Incretin Hormones and Type 2 Diabetes – Mechanistic Insights and Therapeutic Approaches

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.

Molecular mapping and functional validation of GLP-1R cholesterol binding sites in pancreatic beta cells

“…The glucagon-like peptide-1 receptor (GLP-1R), expressed in pancreatic beta cells amongst other tissues including brain, lung, stomach, and heart, is activated by the incretin peptide hormone GLP-1, secreted from enteroendocrine L-cells after food intake (1), to regulate postprandial glucose levels via the potentiation of glucose-dependent insulin secretion (2)(3)(4). Activation of GLP-1R also promotes beta cell survival, inhibits gastric emptying, regulates food intake and reduces appetite (1,5), making it a key pharmacological target for various metabolic disorders including type 2 diabetes (T2D) and obesity (6,7).…”

“…Activation of GLP-1R also promotes beta cell survival, inhibits gastric emptying, regulates food intake and reduces appetite (1,5), making it a key pharmacological target for various metabolic disorders including type 2 diabetes (T2D) and obesity (6,7). Circulation of active GLP-1 hormone is short-lived due to its rapid cleavage into inactive GLP-1 by dipeptidyl peptidase-4 (DPP-4) (2); peptide analogues of GLP-1 have therefore been developed and successfully used clinically for the treatment of T2D and obesity, including exendin-4, liraglutide, and semaglutide, amongst others (1,2,5). Despite their success, access to incretin peptide analogues is challenging for most individuals that require these therapies due to their high cost and complex manufacturing process leading to supply shortages, as well as requirement for refrigeration and administration by injection, together with notable side effects including gastrointestinal disturbances, prompting further research into the development of a new wave of small molecules (8,9), including those targeting the receptor as allosteric or ago-allosteric modulators (10,11).…”