Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

Abstract

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins-glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

Keywords: GIP; GLP-1; cardiovascular disease; incretin-based therapy; incretins; non-alcoholic fatty liver disease; obesity; type 2 diabetes mellitus.

Figure 1

The summary of biological effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) on various organs. ↑: increase; ↓: decrease.

Figure 2

The GIP gene is localized on human chromosome Chr17q21.32 and encodes 153-amino acid (aa) proprotein, which is processed to 42-aa protein glucose-dependent insulinotropic peptide (GIP). GCG gene is localized on human chromosome Chr2q24.2 and encodes preproglucagon—180-aa protein, which undergoes differential posttranslational processing in a particular type of cell. Proteolytic processing of proglucagon by prohormone convertase 1/3 (PC1/3) in the intestine generates glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin, intervening peptide 2 (IP2) and glicentin. Prohormone convertase 2 (PC2) activity in the pancreas forms glucagon, glicentin-related pancreatic polypeptide (GRPP), intervening peptide 1 (IP1), and major proglucagon fragment.

Figure 3

Secretion and metabolism of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). GIP is secreted by K cells of the upper intestine, whereas GLP-1 is secreted by L cells of the lower intestine. Active forms of both incretins GIP(1–42), GLP-1(7–37) and amidated GLP-1(7–36) act directly on the pancreas and are responsible for the incretin effect. Both GIP and GLP-1 are inactivated by dipeptidyl peptidase 4 (DPP-4) to GIP(3–42), GLP-1(9–37) and GLP-1(9–36), which are excreted by the kidneys. Arrows represent pathways of incretins metabolism.

Figure 4

Potential therapeutic effects of GLP-1RA administration in obese patients with co-existing cardiometabolic disorders. T2DM: type 2 diabetes mellitus; NAFLD: non-alcoholic fatty liver disease; CVD: cardiovascular disease. ↑: increase; ↓: decrease.