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.
In gastrointestinal endocrinology, the concept of incretin is today highly topical and generally applied to two distinct gut hormones with technical acronymous names: GIP (originally “gastric inhibitory polypeptide,” later renamed “glucose-dependent insulinotropic polypeptide”) and GLP-1 [“glucagon-like peptide 1,” now in its truncated (7–36) form]. Of course it is more idiomatic to use the single word “incretin” instead of two acronyms. Moreover, many younger scientists and physicians today consider incretin a rather novel and fashionable concept surfacing in the wake of the development of GLP-1-derived drugs for treatment of type 2 diabetes mellitus, a view furthered by the growing business for the diabetes-related pharma industry. In other words, there is at present a marked focus on the two above-mentioned hormones in gastrointestinal endocrinology. To this end, there are also articles which are ostensibly dealing with gut hormones but mainly report about GLP-1 and/or GIP, sometimes accompanied by measurements of a third gut hormone, PYY (“peptide tyrosyl-tyrosyl”), or measurements of ghrelin. These articles contribute to the picture that gastrointestinal endocrinology today is essentially about GIP and GLP-1.
It is exciting that gut hormones are now used as targets for development of drugs for major diseases with large numbers of patients. But this is in fact what has been attempted for more than a century. Likewise, the incretin concept as such is in some respects more than 140 years old. But with the present conceptualization to just two hormones, incretin may lose aspects of its meaning and understanding of what gastrointestinal endocrinology is fundamentally about. Equally unfortunate, initiatives to develop additional relevant drugs may also be lost with today's narrow view on incretin.
In this situation, a review on the origin and early phases of gastrointestinal endocrinology leading to the incretin concept may be pertinent. The report here may hopefully also pave the way for a fuller and more relevant understanding of the biology of gut hormones, and at the same time give due credit to pioneers in the incretin story.
Incretin is a word and concept constructed for a gut hormonal factor assumed to supplement secretin in the effect on pancreatic secretion. Thus, while secretin stimulates the secretion of water and bicarbonate from the exocrine pancreatic cells, it has been suggested from the beginning that (an) other gut hormone(s) would stimulate the internal or endocrine secretion from pancreatic islet-cells. Literally, it was the Belgian physiologist Jean La Barre who coined the word “incrétine” in 1932. Consequently, the original definition suggests that any gut hormone which under physiological circumstances stimulates or contributes to the stimulation of the secretion of pancreatic hormones [insulin, glucagon, PP (pancreatic polypeptide), and pancreatic somatostatin] is an incretin.
The physiological context is of course important. Since the function of hormones in the digestive tract fundamentally is to facilitate digestion and subsequent absorption and metabolism of food elements, the incretin activity is linked to the gastrointestinal processing of ordinary meals. Hence, the original incretin definition challenges unphysiological loadings, such as intake of large amounts of for instance pure glucose or other pure chemicals.
The mental framework for the idea of incretin dates back to the second half of the nineteenth century, where European physiologists began to focus on the mechanisms of the external and internal secretion of the pancreas. It was in this period that Mering and Minkowski showed that the pancreas was the site of origin for diabetes mellitus, and where Claude Bernard tried to explain the fact that significantly larger amounts of glucose can be given orally than intravenously without glucosuria. Hence, Claude Bernard suggested that the liver takes up most of the oral glucose during the first portal circulation in order to prevent hyperglycemia. This explanation had supporters up to the 1950's.
A decisive breakthrough came in 1902, with Bayliss' and Starling's hallmark discovery of secretin that founded not only gastrointestinal endocrinology, but also endocrinology in general. The discovery of secretin was also the background for Starling's Croonian lecture from 1905, in which he coined the word hormone (from Greek “hormoa”: I arouse to activity). According to Moore et al., the discovery of the first hormone, secretin, also led Starling to suggest the possibility that the duodenal mucosa in addition to secretin produces another hormone that stimulates the internal secretion of the pancreas. Moore et al. immediately tested Starling's hypothesis by oral administration of extracts of duodenal mucosa to three recently diagnosed diabetes patients. In hindsight, the results of such oral intake were of course negative and inconclusive, because protein- and peptide-hormones are proteolytically degraded in the stomach. But the idea of incretin was born more than 110 years ago.
After the Banting & Best discovery of insulin in 1922, new attempts were taken to examine extracts of the duodenal mucosa and their influence on blood glucose concentrations. These results were also conflicting and inconclusive, which in retrospect cannot surprise. But promising results were nevertheless obtained by La Barre and Still, who in 1930 reported that they in the in vitro processing of duodenal extracts had obtained two interesting fractions: One with crude secretin, which in sophisticated cross-circulation experiments in dogs stimulated the secretion from the exocrine pancreas, and another which lowered blood glucose concentrations without effect on the secretion of the exocrine pancreas. They also suggested that the glucose-lowering effect was due to stimulated insulin secretion. Then in 1932—as mentioned above—La Barre presented the name, incretin, together with suggestions for treatment of diabetes mellitus with incretin. Strictly speaking, the articulated idea of incretin-therapy for diabetes is thus nearly a century old.
After La Barre's hallmark contributions to the incretin story, the Austrian Hans Heller also prepared an extract of the duodenal mucosa, which he in 1935 reported to lower blood glucose concentrations—even after oral administration to rabbits and man. Heller named the active factor in his extract “duodenin.” His results, however, have not been followed up, and the unspecific name duodenin was rapidly forgotten. Then, synchronously with the onset of the Second World War, the incretin-idea in general suffered an almost deadly blow from the Chicago-school of gastrointestinal endocrinology. The school was founded by Andrew Ivy, well known from the discovery of cholecystokinin (CCK) in 1928. After three publications in rapid succession 1939–40 about acidification of the duodenum in dogs at various blood glucose concentrations, Ivy et al. concluded that the existence of an incretin is unlikely. This opinion was neither challenged nor contradicted during World War II and in the two first post-war decades. On the contrary, the younger Ivy-pupil and -successor as spokesman for American gastrointestinal endocrinology, Morton Grossman, emphasized in a comprehensive high-impact review in 1950 the scepticism against the incretin concept. But as time has shown, Ivy and co-workers were wrong. They drew false-negative conclusions of their experiments that in fact only showed that secretin in dogs is without significant effect on insulin secretion. Nevertheless, their publications paralyzed further ideas and initiatives about incretin for a quarter of a century.
The year 1960 witnessed a major breakthrough for biomedicine and not least endocrinology. It virtually changed the world and revitalized the interest in incretin. It was the invention of the radioimmunoassay (RIA) by Berson and Yalow. The RIA technique allowed for the first time in a fairly uncomplicated, but accurate manner measurement of molecules present in pico- to even femtomolar concentrations. A world of biologically active substances, including peptide hormones, circulates in plasma in those concentrations. Therefore, RIA methods expanded the dimensions of much biological and medical research. Not least in basic and clinical endocrinology, because hormones are defined by their circulation in blood. For good reasons, the RIA technology was first applied to insulin. Therefore, the method was immediately embraced by endocrinologists and diabetologists studying pancreatic endocrine secretion and diabetes mellitus. Only one year later, RIA measurement of glucagon was launched by Unger et al. And each year during the following decades bursted with novel RIAs for known and new pancreatic and gastrointestinal hormones.
The possibility of direct and reliable measurements of insulin in plasma soon reopened the incretin question. In 1964, laboratories in London, UK [McIntyre et al.] and Denver, US [Elrick et al.] independently showed that oral glucose provokes a considerably larger insulin response than intravenous glucose, even at si
