The concept that oral nutrient (glucose) administration promotes a much greater degree of insulin secretion compared to a parenteral isoglycemic glucose infusion underlies the incretin effect, namely the existence of gut-derived factors that enhance glucose-stimulated insulin secretion from the islet β-cell. The hypothetical existence of certain factors produced by the intestinal mucosa in response to nutrient ingestion that are capable of stimulating the release of substances from the endocrine pancreas and thereby reducing blood glucose levels was first postulated in the early 1900's in several landmark publications (Bayliss WM, Starling EH. On the causation of the so-called 'peripheral reflex secretion' of the pancreas. Proceedings of the Royal Society of London[Biol] 1902;69:352-353 and Moore B, Edie ES, Abram JH. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906;1:28-38)

This phenomenon has been dubbed the 'incretin effect' and is estimated to account for approximately 50-70% of the total insulin secreted following oral glucose administration.  Thus, incretins are hormones that are secreted from the gastrointestinal tract into the circulation in response to nutrient ingestion that enhance glucose-stimulated insulin secretion. The term 'incretin' was subsequently used to denote these glucose-lowering, intestinal-derived factors as outlined in La Barre J. Sur les possibilites d'un traitement du diabete par l'incretine. Bull Acad R Med Belg 1932;12:620-634 With the development of the radioimmunoassay, this communication between the intestine and the endocrine pancreas was confirmed when it was demonstrated that oral glucose administration is associated with a much greater increase in plasma insulin levels when compared to the same amount of glucose given intravenously as described in NEW INTERPRETATION OF ORAL GLUCOSE TOLERANCE Lancet. 1964 Jul 4;2:20-1 and Intestinal factors in the control of insulin secretion J Clin Endocrinol Metab. 1965 Oct;25(10):1317-24.

The first incretin hormone to be identified was isolated from crude extracts of porcine small intestine and initially named gastric inhibitory polypeptide (GIP ), based on its ability to inhibit gastric acid secretion in dogs.However, subsequent studies using more purified preparations of GIPrevealed that GIP  could also stimulate insulin secretion in animals and humans  Stimulation of insulin secretion by gastric inhibitory polypeptide in man J Clin Endocrinol Metab. 1973 Nov;37(5):826-8.  As the inhibitory effect of GIP  on gastric acid secretion was seen only at pharmacological doses, whereas its incretin action occurred at physiological levels, GIP  was renamed 'glucose-dependent insulinotropic polypeptide,' to reflect its physiological action yet retain the acronym. In accordance with its role as an incretin hormone, GIP  is released from K-cells of the small intestine, primarily in response to glucose or fat ingestion, and potentiates glucose-stimulated insulin secretion.  It was recognized however, that GIP  alone could not fully account for the incretin effect in vivo.  This was based on the observations that immunoneutralization of endogenous GIP  activity attenuates but does not abolish the incretin effect in rodents and in humans, surgical resection of the ileum is associated with diminished incretin activity, despite preservation of normal postprandial  plasma GIP  levels. Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection in man Scand J Gastroenterol. 1980;15(7):833-40

 

The discovery of a second incretin hormone, glucagon-like peptide-1 (GLP-1), followed the cloning and sequencing of mammalian proglucagon genes and complementary DNAs (see Glucagon Gene).  In addition to glucagon, the proglucagon gene also encoded two peptides that were approximately 50% homologous to glucagon and thus aptly named glucagon-like peptide-1 and -2.  Based on their homology to glucagon, both peptides were tested for insulinotropic activity, but only GLP-1 was capable of stimulating insulin secretion.  GLP-1 is a tissue-specific posttranslational proteolytic product of the proglucagon gene that is released from intestinal L-cells in response to nutrient ingestion and enhances glucose-stimulated insulin secretion in human subjects Glucagon-like peptide-1 7-36: a physiological incretin in man Lancet. 1987 Dec 5;2(8571):1300-4.

To date, only GIP  and GLP-1 fulfill the definition of an incretin hormone in humans.  Furthermore, studies have shown that these two peptides potentiate glucose-stimulated insulin secretion in an additive manner, likely contribute equally to the incretin effect and together can fully account for the majority of the incretin effect in man. The secretion of both incretin hormones may exhibit some degree of temporal periodicity and appear to be greater after meal ingestion in the morning compared to effects seen after comparable nutirent ingestion later in the day Differential Islet and Incretin Hormone Responses in Morning vs. Afternoon after Standardized Meal in Healthy Men. J Clin Endocrinol Metab. 2009 May 12. [Epub ahead of print]

Are there other hormones and mediators beyond GIP  and GLP-1 with incretin like activity? Several other peptide hormones, nutrients, bile acids, and lipid amides are also secreted following nutrient ingestion, bind to receptors on islet b-cells and stimulate glucose-dependent insulin secretion. For example, CCK is a prototype peptide hormone secreted from the gut that also enhances insulin secretion, however CCK secretion and levels achieved following oral nutrient ingestion is comparatively modest relative to GIP and GLP-1 in normal human subjects. Ali and colleagues demonstrated that disruption of the normal incretin axis in mice can be associated with upregulation of the islet CCKAR and enhanced sensitivity to CCK both in vitro and in vivo. Similarly islet GPR119 expression is dynamically regulated under the same cicrcumstances and incretin receptor knockout mice exhibit substantially increased sensitivity to GPR119 agonists. Hence, the murine b-cell exhibits considerable plasticity and is capable of upregulating non-classical incretin receptors to preserve the intestinal-islet incretin axis in vivo Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis J Clin Invest. 2011 doi:10.1172/JCI43615.

Infusion of the GLP-1 antagonist exendin (9-39) blocked the insulinotropic and glucagonostatic effects of exogenous GLP-1, and also increased plasma glucagon during euglycemia and hyperglycemia. Exendin (9-39 also increased insulin during hyperglycemia. Similarly, human GLP-1 is essential for control of anteroduodenal motility, as demonstrated in studies using exendin(9-39). Nicolaus and colleagues administered exendin(9-39) to healthy subjects for 50 minutes prior to a meal and during consumption a semi-solid meal. Ex(9-39) increased basal fasting and postprandial glucose, but did not significantly impair the insulin:glucose ratio. Gastric emptying was not affected by Ex(9-39) however ` levels were increased following Ex(9-39)`These findings agree with similar studies in rodent "loss of function" models, and demonstrate the physiological importance of GLP-1 action for glucose regulation in normal human subjects. See Endogenous GLP-1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2005 Jun 28; [Epub ahead of print] and Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30. Similarly, blockade of endogenous GLP-1 with Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999 Jan;48(1):86-93 See GLP-1 action in normal human subjects and GLP-1 action in Type 2 diabetes and The Role of Endogenous Incretin Secretion as Amplifier of Glucose-Stimulated Insulin Secretion in Healthy Subjects and Patients With Type 2 Diabetes Mellitus Diabetes. 2012 Jun 20. [Epub ahead of print]

The importance of endogenous GLP-1 action in healthy human non-diabetic subjects was examined by infusing the antagonist exendin(9-39) during oral glucose administration while plasma glucose was kept constant via glucose infusion. The infusion of exendin(9-39) resulted in increased levels of glucagon and decreased levels of insulin following oral glucose ingestion, but no significant change in the rate of gastric emptying as assessed by appearance od d-xylose. Hence, consistent with the above studies, endogenous GLP-1 is essential for control of islet function. Regulation of islet hormone release and gastric emptying by endogenous GLP-1 following glucose ingestion. J Clin Endocrinol Metab. 2008 Sep 30. [Epub ahead of print]

The Incretin effect and Type 2 diabetes

There is considerable interest in determining whether diabetes is associated with one or more defects in the incretin axis and whether these defects contribute to the development of type 2 diabetes or arise as a consequence of hyperglycemia and or other metabolic manifestations of diabetes  itself.  Early now classic studies by Nauck and colleagues Reduced incretin effect in type 2 (non-insulin-dependent) diabetes Diabetologia. 1986 Jan;29(1):46-52 demonstrated that the incretin effect was diminished in subjects with type 2 diabetes. This reduced incretin effect has been attributed to defective GIP action and reduced GLP-1 secretion. The relative importance of the incretin effect is preserved in diabetic subjects, despite the concomitant presence of relative b-cell failure The Role of Endogenous Incretin Secretion as Amplifier of Glucose-Stimulated Insulin Secretion in Healthy Subjects and Patients With Type 2 Diabetes Mellitus Diabetes. 2012 Jun 20. [Epub ahead of print]

Both normal subjects and patients with T2DM demonstrate an ability to upregulate the secretion of GLP-1 and GIP in response to increasing glucose loads (25-125g oral glucose), however only healthy subjects were able to enhance the insulinotropic response to oral glucose at progressively higher glucose loads. These findings reaffirm the central defect in b-cell function contributing to the "incretin defect" in type 2 diabetes. Impaired regulation of the incretin effect in patients with type 2 diabetes J Clin Endocrinol Metab. 2011 Mar;96(3):737-45. Although a modest increase in glucose from 8-10.5 mM glucose (achieved by clamp studies) does not blunt GIP secretion in response to oral glucose in healthy subjects, the GLP-1 response to oral glucose is significantly reduced at this level of modest hyperglycemia. Nevertheless, the "incretin effect", namely the effect of oral glucose to substantially enhance insulin secretion is maintained at 10.5 mM glucose, despite reduced gut motility as assessed by the plasma appearance of d-xylose, and the relatively reduced plasma levels of GLP-1 under conditions of 10.5 mM glucose.  Effect of Glycemia on Plasma Incretins and the Incretin Effect During Oral Glucose Tolerance Test Diabetes. 2012 Jun 25 Diabetes. 2012 Jun 25

The majority of studies indicate that defective GLP-1 secretion does not appear to predate the development of glucose intolerance, rather diabetes itself seems to be associated with the acquired defect in GLP-1 secretion and GIP action, as partially outlined in Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007 Aug;56(8):1951-9 and summarized in Incretins and the development of type 2 diabetes Curr Diab Rep. 2006 Jun;6(3):194-201. Although some studies described below document a significant reduction in meal-stimulated GLP-1 levels from 60 minutes to 2 hrs after meal ingestion, the available evidence, summarized by Nauck and colleagues, suggest that inter-individual differences in GLP-1 secretion, age of patients, duration of diabetes, concomitatnt drug therapy, and other variables, preclude definitive conclusions that diabetes is invariably associated with reduced GLP-1 secretion. Clearly larger, better controlled and more longitudinal studies of this issue are needed as outlined in Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011 Jan;54(1):10-8

Studies in a small group (n=10) of male obese patients with type 2 diabetes demonstrated significantly lower basal and defective glucose-stimulated levels of GLP-1 following a short-term euglycemic isoinsulinemic clamp. Glucagon-like peptide (GLP)-1 and leptin concentrations in obese patients with Type 2 diabetes mellitus Diabet Med 2000 Oct;17(10):713-9.

Holst and colleagues studied 12 subjects with Type 2 diabetes and examined postprandial levels of intact GIP and GLP-1 at multiple time points following meal ingestion. The data shows that intact GIP  responses were minimally decreased in patients with type 2 diabetes, whereas the late intact GLP-1 response was strongly reduced. The findings clearly highlight the importance and utility of assays that specifically assess levels of the intact biologically active peptides. See Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001 Mar;50(3):609-13. A larger study of circulating GLP-1 in response to meal ingestion was carried out in patients with Type 2 diabetes, and subjects with impaired glucose tolerance (IGT). Postprandial levels of GLP-1 were significantly decreased in subjects with Type 2 diabetes, with intermediate GLP-1 responses observed in the group with IGT. Lower GLP-1 responses correlated with increasing BMI, as did male gender. To review the data, see Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23

Subsequent studies examined GIP and GLP-1 secretory responses in patients with both Type 1 and Type 2 diabetes after ingestion of small and large meals. Not surprisingly, incretin responses were greater after the large meal. GLP-1 responses were normal in Type 1 diabetes, but reduced in Type 2 diabetes. In contrast, no defects in GIP secretion were observed in any study groups. See Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus

Even more striking data was obtained by Lugari and colleagues in a study of 14 diabetics treated with oral agents and 11 patients with Type 2 diabetes managed on diet alone. Although fasting levels of GLP-1 were comparable in the control and patient groups, the increment in meal-stimulated GLP-1 was markedly reduced, and essentially absent in patients with Type 2 diabetes. The authors speculate that the defect in glucagon suppression observed in the diabetic subjects may be due in part to the defect in GLP-1 release. See Evidence for early impairment of glucagon-like Peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes. Horm Metab Res. 2002 Mar;34(3):150-4.

Is there a defect in clearance of GLP-1 in human diabetic subjects that explains the decreased levels of plasma GLP-1? This possibility has been examined by infusing GLP-1 in association with a meal test in normal and diabetic human subjects. No difference in the elimination t1/2 of GLP-1 was noted in the different study subjects. See Similar elimination rates of glucagon-like Peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab. 2003 Jan;88(1):220-4.

Analysis of a spectrum of GLP-1 responses in 35 insulin-resistant non-diabetic men demonstrated a correlation between the presence of insulin resistance, and impaired responses of GIP and GLP-1 to a mixed meal. In this study, insulin resistance, but not obesity was an independent variable predictive of diminished incretin secretion. See Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care. 2001 Sep;24(9):1640-5. However, reanalysis of these variables in a separate population has indeed shown that BMI may be an independent predictor of GLP-1 secretion in some subjects.

Muscellia and colleagues examined the incretin effect as a function of glucose tolerance and body weight in normal subjects, individuals with IGT, and patients with type 2 diabetes. A defect in GLP-1 secretion was observed in subjects with diabetes (but not in patients with IGT) independent of BMI. The GLP-1 secretory response was progressively diminished with increasing BMI and glucose control and BMI appeared to be independent variables impacting on GLP-1 secretion. In contrast, GIP secretion did not appear to be affected by these 2 variables. See Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients Diabetes. 2007 Dec 27; [Epub ahead of print]

Plasma levels of GIP and GLP-1 have been examined in 13 women with gestational diabetes. Fasting GLP-1 concentrations were higher in the GDM group relative to the non-diabetic control group of pregnant women but no differences were observed in GLP-1 or GIP responses after glucose loading. See Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus. Gynecol Endocrinol. 2007 Jan;23(1):58-62.

Although the majority of studies examining the incretin effect have focused on insulin secretion, experimental data indicated that impaired meal-related suppression of glucagon secretion may be a secondary manifestation possibly associated with reduced GLP-1 secretion and defective incretin action as outlined in Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects Diabetologia. 2007 Apr;50(4):806-13 and Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus Diabetologia. 2007 Apr;50(4):797-805

For additional summaries of GLP-1 secretion, see GLP-1 synthesis and secretion, and degradation