RD Lawrence Lecture 2008: Targeting GLP-1 release as a potential strategy for the therapy of Type 2 diabetes

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic beta-cells. Agents that either mimic GLP-1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP-1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development.

FIGURE 1

Glucose-dependent stimulation of insulin release by glucagon-like peptide-1 (GLP-1). At low glucose concentrations (left), intracellular [Ca²⁺] is low, and although stimulation by GLP-1 causes an increase in cyclic adenosine monophosphate (cAMP), this causes only small increases in [Ca²⁺] and minimal enhancement of insulin release (dashed arrows). The amount of insulin released is not enough to induce hypoglycaemia. At high glucose concentrations or in the presence of sulphonylureas (right), [Ca²⁺] is elevated, and the elevation of cAMP by GLP-1 can then potently enhance the rate of insulin release, as well as further increasing [Ca²⁺].

FIGURE 2

A working model of glucagon-like peptide-1 (GLP-1) release from the intestinal L-cell. Dietary nutrients stimulate GLP-1 release from intestinal L-cells, as a consequence of their Na⁺-coupled uptake and subsequent metabolism, which cause membrane depolarization (ΔΨ) and Ca²⁺ entry. Indirect signals from hormones and neurotransmitters can stimulate release by a variety of mechanisms, including elevation of cyclic adenosine monophosphate (cAMP) (which acts as both an initiator and an amplifier of GLP-1 release), and Ca²⁺ release from stores. GLP-1 released at the basolateral membrane stimulates insulin release from pancreatic β-cells and reduces appetite.