Source of Incretin effect

{{Infobox concept | name = Incretin effect | subtitle = Oral versus intravenous glucose response | Also known as = Incretin phenomenon | Components = GLP-1 and GIP secretion in response to oral glucose | Magnitude in healthy adults = 50–70% of the total insulin secretory response to oral glucose }} {{hatnote|For the hormones that mediate this effect, see [[Glucagon-like peptide-1]] and [[Glucose-dependent insulinotropic polypeptide]].}} The '''incretin effect''' is the observation that oral intake of glucose evokes a substantially larger [[Insulin secretion|insulin secretory response]] than intravenous infusion of glucose at an identical glycaemic excursion. This difference was first documented in the early 20th century but was not explained until the 1960s, when two [[peptide]] hormones secreted by the small intestine — [[Glucagon-like peptide-1]] (GLP-1) and [[Glucose-dependent insulinotropic polypeptide]] (GIP) — were shown to potentiate insulin secretion in response to nutrients.{{r|creutzfeldt1979}} In healthy adults, the incretin effect accounts for approximately 50–70% of the total insulin secretion that follows oral glucose intake. The remaining 30–50% comes from direct stimulation of beta cells by the rising blood glucose itself, termed the glucose-stimulated response. This dual-mechanism design — nutrient-sensing via hormones, plus direct glucose sensing — confers tight glycaemic control in the postprandial state while minimizing the risk of hypoglycaemia when glucose is low.{{r|holst2007}} In type 2 diabetes, the incretin effect is markedly reduced, accounting for only 10–30% of the insulin secretory response. This defect is a primary lesion in the pathophysiology of the disease and is the mechanistic rationale for [[GLP-1 receptor agonist|GLP-1-directed]] and [[Dual incretin agonist|dual-agonist]] therapeutics, which restore or amplify this pathway.{{r|nauck2018}} == Historical discovery == The observation that oral glucose intake provokes a larger insulin response than intravenous glucose at matched glycaemic levels was documented in the 1920s, but the mechanism was unknown for over 40 years. Early hypotheses included a direct effect of the intestinal mucosa on the pancreas (Loewi's "enteroinsular axis") and nervous reflexes, but these remained speculative until the insulin-secreting peptide hormones of the gut were isolated and characterized.{{r|creutzfeldt1979}} Glucagon, isolated in 1923, was the first gut hormone to be recognised, but its insulinotropic effect is glucose-independent and was therefore insufficient to explain the oral-glucose phenomenon. The isolation and characterization of GLP-1 (in the early 1980s) and the demonstration of its glucose-dependent insulinotropic properties resolved the question. GIP, previously known only as a gastric-inhibitory peptide, was subsequently recognised to be the second arm of the incretin axis.{{r|holst1987}} == Mechanisms: GLP-1 and GIP == GLP-1 and GIP together account for the incretin effect through glucose-dependent potentiation of insulin secretion. Neither hormone stimulates insulin secretion at low glucose concentrations, a feature that minimizes hypoglycaemia risk compared to insulin secretagogues like sulfonylureas, which do so.{{r|holst2007}} GLP-1 is secreted by L cells of the distal small intestine and colon, in response to glucose, fat and amino acids. Its plasma half-life is approximately 2 minutes due to rapid inactivation by [[Dipeptidyl peptidase-4]]. GIP is secreted earlier, by K cells of the duodenum and proximal jejunum, and has a half-life of approximately 7 minutes. The two hormones act through distinct receptors on beta cells; both couple to adenylyl cyclase and raise intracellular cAMP, but through non-identical signalling cascades, and each contributes approximately equally to the total incretin effect in health.{{r|nauck2018}} == Quantification and measurement == The incretin effect is usually quantified as a percentage: {{math|\text{Incretin effect} = (I_{\text{oral}} - I_{\text{iv}}) / I_{\text{oral}} \times 100\%}} where {{math|I_{\text{oral}}}} is the integrated insulin secretion over 2–3 hours following oral glucose, and {{math|I_{\text{iv}}}} is that following intravenous glucose at matched glucose kinetics.{{r|nauck2018}} Measurement requires both an oral glucose-tolerance test and a euglycaemic-hyperglycaemic clamp on separate days. Because the clamp is labour-intensive and requires careful blood sampling, the incretin effect is not routinely measured in clinical practice; it is a research tool for mechanistic investigations and for assessing drug effects. == Loss of the incretin effect in disease == In type 2 diabetes, the incretin effect is reduced to approximately 10–30% of the normal value. This is a primary pathophysiological lesion rather than a secondary consequence of hyperglycaemia, as it is present early in the course of the disease, in first-degree relatives of affected individuals, and in people with impaired glucose tolerance.{{r|nauck1986}} The defect is asymmetric: GIP-mediated insulin secretion is lost disproportionately, whereas GLP-1 responsiveness is better preserved, though also impaired. This asymmetry is clinically important: it explains why GLP-1-directed drugs work as monotherapy in type 2 diabetes whereas GIP-directed drugs do not, and why the later addition of GIP agonism to GLP-1 monotherapy produces further benefit.{{r|nauck2018}} In type 1 diabetes, the incretin effect is preserved in those with residual beta-cell function, suggesting the lesion in T2D is beta-cell-intrinsic rather than a defect in hormone secretion or action at the receptor level. == References == {{reflist}} <ref name="creutzfeldt1979">Creutzfeldt W, Ebert R, Willms B. "Gastro-intestinal peptide hormones and insulin secretion." ''Diabetologia'' 20 Suppl:85–98 (1979).</ref> <ref name="holst2007">Holst JJ. "The physiology of glucagon-like peptide 1." ''Physiological Reviews'' 87(4):1409–1439 (2007). DOI:10.1152/physrev.00034.2006. PMID 17928588.</ref> <ref name="holst1987">Holst JJ, Ørskov C, Nielsen OV, Schwartz TW. "Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut." ''FEBS Letters'' 211(2):169–174 (1987). PMID 3542566.</ref> <ref name="nauck1986">Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. "Reduced incretin effect in type 2 (non-insulin-dependent) diabetes." ''Diabetologia'' 29(1):46–52 (1986). PMID 3514343.</ref> <ref name="nauck2018">Nauck MA, Meier JJ. "Incretin hormones: their role in health and disease." ''Diabetes, Obesity and Metabolism'' 20(Suppl 1):5–21 (2018). DOI:10.1111/dom.13129. PMID 29364588.</ref> == Further reading == * Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." ''Cell Metabolism'' 17(6):819–837 (2013). == External links == * [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341159/ NCBI review: Incretin hormones] — PubMed Central review of incretin physiology and pathophysiology. == See also == * [[Glucagon-like peptide-1]] * [[Glucose-dependent insulinotropic polypeptide]] * [[Beta cell function]] * [[Dual incretin agonist]] {{DEFAULTSORT:Incretin effect}} [[Category:Incretin biology]] [[Category:Gastrointestinal physiology]] [[Category:Appetite regulation]]