Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Abstract

The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Daniel J. Drucker, MD, of the Department of Medicine, Mount Sinai Hospital and the Lunenfeld-Tanenbaum Research Institute in Toronto, Ontario, Canada, received the prestigious award at the ADA's 74th Scientific Sessions, 13–17 June 2014, in San Francisco, California. He presented the Banting Lecture, “Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation,” on Sunday, 15 June 2014. Gut peptides convey nutrient-regulated signals to the enteric nervous system and to distal organs, acting as circulating hormones secreted in the basal and postprandial state. Here I provide an overview of the actions of glucagon-like peptide (GLP)-1 and GLP-2, the two major enteroendocrine L-cell peptides. The endogenous physiological actions of GLP-1 have been delineated using antagonists and Glp1r−/− mice and include the control of islet hormone secretion in a glucose-dependent manner, leading to improvement of fasting and postprandial glucose homeostasis. GLP-1 receptors (GLP-1Rs) are also widely distributed in multiple extrapancreatic organs, providing a mechanistic explanation for the nonglycemic actions attributed to GLP-1. The multiple metabolic actions of GLP-1 enable reduction of glycemia and body weight in diabetic and obese subjects, providing the opportunity to reduce glycemia in human subjects with diabetes with a low risk of hypoglycemia. GLP-2 plays a key role in the control of energy absorption and in the integrity of the intestinal mucosa, and a GLP-2R agonist, teduglutide, is now used for augmentation of energy absorption in parenteral nutrition–dependent subjects with short bowel syndrome. GLP-1 and GLP-2 are both cleaved by dipeptidyl peptidase-4 (DPP-4); hence, inhibition of DPP-4 activity enables yet another pathway for potentiation of incretin action and the therapy for type 2 diabetes. Here I review our 30-year experience with the elucidation of gut hormone action and, wherever possible, highlight therapeutic implications of our preclinical studies and future opportunities for incretin research.

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…Thus, GIP receptor agonism augments beta cell-induced glucose-dependent insulin secretion, akin to the actions of clinically approved GLP-1 mimetics [3]. This approach is very encouraging given that the issue of GIP sensitivity in type 2 diabetes is now being addressed.…”

“…The main impairments are recognised as reduced postprandial GLP-1 secretion and defective GIP receptor signalling [1]. The inadequacy in the GLP-1 arm of the incretin effect can be easily overcome through administration of exogenous GLP-1, which significantly amplifies circulating concentrations [2,3]. In contrast, pharmacological augmentation of circulating GIP levels fails to evoke an effective increase in insulin secretion in patients with type 2 diabetes [4].…”

“…For GIP, the first 14 N-terminal amino acid residues contain the bioactive domain important for insulin-secretory function [25,26]. Based on this knowledge, we constructed a novel GIP/xenin hybrid peptide, (DAla 2 )GIP/xenin-8-Gln, by linking GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) to xenin-8-Gln, retaining the regions of each peptide known to be important for biological activity (see electronic supplementary material [ESM] Table 1). Importantly, since GIP is a substrate for dipeptidyl peptidase-4 (DPP-4) [27], the hybrid peptide includes substitution of the naturally occurring alanine L isomer residue by a D isomer at position 2 [28,29].…”

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)

“…This study investigated whether CEACAM2 regulates insulin secretion. We report here that CEACAM2 plays a role in insulin secretion via a mechanism implicating the release of the insulinotropic glucagon-like peptide-1 (GLP-1), an incretin that potentiates glucose-stimulated insulin secretion from pancreatic ␤-cells (11)(12)(13)(14)(15)(16)(17).…”

Relationship between deterioration of glycated hemoglobin‐lowering effects in dipeptidyl peptidase‐4 inhibitor monotherapy and dietary habits: Retrospective analysis of Japanese individuals with type 2 diabetes

“…This enhanced efficacy has been attributed to the unique type 2 diabetes phenotype in East Asians, who tend to be non‐obese and to show β‐cell dysfunction2, 5. However, differences in dietary habits might also affect the HLE of DPP4is, as the glucose‐lowering mechanisms of DPP4i involve the incretins, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide (GIP), hormones that are secreted in response to meal ingestion and enhance insulin secretion in a glucose‐dependent manner 6, 7. Indeed, we and others have shown that the HLE of DPP4i in the relatively short‐term are enhanced by fish intake, as estimated by food records and serum levels of eicosapentaenoic acids and docosahexaenoic acids, in type 2 diabetes individuals8, 9.…”