The evolving story of incretins (GIP and GLP‐1) in metabolic and cardiovascular disease: A pathophysiological update

Abstract

The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) have their main physiological role in augmenting insulin secretion after their nutrient‐induced secretion from the gut. A functioning entero‐insular (gut‐endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to “isoglycaemic” intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP‐1 have additive effects on insulin secretion. Local production of GIP and/or GLP‐1 in islet α‐cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP‐1 suppresses, and GIP increases glucagon secretion, both in a glucose‐dependent manner. GIP plays a greater physiological role as an incretin. In type 2‐diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP‐1. While insulinotropic effects of GLP‐1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP‐1 have additional biological functions: GLP‐1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP‐1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP‐1, play a role in bone remodelling. GLP‐1, but not GIP slows gastric emptying, which reduces post‐meal glycaemic increments. For both GIP and GLP‐1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP‐1 receptor co‐agonists like tirzepatide have superior efficacy compared to selective GLP‐1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long‐term interaction of GIP and GLP‐1 receptor signalling. A GLP‐1 receptor antagonist (exendin [9‐39]) and, more recently, a GIP receptor agonist (GIP [3‐30] NH2) and, hopefully, longer‐acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin‐based diabetes drugs.

Managing weight and glycaemic targets in people with type 2 diabetes—How far have we come?

“…Pharmacological doses of GLP‐1 RAs have been found to elicit insulinotropic effects. The combination of GIP and GLP‐1 tends to have a lower insulinotropic effect than the sum of the individual effects of GIP and GLP‐1 administered separately 147 …”

“…On the other hand, GLP‐1 suppresses glucagon concentration during hyperglycaemia but not during euglycaemia or hypoglycaemia. The combination no longer lowers glucagon concentration, suggesting an interaction between GIP and the suppression of glucagon secretion observed with GLP‐1 alone 147 …”

Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment

“…GIP is secreted from K-cells of the proximal small intestine (duodenum and jejunum) [8,41], while GLP-1 secretion from L-cells of the small and large intestine (distal ileum and colon) [42] following an introduction of carbohydrates, triglycerides, protein, or amino acids. An important exception is glutamine, which is a specific stimulator for GLP-1 [43]. It is important to underline that the GIP response does not depend on the quantity of the food ingested as on the composition [44] (Figure 1).…”

“…Although GLP1 stimulates lipolysis [10,[71][72][73][74][75][76][77], GIP leads to the accumulation of body fat through fatty acid synthesis and re-esterification, augmentation of integration of fatty acids into triglycerides, increased synthesis of lipoprotein lipase, and reduction of lipolysis. GIP, and perhaps to a lesser extent GLP-1, which does not present clear evidence of bone metabolism, act on bone remodeling through the effects on osteoclasts and osteoblasts [43]. Incretins have been shown to indirectly affect hepatic and muscle metabolism, specifically through changes in circulating concentrations of insulin and glucagon [31,[78][79][80].…”

Cardiometabolic Alterations in the Interplay of COVID-19 and Diabetes: Current Knowledge and Future Avenues

“…This is particularly true during the current pandemic where we have observed a significant increase in cardiovascular complications in patients with diabetes or obesity [26,27]. In this context, some novel antidiabetic agents, such as glucagon-like peptide (GLP)-1 receptor agonists seems to play a role due to their anti-inflammatory and anti-atherogenic/thrombotic effects [28,29], with a likely direct mechanism against COVID-19 onset and severity [30]. Notably, these novel drugs are also able to reduce small, dense LDL [31], in contrast to what found with the use of some traditional antidiabetic drugs [32].…”