Incretin physiology and its history

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are responsible for the so-called incretin effect. The incretin effect refers to the amplification of insulin secretion that occurs when glucose is ingested orally as opposed to infused intravenously in amounts that result in identical glucose excursions - isoglycaemia. The scientific history of the incretin effect extends back to the very early 20th century, and the scientific interest surrounding it has only intensified over time.

In 1906, extracts of mucosa from porcine small intestine were used by Moore et al. as a treatment for diabetes, hoping that “the pancreas secretion might be stimulated by the substance of the nature of a hormone yielded by the duodenal mucosa membrane” [1]. In 1928, Zunz and LaBarre described a hypoglycaemic effect following injection of “secretin” extracted from small intestinal mucosa and, using cross-circulation experiments, they were able to show that the effect was mediated through the pancreas[2]. In 1932 La Barre was the first to introduce the term “incrétine” (incretin ) for a substance extracted from the upper gut mucosa, which produces hypoglycaemia and does not stimulate pancreatic exocrine secretion - as opposed to secretin[3]. In 1964, McIntyre et al. and Elrick et al. demonstrated that orally administered glucose evokes a greater insulin response than does intravenously administered glucose, and both groups hypothesized that gut-derived factors could have potentiating effects on insulin secretion after oral ingestion of glucose[4][5]. A few years later, in 1967, this finding was confirmed by Perley and Kipnis, who administered oral glucose; and, on a separate day, copied the oral glucose curve with an isoglycaemic intravenous (iv) glucose infusion in obese and normal weight patients with diabetes and in healthy control subjects[6]. They concluded that the insulin response to isoglycaemic iv glucose administration only amounted to 30-40% of that seen after oral glucose. Today, the isoglycaemic method used by Perley and Kipnis is widely accepted as the method of choice to measure the incretin effect. The effect is defined as the beta cell secretory response evoked by factors other than glucose itself, and is represented by the difference in integrated responses of plasma insulin, plasma C-peptide or insulin secretion rate, measured during oral glucose ingestion versus isoglycaemic iv glucose infusion. In healthy subjects, the incretin effect accounts for up to 70% of the total amount of insulin released in response to an oral glucose load (depending on the size of the glucose load: the more glucose ingested, the higher incretin effect elicited)[7][8]. This amplification of glucose-induced insulin secretion is the result of the actions of incretin hormones, which are released from the gut in the presence of intraluminal nutritional components. Incretin hormones potentiate glucose-induced insulin secretion and, therefore, play an essential role in the regulation of glucose homeostasis - in particular postprandial glucose levels.

As outlined by Creutzfeldt[9] an incretin hormone must 1) be released from gut endocrine cells after ingestion of nutrients, especially of glucose, 2) stimulate insulin secretion in a concentration which is easily achieved after ingestion of a nutrient, and 3) do so only at elevated glucose levels (glucose dependence). Many hormones have been suspected to contribute to the incretin effect, but today, there is ample evidence to suggest that the incretin effect mainly is conveyed by the two peptide incretin hormones: GIP (released form enteroendocrine K cells) and GLP-1 (released form enteroendocrine L cells). Both have been established as important incretin hormones in mimicry experiments in humans, where the hormones were infused together with iv glucose to concentrations approximating those observed during oral glucose tolerance tests. Both hormones powerfully enhanced insulin secretion during the iv glucose stimulus, actually to an extent that could fully explain the different insulin response during oral glucose and iv glucose infused alone[10][11]. The insulinotropic action of both hormones is strictly glucose-dependent and consists of potentiation of glucose-induced insulin secretion. Therefore, neither hormone has insulinotropic activity at lower glucose concentrations (less than 4 mM). Nevertheless, experiments have documented that both are active with respect to enhancing insulin secretion from the beginning of a meal (even at fasting glucose levels), and that they contribute almost equally, but with the effect of GLP-1 predominating at higher glucose levels[12]. Furthermore, the effects of the two hormones with respect to insulin secretion have been shown to be additive in humans[13].

Thus, GIP and GLP-1 form the endocrine part of the so-called “entero-insular axis” and, albeit indirectly via their strong insulinotropic properties, they are responsible for the majority of glucose uptake in muscle, liver and adipose tissue following ingestion of nutrients in man. In fact the percentage of an individual’s glucose disposal (following oral glucose tolerance test) which is caused by the oral route of glucose administration can be evaluated by measuring gastrointestinally-mediated glucose disposal (GIGD), which in healthy subjects amounts to ~60%[14][15]. GIGD is calculated on the basis of the amount of iv glucose needed to ‘copy’ the plasma glucose curve during a fixed oral glucose load (GIGD (%) = 100%×(glucoseoral-glucoseiv)/glucoseoral)14 15. It describes not only the impact of the incretin effect (insulinotropic substances released upon intestinal stimulation) but includes all factors affecting glucose disposal differently during oral vs. iv administration of glucose (including neural reflexes, activation of afferent nerves in the intestinal mucosa, differences in glucagon secretion, hepatic glucose production and first-pass hepatic uptake of glucose, differences in portal and venous blood glucose concentrations and/or at the present unknown factors) 14 15. It is likely that the incretin effect constitutes a major contributor to GIGD.

Besides stimulating insulin release (incretin effect) and thereby glucose-uptake, GLP-1 and GIP have several other actions. Both hormones stimulate insulin gene transcription, increase pancreatic beta cell mass and protect against beta cell apoptosis[16]. Furthermore, GIP and GLP-1 exert opposing effects on glucagon secretion (GIP stimulates and GLP-1 inhibits glucagon secretion glucose-dependently). Moreover, GLP-1 regulates body weight by inhibiting appetite and gastric emptying (possibly via a combination of direct and indirect effects including activation of central GLP-1 receptors) and, perhaps, stimulating resting energy expenditure. GIP, too, has actions other than its physiological glucose-dependent incretin effect. In vitro and animal studies indicate that GIP exerts direct effects on adipose tissue and lipid metabolism, promoting fat deposition.

References

  1. ^ Moore B (1906) On the treatment of Diabetus mellitus by acid extract of Duodenal Mucous Membrane. Biochem J 1:28-38

  2. ^ Zunz E, LaBarre J (1928) Hyperinsulinémie consécutive a l'injection de solution de secrétine non hypotensive. C R Soc Biol (Paris):1435-1438 (Abstract)

  3. ^ La Barre J (1932) Sur les possibilite´s d'un traitement du diabète par l'incrétine. Bull Acad R Med Belg 12:620-634

  4. ^ Elrick H, Stimmler L, Hlad CJJr, Rai Y (1964) Plasma insulin responses to oral and intravenous glucose administration. J Clin Endocrinol Metab 24: 1076-1082

  5. ^ McIntyre N, Holdsworth CD, Turner DS (1964) New interpretation of oral glucose tolerance. Lancet 2: 20-21

  6. ^ Perley MJ, Kipnis DM (1967) Plasma insulin responses to oral and intravenous studies in normal and diabetic sujbjects. J Clin Invest 46:1954-1962

  7. ^ Nauck MA, Homberger E, Siegel EG, et al (1986) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63:492-498

  8. ^ Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T (2011) Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 96:737-745

  9. ^ Creutzfeldt W (2005) The [pre-] history of the incretin concept. Reg. Pept 128:87-91

  10. ^ Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 7-a physiological incretin in man. Lancet 2:1300-1304

  11. ^ Nauck M, Schmidt WE, Ebert R, et al (1989) Insulinotropic properties of synthetic human gastric inhibitory polypeptide in interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab 69:654-662

  12. ^ Vilsbøll T, Krarup T, Madsbad S, Holst JJ (2003) Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114:115-121

  13. ^ Nauck MA, Bartels E, Ørskov C, Ebert R, Creutzfeldt W (1993) Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 76: 912-917

  14. ^ Hansen KB, Vilsbøll T, Bagger JI, Holst JJ, Knop FK (2010) Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 95:3309-3317

  15. ^ Hare KJ, Vilsbøll T, Holst JJ, Knop FK (2010) Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 298:E832-E837

  16. ^ Hare KJ, Knop FK (2010) Incretin-based therapy and type 2 diabetes. Vitam Horm 84:389-413

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