, and PAI1 [ 37 , 93 ] and monocyte migration and macrophage activation in a NFkB-dependent manner [ 36 ]. Other observed actions are the blocking of proinflammatory monocyte aortic infiltration, the decrease in Cd36 and Acat1 expression, foam cell formation, LPS-induced IL-6 secretion, and MMP-9 activity [ 36 , 37 , 93 ].…”

“…GIP serum levels are elevated in patients with atherosclerotic vascular disease [ 36 ]. In humans, physiological doses of GIP increased heart rate, arterial blood pressure, and blood levels of osteopontin CCL8 and CCL2, accordingly with reduced CCL2/CCR2-mediated migration of cultured human monocytes (THP-1 cells) [ 93 ].…”

Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology

“…Mori with coauthors [ 30 ] in their review summarized the cardiovascular effects of the glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor agonists (GIPRAs) in cell culture systems, animal models, and humans. Recently, pharmacological doses of GIPRAs have been found to exert anti-obesity effects in animal models.…”