Incretin-Based Therapies
Viewpoints on the way to consensus
- Michael. A. Nauck, MD1,
- Tina Vilsbøll, MD2,
- Baptist Gallwitz, MD3,
- Alan Garber, MD4 and
- Sten Madsbad, MD5
- 1Diabetes Center Bad Lauterberg, Bad Lauterberg im Harz, Germany;
- 2Department of Internal Medicine, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark;
- 3Department of Medicine IV, Eberhard-Karls University Tübingen, Tübingen, Germany;
- 4Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston, Texas;
- 5Department of Endocrinology, Hvidovre University Hospital, University of Copenhagen, Copenhagen, Denmark.
- Corresponding author: Michael A. Nauck, m.nauck{at}diabeteszentrum.de.
Viewpoints on the way to consensus
INTRODUCTION (by M.A.N.)
Incretin mimetics and inhibitors of the protease dipeptidyl peptidase (DPP)-4 are new classes of antidiabetic agents first introduced in the years 2005 (exenatide) and 2007 (sitagliptin), respectively. Both use the antidiabetic properties of the incretin hormone, glucagon-like peptide (GLP)-1 (1). This gut-derived peptide hormone not only augments glucose-induced insulin secretion (required to fulfill the definition of an incretin hormone), but does so in a highly glucose-dependent manner (2), thus preventing GLP-1 alone from provoking hypoglycemia. Additional beneficial effects of GLP-1 on endocrine pancreatic islets are that it 1) supports the synthesis of proinsulin to replenish insulin stores in β-cells; 2) reduces the rate of β-cell apoptosis when islets are incubated in a toxic environment (glucotoxicity, lipotoxicity, cytotoxic cytokines); and 3) promotes differentiation of precursor cells with the ability to develop into β-cells and proliferation of β-cell lines, and in whole animals (rodent studies), this leads to an increased β-cell mass within a few days or weeks (1,3). Furthermore, GLP-1 can lower glucagon concentrations, i.e., induce α-cells to respond again to the inhibitory action of hyperglycemia, while leaving the counterregulatory glucagon responses undisturbed, as in the case of hypoglycemia (2,4). Additional activities of GLP-1 are the deceleration of gastric emptying (5), which slows the entry of nutrients into the circulation after meals, a reduction in appetite, and earlier induction of satiety (6), leading to weight reduction with chronic exposure (7). Renal effects (promotion of sodium and water excretion (8), as well as neuro- (9) and cardioprotective (10) properties of GLP-1, have also been described. While GLP-1 is perfectly suitable for lowering, or even stabilizing, glucose concentrations in short-term experiments, its short half-life (∼1–2 min for the intact, biologically active form) caused by rapid proteolytic degradation and inactivation through the ubiquitous enzyme DPP-4 and renal elimination (Fig. 1 …