Incretin Hormones and Insulin Secretion

At the beginning of the 20^th century, two gastrointestinal hormones - secretin and gastrin - were discovered [1] [2]. These hormones were shown to be involved in the regulation of pancreatic and gastric acid secretion. The gastrointestinal hormones were also thought to regulate islet function, and the term incretin was introduced by Zunz and La Barr in 1929 for a gut hormone that stimulated islet function [3]. The role of the incretins was then explored in many studies [4]. Today, we know that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are the main incretin hormones [5].

The possibility of using gastrointestinal hormones for the treatment of diabetes was raised early. In fact, as early as in 1905, Moore and co-workers administered gut extracts to diabetic patients in Liverpool, UK, with the purpose of stimulating their pancreatic internal secretion for treatment of the disease [6]. Several gastrointestinal hormones, such as cholecystokinin [7], have subsequently been studied for this purpose. The breakthrough was the discovery of a potent antidiabetic action of GLP-1 in 1992 [8] [9]. This initiated the huge interest in this field, which has opened the possibility of treating subjects with diabetes with compounds based on the incretin hormones - a hundred years after the concept was originally presented.

Today, therapy based on mimicking the action of GLP-1 (GLP-1 receptor agonists) or inhibiting its inactivation (DPP-4 inhibitors) is in late clinical trials with such success that we can anticipate introduction of these novel treatments in clinical practice within a few years. Such treatment represents a major breakthrough in clinical diabetology. The field has developed very rapidly over the last few years, and recent findings have shown that GLP-1 has effects beyond its incretin action. Thus, GLP-1 is now also known to be involved in the regulation of pancreatic beta cell turnover, of glucagon secretion and of the function of a number of extrapancreatic tissues, including the central nervous system. With this background of expanding knowledge and success in clinical studies using GLP-1-based therapy in diabetes, it is of interest to summarize the present-day basic and clinical knowledge on the incretin hormones with special reference to their potential use in the treatment of diabetes.

The 2004 Special Issue of Hormone Metabolic Research is therefore focused on Incretin Hormones and Insulin Secretion. It covers the background of the incretin hormones as part of gastrointestinal endocrinology as well as the effects and mechanisms of action of the main incretin hormones (GIP and GLP-1) as reported in basic, experimental and clinical studies. This Special Issue also covers the development of GLP-1-based therapy into clinical practice. The illustration on the front of the issue captures the historical development. The upper panels show the important findings in the 1960 s that intrajejunal glucose has a much augmented insulin response compared to intravenous glucose, in spite of having a slightly lower glucose response due to the action of the incretin hormones [10]. The middle panel shows the important finding that GLP-1 is released from the gut following carbohydrate ingestion and augments insulin secretion in association with glucose (adapted from [11]), and the lower panel shows the novel findings of augmented islet size following activation of GLP-1 receptors (adapted from [12]).

In the Special Issue, the present day international authorities within this field present the background as well as most current development within their respective expertise. New findings are also presented; in fact, this Special Issue contains material that has never been published before, therefore representing the knowledge of incretin hormones in 2004.

The Special Issue combines the efforts of many individuals. The Guest Editors thank all contributing authors for their excellent work and for the willingness of taking their time to summarize and share their expertise. We also wish to express our gratitude to our Editorial Assistant, Linda Edge Svendsen, for her excellent work.

Bo Ahrén, Jesper Gromada and Ole Schmitz

Guest Editors

Lund, Sweden; Hamburg, Germany, and Århus, Denmark, in August, 2004

References

• 1 Bayliss W M, Starling E H. The mechanism of pancreatic secretion.  J Physiol. 1902;  28 325-353
• 2 Edkins J S. The chemical mechanism of gastric secretion.  J Physiol. 1906;  34 133-144
• 3 Zunz E, La Barre J. Contributions à l'eŽtude des variations physiologiques de la secretion interne du pancreas: relations entre les secretions externe et intene du pancreas.  Arch Int Physiol Biochim. 1929;  31 20-44
• 4 Creutzfeldt W. The incretin concept today.  Diabetologia. 1979;  16 75-85
• 5 Holst J J, Ørskov C. Incretin hormones - an update.  Scand J Clin Lab Invest. 2001;  234 (1) 75-85
• 6 Moore B, Edie E S, Abram J H. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane.  Biochem J. 1906;  1 28-38
• 7 Ahrén B, Holst J J, Efendic S. Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes.  J Clin Endocrinol Metab. 2000;  85 1043-1048
• 8 Gutniak M, Ørskov C, Holst J, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.  N Engl J Med. 1992;  326 1316-1322
• 9 Nathan D M, Schreiber E, Fogel H, Mojsov S, Habener J F. Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects.  Diabetes Care. 1992;  15 270-276
• 10 McIntyre N, Holdsworth C D, Turner D S. New interpretation of oral glucose tolerance.  Lancet. 1964;  2 20-21
• 11 Yamada Y, Seino Y. Physiology of GIP - lessons from GIP receptor KO mice.  Horm Metab Res. 2004;  36 771-774
• 12 Stoffers D A. The development of ß cell mass: recent progress and potential role of GLP-1.  Horm Metab Res. 2004;  36 811-821