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From the Incretin Concept and the Discovery of GLP-1 to Today's REVIEW published: 26 April 2019 doi: 10.3389/fendo.2019.00260 From the Incretin Concept and the Discovery of GLP-1 to Today’s Diabetes Therapy Jens Juul Holst* Department of Biomedical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark Researchers have been looking for insulin-stimulating factors for more than 100 years, and in the 1960ties it was definitively proven that the gastrointestinal tract releases important insulinotropic factors upon oral glucose intake, so-called incretin hormones. The first significant factor identified was the duodenal glucose-dependent insulinotropic polypeptide, GIP, which however, turned out not to stimulate insulin secretion in patients with type 2 diabetes. But resection experiments clearly indicated the presence of an additional incretin, and in 1986, an unexpected processing fragment of the recently identified glucagon precursor, proglucagon, namely truncated glucagon-like peptide 1 (GLP-1 7–36 amide), was isolated from the gut and found to both stimulate insulin Edited by: Ross Bathgate, secretion and inhibit glucagon secretion. The peptide also inhibited appetite and food Florey Institute of Neuroscience and intake. Unlike GIP, this peptide had preserved effects in patients with type 2 diabetes and Mental Health, Australia it was soon documented to have powerful antidiabetic effects in clinical studies. Its utility Reviewed by: Linda Jane Fothergill, was limited, however, because of an extremely short half-life in humans, but this problem Florey Institute of Neuroscience and had two solutions, both of which gave rise to important antidiabetic drugs: (1) orally active Mental Health, Australia inhibitors of the enzyme dipeptidylpeptidase 4 (DPP-4 inhibitors), which was responsible Patrick T. Fueger, Beckman Research Institute, City of for the rapid degradation; the inhibitors protect endogenous GLP-1 from degradation Hope, United States and thereby unfold its antidiabetic activity, and (2) long-acting injectable analogs of *Correspondence: GLP-1 protected against DPP-4 degradation. Particularly, the latter, the GLP-1 receptor Jens Juul Holst [email protected] agonists, either alone or in various combinations, are so powerful that treatment allows more than 2/3 of type 2 diabetes patients to reach glycemic targets. In addition, these Specialty section: agents cause a weight loss which, with the most successful compounds, may exceed This article was submitted to Molecular and Structural 10% of body weight. Most recently they have also been shown to be renoprotective and Endocrinology, reduce cardiovascular risk and mortality. a section of the journal Frontiers in Endocrinology Keywords: proglucagon, glucagon, GIP, oxyntomodulin, glicentin Received: 12 February 2019 Accepted: 08 April 2019 Undoubtedly inspired by the discovery of the first hormone ever, secretin, in 1902 and gastrin in Published: 26 April 2019 1905, Moore et al. proposed in 1906 that the duodenal mucosa might secrete a hormonal substance, Citation: which would affect the disposal of glucose from the blood by acting as “a chemical excitant for the Holst JJ (2019) From the Incretin Concept and the Discovery of GLP-1 internal secretion of the pancreas” and tried to treat diabetes (not very successfully) by injections to Today’s Diabetes Therapy. of gut extracts (1). But in 1929, Zunz and LaBarre (2) used cross-circulation experiments in dogs to Front. Endocrinol. 10:260. demonstrate pancreas-dependent hypoglycemic effects after injection of upper intestinal extracts; doi: 10.3389/fendo.2019.00260 such extracts clearly promoted pancreatic exocrine secretion (“excretin”), but the hypoglycemic Frontiers in Endocrinology | www.frontiersin.org 1 April 2019 | Volume 10 | Article 260 Holst Development of GLP-1-Based Therapies effects via pancreatic endocrine secretion (insulin had been insulin secretion themselves, and it is technically very difficult discovered in 1921) was thought to be due to an “incretin” (3). to control for the influence of all of the circulating nutrients Another hypoglycemic duodenal extract, supposed to stimulate and metabolites formed during meal ingestion. Interestingly, insulin secretion, was prepared by Heller in 1929 (4). However, an incretin effect i.e., enhanced insulin response elicited during it was not possible at the time to isolate and identify the oral as opposed to intravenous intake, can be demonstrated “incretin” and it was only when it became possible to measure not only for carbohydrate meals but also for protein and fat insulin (through the work of Yalow and Berson in the late meals (12, 13). This observation is probably consistent with 50ties) that the incretin effect could be further substantiated. release of insulinotropic hormones during ingestion of all three With the insulin assay, it was possible to directly demonstrate macronutrients. All these stimulatory factors have been discussed increased insulin secretion after oral vs. intravenous glucose under the common designation: the entero-insular axis (10). administration in spite of identical glucose concentrations, an Clearly mapping of all components on the axis is complex, and effect which today is referred to as the “incretin effect” (5, 6). an exhaustive mapping cannot be provided at present. In elegant experiments, Perley and Kipnis in 1964 demonstrated As already briefly alluded to, the incretin effect in its strict that gastrointestinal, endocrine factors were responsible for the sense is quantified by performing an oral glucose tolerance test augmented insulin secretion (7) and also demonstrated that (typically with 75g of glucose in healthy individuals; for people this mechanism was greatly impaired in “non-insulin requiring with diabetes lower amounts can be given, but this complicates maturity onset diabetes.” The question then arose, which factors the estimation because the magnitude of the effect depends on might be responsible, and the interest again turned toward the amount of glucose ingested) (14, 15) on 1 day, with blood the gastrointestinal hormones. Several hormones were tested sampling for glucose and insulin and for investigative purposes for insulin-releasing activity and many of them were able to hormone measurements. On a subsequent day, a glucose infusion stimulate insulin secretion, so a set of criteria for assigning an is given, the rate of which is adjusted manually to copy the incretin role to a hormone was established. First, the hormone excursions from the oral day. This is not as difficult as it had to be released after ingestion of glucose, since this stimulus sounds (numerous descriptions in the literature). In addition defined the incretin effect. Secondly, the hormone should be to sampling for glucose determinations (every 5 min) blood capable of stimulating insulin secretion, when infused at rates is sampled at certain intervals for insulin and perhaps other resulting in plasma concentrations similar to those elicited by hormone measurements. For accurate determination of insulin the oral glucose (8). This constitutes the “mimicry requirement.” secretion, independent of varying hepatic insulin extraction, it Whether or not insulin secretion should be pre-stimulated with may be useful to measure plasma levels of C-peptide, proinsulin’s glucose was discussed, but given that the incretin definition connecting peptide, which is not extracted in the human liver. included a comparison of insulin secretion during isoglycemic The incretin effect may then be calculated as the difference glucose challenges, it seems reasonable that the incretin candidate between the integrated insulin responses to the oral and the would stimulate insulin secretion primed by elevated plasma intravenous glucose challenge and expressed in per cent of the glucose concentrations. These criteria clearly excluded a number response to the oral load (16). In healthy subjects, this usually of hormones (e.g., cholecystokinin and gastrin), although it amounts to up to 70%, which shows that the incretin effect is may still be argued that some of them could contribute to responsible for a major part of the postprandial insulin response. stimulation of insulin secretion under special circumstances (6). As mentioned, the effect, expressed in this way, is dependent on This applies, for instance, to secretin, which quite powerfully the amount of glucose ingested–with much lower values observed stimulates glucose-induced insulin secretion, but when infused in for lower amounts of glucose (14, 15). healthy volunteers reaching postprandial concentrations, it failed An interesting, alternative way of looking at the to do so (9). However, in situations with high concentrations gastrointestinal influence on the disposal of a glucose meal, of the hormone, which may be observed for instance after is to calculate the amount of intravenously infused glucose gastric bypass operations, plasma levels may be sufficient to required to mimick the oral challenge. For a 75 g oral glucose stimulate insulin secretion. For cholecystokinin, there is an on- load this usually requires about 25 g of glucose. It follows that going debate as to which molecular component of it is the most 2/3 of the ingested glucose is removed from the circulation prevalent and/or important and whether or not this component by a mechanism that is dependent on the oral route. This has sufficient insulinotropic effects in the very low concentrations estimate has been designated GIGD, gastro-intestinally mediated at which it is circulating. Gastrin
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