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Glucagon as the First Incretin: Objects (in the Rearview Mirror) Are Closer Than They Appear

The term “incretin” was coined in 1932 by the Belgian physiologist Jean La Barre to describe hormones that stimulated the internal (i.e., islet) secretions of the pancreas; it was also suggested these hormones would be useful for the treatment of diabetes. Indeed, in the last four decades of the 20th century, considerable research activity was dedicated to the identification and study of incretins, leading to a general consensus that glucose-dependent insulinotropic polypeptide (GIP), discovered in 1970, and glucagon-like peptide 1 (GLP-1), discovered 1983–1987, were the factors that accounted for the incretin effect. GIP and GLP-1 are made and released from intestinal enteroendocrine cells…

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 Incretins: How we got here, where we’re at and what is coming next

The two primary incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulotropic polypeptide (GIP), are secreted from the intestine in response to the ingestion of food, stimulating the release of insulin by the pancreas. GLP-1 receptor agonists were developed to mimic the action of native GLP-1.

Articles of Interest

The Origin and Understanding of the Incretin Concept

Gastrointestinal hormones that stimulate insulin secretion at physiological concentrations are incretins. This concept has recently attracted considerable attention in the wake of drugs developed from the gut hormone GLP-1 (glucagon-like peptide-1) for diabetes therapy. But the renewed enthusiasm has also restricted the concept to just two hormones, GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). The purpose of the present overview is two-fold: First to tell that the incretin concept is far from new. It has a more than a century long history full of ups and downs. Second, that the incretin concept may now have become too narrow. Thus, it is likely that incretin comprises additional gastrointestinal hormones, which interact with GIP and GLP-1 during normal meals containing protein, fat and complex carbohydrates (and not just pure glucose). Such broader incretin concept may stimulate development of novel gut hormone-derived drugs.

Biology of incretins: GLP-1 and GIP

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients

Incretin hormones and type 2 diabetes

Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes.

Incretin hormones: Their role in health and disease

Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present.

Incretin mimetics and enhancers: mechanisms of action

The incretins are peptide hormones. They are released into the circulation, in response to luminal nutrients, within minutes of eating. In humans, the major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is secreted by the L cells in the ileum and colon, while GIP is secreted by the K cells in the duodenum. Both incretins have hormonal effects on multiple organs, notably the endocrine pancreas, the gut and the brain (Table 1). Their predominant role is regulation of energy homeostasis.

Incretin-based therapy of metabolic disease

The most recent developments regarding therapies based on incretin hormones (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) are likely to fundamentally change our therapy for type 2 diabetes mellitus (T2DM), obesity and conditions associated with diabetes and obesity, i. e. cardiovascular disease, stroke, cognitive impairment and diabetic kidney disease.

Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Whereas glucose-tolerant individuals are capable of adjusting their insulin secretion to their actual insulin sensitivity, people with type 2 diabetes are incapable of doing so. β-Cell failure is therefore the hallmark of this disease, although failure may be precipitated by the development of insulin resistance, typically as a consequence of obesity. In healthy subjects, a considerable part of the postprandial insulin response is due to the actions of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, the two hormones are responsible for the so-called incretin effect, i.e., the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide identical plasma glucose concentrations.

New Drugs Could Help Treat Obesity. Could They End the Stigma, Too?

Incretins appear to elicit significant weight loss in most patients, enough to make a real medical and aesthetic difference. But experts hope that the drugs also do something else: change how society feels about people with obesity, and how people with obesity feel about themselves.

Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action

Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways.

The biology of incretin hormones

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote β cell proliferation and inhibit apoptosis, leading to expansion of β cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion.

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

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).

The expanding incretin universe: from basic biology to clinical translation

Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes.

The incretin system in healthy humans: The role of GIP and GLP-1

GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d’être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4).

Unraveling the Science of Incretin Biology

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes.

What Are Incretin Mimetics, and How Do They Affect Weight Loss, Blood Sugar, and Type 2 Diabetes?

Incretin mimetics are medications that mimic incretin hormones. They’re currently approved for Type 2 diabetes or chronic weight management in certain people. Most incretin mimetics come as daily or weekly injections. And currently they’re only available as brand-name medications. But most manufacturers provide a copay savings card and patient assistance programs to help you save on the cost