GLP-1 and GLP-2 are produced in the same gut endocrine cells and liberated, following posttranslational processing of a single proglucagon precursor. The available evidence suggests that only one proglucagon gene is expressed in mammals that gives rise to an identical mRNA in brain, pancreas, and intestine, as described in Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing.  J Biol Chem. 1986 5;261:11880-9

A large number of studies in rodents, larger mammals and humans have determined that GLP-1 and GLP-2 are secreted in a nutrient-dependent manner Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993 Jul;138(1):159-66.

Incretin secretion is more pronounced in the morning, relative to the late afternoon, as assessed in healthy lean males who ingested an identical meal at 8 AM or 5 PM. Plasma and peak levels of GLP-1, and to a lesser extent GIP, were modestly but significantly higher after a mixed meal in the am Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men  Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men J Clin Endocrinol Metab. 2009 Aug;94(8):2887-92

Is there a defect in GLP-1 release associated with  human diabetes? 

The answer to this interesting question continues to be debated. In the largest (1,462 subjects) single study to tackle this question to date, a substudy of individuals enrolled in and followed within the ADDITION-Denmark study, namely the ADDITION-PRO study, GLP-1 levels were examined using an OGTT (75 grams, blood samples done t time 0, 30 and 120 minutes) in normal subjects (NGT), as well as in subjects with pre-diabetes (IFG or IGT) and screen-detected type 2 diabetes, analyzing the data by stratification by age, sex, and BMI. Individuals with prediabetes or screen-detected diabetes had lower GLP-1 responses to an OGTT, either AUC GLP-1, or notably, 120 minute plasma GLP-1. Obese and overweight patients also had lower levels of GLP-1 independent of glycemic status. As previously demonstrated, preservation of insulin sensitivity correlated with the findings of normal GLP-1 secretion. The authors suggest that these findings support a role for reduced GLP-1 in disease pathogenesis (diabetes/obesity), however as noted below, it is much more difficult to consistently detect a deficiency in plasma GLP-1 levels when using the meal tolerance test, a more real world assessment of day to day L cell function.

Glucagon-Like Peptide-1 (GLP-1) Response to Oral Glucose is Reduced in Pre-diabetes, Screen-detected Type 2 Diabetes and Obesity, and Influenced by Sex: The ADDITION-PRO Study Diabetes. 2015 Feb 12. pii: db14175

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, concomitant 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, using both OGTT and meal-stimulated challenges, 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.

Consistent with the lack of evidence supporting a significant reduction in plasma GLP-1 levels in subjects with type 2 diabetes, Smushkin and colleagues assessed fasting and oral glucose-stimulated levels of GLP-1 in a large cohort of 165 subjects with a fasting glucose below 7 mM an either NGT, IFG, IGT and subjects with IFG/DM. Fasting levels of total GLP-1 was not associated with any of the above glycemic categories. Post glucose peak and mean AUC total or active GLP-1 levels were not significantly different in any of the groups. Defects in GLP-1 Response to an Oral Challenge Do Not Play a Significant Role in the Pathogenesis of Prediabetes J Clin Endocrinol Metab. 2011 Nov 16

Studies in a very 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):713-9Holst 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 subsequent study demonstrated that 4 weeks of intensive glucose control using insulin to treat subjects with type 2 diabetes was not sufficient to increase in GLP-1 levels in subjects with previously poor metabolic control, despite concomitant improvements in beta cell function. See Four weeks of near-normalization of blood glucose has no effect on postprandial GLP-1 and GIP secretion, but augments pancreatic B-cell responsiveness to a meal in patients with Type 2 diabetes. Diabet Med. 2008 Nov;25(11):1268-75

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-1in 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.

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.

Studies of myoelectric function and gut hormone release in 12 subjects with myotonic dystrophy revealed evidence for abnormal gastric electrical motility, and decreased meal-stimulated GLP-1 and motilin secretion. In contrast, secretion of cholecystokinin (CCK), neurotensin (NT), peptide YY (PYY) and somatostatin (SOM) were not significantly affected. See Gastric myoelectrical activity and gut hormone secretion in myotonic dystrophy. Eur J Gastroenterol Hepatol. 2001 Jul;13(7):825-831

The importance of DPP-4 for the N-terminal inactivation of GLP-1 has been demonstrated in many studies, as reviewed in DPP- 4. GLP-1 Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept. 1995 Aug 22;58(3):149-56 and  Endoproteolysis of glucagon-like peptide (GLP)-1 (7-36) amide by ectopeptidases in RINm5F cells. Peptides. 1997;18(5):625-32. and Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia. 2005 Jul 16; [Epub ahead of print]

Inflammation, the microbiome, enterendocrine cells and GLP-1 secretion

                                                  

Administration of the cytokine, IL-6, rapidly increases plasma GLP-1 levels in normal and diabetic rodents. Similarly, exercise was associated with increased levels of IL-6 and increased GLP-1 levels detectable within 90 minutes. Remarkably, IL-6 induces GLP-1 synthesis not only in L cells, and in GLUTag cells but also increases proglucagon gene expression, PC1 expression, and GLP-1 production directly from rodent and human islet alpha cells. These changes were mirored by increases in plasma GLP-1 levels and improved glucose tolerance in the setting of IL-6 administration or exercise in mice. Immunoneutralization of IL-6 reduced levels of GLP-1 and deteriorated glucose tolerance. Conversely, alpha cells from IL-6 knockout mice were unable to augment GLP-1 synthesis and secretion in response to high fat feeding. Il-6 failed to improve glucose control in Glp1r-/- mice.   Interleukin-6 enhances insulin secretion by increasing L cell and a cell glucagon-like peptide-1 secretion Nature Medicine 2011 30 October 2011 | doi:10.1038/nm.2513

Nguyen and colleagues demonstrated that injection of LPS enhanced GSIS and improved glycemia in part through stimulation of GLP-1 secretion in mice. The beneficial actions of LPS on insulin secretion and glucose toelrance were blunted by exendin(9-39) and abrogated in Glp1r-/- mice. Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: Involvement of the glucagon-like peptide 1 (GLP1) pathway Diabetes. 2013 Nov 1. Similarly, Kahles et al demonstrated that inflammatory stimuli such as IL-6, interleukin-1β (IL-1β), and LPS (endotoxin) acutely increase GLP-1 secretion in mice. The IL1b-depndent induction of GLP-1 secretion was markedly attenuated in Il6-/- mice. GIP and IL-6 but not Il1b or LPS directly increased GLP-1 secretion from GLUTag cells. The actions of LPS to increase insulin and lower glucose in mice were attenuated by exendin(9-39). Mean plasma total GLP-1 levels were 6.9 times higher in 155 critically ill ICU patients compared with 134 healthy control subjects (97.0 vs. 13.9 pmol/L, P < 0.001), although no information on GFR or renal status was provided. GLP-1 levels correlated with severity of illness and levels of circulating IL-6 in critically human subjects. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering Diabetes. 2014 Oct;63(10):3221-9

Chimerel et al provided an additional mechanism linking micorbial metabolism with the control of GLP-1 secretion through generation of indole via tryptophan metabolism. Indole rapidly stimulated GLP-1 secretion directly from GLUTag enteroendocrine cells cells, however more prolonged exposure to indole then attenuated GLP-1 secretion. The delayed suppressive effects of indole were evident at [] as low as 0.3 mM. Indole widened GLP-1 action potentials by reducing the amplitude of the K+ current, in association with a rapid increase in levels of intracellular calcium (also noted in mouse L cells). More prolonged exposure of GLUTag cells to indole decreased the ATP/ADP ratio (indole inhibits NADH dehydrogenase and an uncoupler of mitochondrial oxidative phosphorylation), consistent with the second phase of reduced GLP-1 secretion. Similarly, indole also suppressed GLP-1 release from primary murine colonic cultures Bacterial Metabolite Indole Modulates Incretin Secretion from Intestinal Enteroendocrine L Cells http://dx.doi.org/10.1016/j.celrep.2014.10.032

Breton and colleagues examined the actions of E. Coli proteins prepared from bacteria during the exponential(Exp) or stationary (Stat) phase of 'growth', using colonic infusions in rats. Remarkably, E. coli proteins from the Exp phase increased plasma GLP-1 levels, whereas levels of another "L cell"-derived peptide, PYY, were increased following infusion of E. coli proteins from the Stat phase. The authors interpreted this data to imply that rapidly growing E. coli influence short term (GLP-1-mediated) appetite, whereas they infer that a different population of L cells are targeted by E. Coli proteins produced during the Stat phase. Gut Commensal E. coli Proteins Activate Host Satiety Pathways following Nutrient-Induced Bacterial Growth Cell Metab. 2015 Nov 20. pii: S1550-4131(15)00566-5

Direct vs. indirect contol and mediators of GLP-1 secretion

Tolhurst and colleagues examined the effects of short chain fatty acids (SCFAs) on GLP-1 secretion in mice. Acetate and propionate both stimulated GLP-1 secretion and triggered an increase in intracellular calcium from L cells within primary murine colonic cultures. Expression of the SCFA receptors Ffar2 and Ffar3 was detected in isolated murine enteroendocrine L cells. Studies using primary cultures from knockout mice revealed the importance of Ffar2, and to a lesser extent, Ffar3,for SCFA-mediated Gq-dependent stimulation of GLP-1 secretion and Ffar2 also appears important for PGDP synthesis. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2 Diabetes doi:10.2337/db11-1019

Chambers et al designed and tested a novel inulin-propionate ester for delivery of propionate to the human colon, thereby enabling enhanced L cell secretion of GLP-1 and PYY. Propionate alone stimulated PYY and GLP-1 secretion from human colonic cells in vitro, and propionate was liberated from inulin propionate in human subjects after oral ingestion of the cojugated ester. Acute administration of insulin propionate reduced food intake and increased plasma levels of both GLP-1 and PYY, from 240-420 minutes after ingestion. Chronic administration of insulin propionate to normal human volunteers for 24 weeks prevented weight gain but did not appear to increase postprandial levels of PYY or GLP-1, and had no significant effect on composition of major bacterial species in the gut microbiota. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults Gut. 2014 Dec 10. pii: gutjnl-2014-307913. doi: 10.1136/gutjnl-2014-307913.

Although most studies demonstrate that fatty acids of different chain length stimulate L cell and GLP-1 secretion, this may not always be the case. Wichmann and colleagues demonstrated increased intestinal (cecum and colon) proglucagon gene expression, a 3-fold increase in numbers of colonic L cellsm and three-fold higher circulating levels of GLP-1, leading to reduced gut motility in germ free or antibiotic-treated mice which exhibt reduced levels of short chain fatty acids (SCFA) in colon/cecum. Colonization of germ free mice with polysaccharide-fermenting bacteria restored GLP-1 levels to normal Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit Cell Host & Microbe 14(5) 582-590, 13 November 2013

One of the ongoing questions in the field is the identity of the signals that promote a rapid increase in plasma levels of the intestinal PGDPs following feeding, as the increased secretion of GLP-1 and GLP-2 cannot be accounted for only by direct nutrient stimulation of L cells in the distal ileum and colon. Indeed eating very quickly (5 minutes) is associated with a modest reduction in maximal levels of PYY and GLP-1 compared to a moderate eating pace (30 minutes). Eating slowly increases the postprandial response of the anorexigenic gut hormones, peptide YY and glucagon-like peptide-1. J Clin Endocrinol Metab. 2010 Jan;95(1):333-7. The rapid increase in plasma gut hormone levels witrhin minutes of food ingestion has prompted the suggestion that there are other factors, perhaps hormonal and neural, that constitute a proximal to distal loop serving to amplify secretion of the intestinal PGDPs from distal L cells once nutrients enter the stomach and proximal small bowel. The importance of the vagus nerve for these effects is illustrated in transfection studies Endocrinology 1999: 140(4):1687-94. Similarly, studies by Hira and colleagues demonstrate that a corn protein hydrosylate (ZeinH) appeared to directly stimulate GLP-1 secretion in the rat ileum and in GLUTag cells, whereas more proximal duodenal stimulation of GLP-1 secretion appeared to be indirect and required functional vagal afferent activity. GLP-1 secretion is enhanced directly in the ileum, but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate in rats Am J Physiol Gastrointest Liver Physiol. 2009 Aug 6. [Epub ahead of print]

Is their a cephalic phase of GLP-1 secretion that results from meal anticipation? The answer appears to depend on the species studied and how the experiments are done. Vahl and colleagues demonstrated that plasma GLP-1 levels increase transiently in rats prior to meal ingestion, in association with a subsequent increase in insulin secretion Meal-Anticipatory Glucagon-Like Peptide-1 Secretion in Rats. Endocrinology. 2009 Nov 13. [Epub ahead of print]. In contrast, Ahren and Holst demonstrated that insulin levels increased in the preabsorptive phase after meal ingestion, at a time when GLP-1 levels had not yet increased. The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia Diabetes. 2001 May;50(5):1030-8

Glucose stimulates GLP-1 secretion in rodents and human subjects when given orally but systemic hyperglycemia does not activate L cell secretion. The actions of enteral glucose appear to be mediated by taste receptors expressed on L cells. The taste G protein gustducin is essential for transduction of glucose-stimulated GLP-1 secretion in mice and human enteroendocrine L cells express gustducin, T1R2, and T1R3. In contrast, the glucose-stimulated secretion of GIP is not dependent on gustducin. See Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci U S A. 2007 Aug 27; [Epub ahead of print] and T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15075-80. Epub 2007 Aug 27.

Compelling evidence for a key role for SGLT1 in GLP-1 and GIP secretion has also been derived from studies of WT and Sglt1-/- mice. Moriya and colleagues demonstrated that glucose administration into the small bowel but not the colon of mice rapidly increased GLP-1 and GIP levels, in a phlorizin-senitive manner. Furthermore, alpha-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, actions blocked by phlorizin. Even administration of MDG alone, without oral glucose, improved IP glucose tolerance and increased plasma incretin levels. Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1358-65 .

Goroulev et al used a genetic approach to assesss the phenotype of Sglt1-/- mice. A marked reduction in plasma levels of GIP and GLP-1 was observed following oral glucose challenge in Sglt1-/- mice, and glucose failed to stimulate incretin secretion from intestinal cultures in vitro. Na+-d-glucose Cotransporter SGLT1 is Pivotal for Intestinal Glucose Absorption and Glucose-Dependent Incretin Secretion Diabetes November 28, 2011, doi:10.2337/db11-1029

Gerspach and colleagues examined the importance of a subset of taste receptors for gut hormone secretion through use of lactisole, a sweet taste receptor T1R2/T1R3 antagonist. Administration of lactisole to healthy subjects in the context of glucose challenge did blunt the rise in GLP-1 and PYY but not CCK. However lactisole had little effect on plasma levels of peptide hormones when a more complex liquid meal was administered. Hence control of GLP-1 secretion is mediated through multiple mediators activated by diverse nutrient components of a liquid meal. The role of the gut sweet taste receptor in regulating GLP-1, PYY and CCK release in humans Am J Physiol Endocrinol Metab. 2011 May 3. [Epub ahead of print]

Fatty acids stimulate both insulin secretion and enhance GLP-1 release in human subjects, as shown in Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr. 1999 Jun;69(6):1135-43.   Lipid appears to stimulate incretin hormone secretion through enteral mechanisms, as simply increasing plasma triglyceride levels via an intravenous Intralipid infusion had no effect on circulating levels of GLP-1 on GIP or insulin, whereas the corresponding oral administration of Intralipid produce a significant and sustained increase in levels of GIP and GLP-1 Incretin Hormone and Insulin Responses to Oral Versus Intravenous Lipid Administration in Humans J Clin Endocrinol Metab. 2011 May.

The importance of the CCK-1 receptor for fat-induced GLP-1 release was demonstrated by Beglinger and colleagues in subjects treated with a duodenal fat infusion, with or without orlistat, with or without the GLP-1receptor antagonist dexloxiglumide. Inhibition of fat hydrolysis using orlistat significantly diminished the secretion of both CCK and GLP-1. Sodium oleate (C18:1) alone, but not sodium caprylate (C8:0), produced a 3-fold increase in GLP-1 levels, whereas co-administration of GLP-1 and intravenous dexloxiglumide markedly diminished the increase in plasma GLP-1. Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion J Clin Endocrinol Metab. 2010 Feb;95(2):879-86

Increased levels of plasma non-esterified fatty acids differentially promote increased glucose-stimulated insulin release, with mono-unsaturated fatty acids associated with the greatest increment in circulating levels of GLP-1 in human subjects, as shown in Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Diabetologia. 2002 Nov;45(11):1533-41. Similarly, although fat is now a clearly recognized stimulant of GLP-1 secretion in humans, the type of fat, (butter versus olive oil, for example) differentially stimulates GLP-1 secretion in diabetic subjects, as shown in Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes. Am J Clin Nutr. 2003 Mar;77 (3): 605-11

                                                                        Mechanisms and receptors controlling intestinal GLP-1 secretion

The molecular mechanisms linking fatty acids to GLP-1 secretion from gut endocrine cells remain incompletely understood. Hirasawa and colleagues have identified a GPCR, designated GPR120 that serves as a receptor for fatty acids on gut endocrine cells. Fatty acids activate the receptor in vitro in association with stimulation of GLP-1 secretion. Whether GPR120 is essential for fatty acid-stimulated GLP-1 secretion in vivo remains unclear. See Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005 Jan;11(1):90-4. Epub 2004 Dec 26

A role for PKCz in the oleic acid-induced stimulation of GLP-1 secretion has been described in studies using gut endocrine cells. Reduction of PKCz expression in GLUTag cells, or addition of a PKCz inhibitor significantly diminished the secretory response to oleic acid, as shown in Protein kinase C{zeta} is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells. Endocrinology. 2006 Nov 16;in press

Daoudi and colleagues, using a variety of experimental cellular and animal models, have demonstrated that activation of the PPARb/d receptor, promotes GLP-1 synthesis and secretion from gut endocrine cells. Increasing levels of glucose-induced expression of the proglucagon and PC1/2 genes but not the genes for GBAR1/TGR5 nor the PPARb/d receptor in GLUTag cells. PPARg activation with rosiglitazone decreased proglucagon mRNA however the PPARb/d agonist GW501516 significantly increased (2-4-fold) proglucagon gene expression and GLP-1 secretion in GLUTag cells and in human NCI-H716 cells. Knockdown of PPARb/d using siRNA completely eliminated the effect of PPARb/d agonists on proglucagon gene expression. Treatment of jejunal tissue obtained from obese human subjects with GW51056 for 24 hrs induced proglucagon gene expression and enhanced glucose- and bile acid-stimulated GLP-1 release. PPARb/d agonists also increased the activity of proglucagon promoter plasmids in transfected GLUTag cells through mechanisms requiring TCF4. GW0742, another PPARb/d agonist increased intestinal but not pancreatic proglucagon gene expression in WT mice but not in PPARb/d-/- mice. Intriguingly, GLP-1 receptor mRNA transcripts were also increased in the pancreas of GW501516-treated mice and in isolated human islets. Furthermore, mice treated with PPARb/d agonists exhibited increased levels of GLP-1 and insulin and improved glycemia following oral glucose challenge. Similar salutary effects on GLP-1 levels and glucose tolerance were also observed in ob/ob mice treated with PPARb/d agonists. PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production Gastroenterology. 2011 Feb 4

Studies using knockout mice and GLUTag cells have demonstrated a role for synaptogamin-7 as a molecular component of the exocytotic machinery regulating GLP-1 secretion in L cells. Synaptogamin-7 KO mice exhibited defective GLP-1 secretion in response to oral glucose and knockdown of synaptogamin-7 in GLUTag L cells reduced GLP-1 secretion in vitro Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice Diabetologia. 2011 Mar 22. [Epub ahead of print]

Similar studies using the STC-1 cell line have identified a receptor for bile acids, designated TGR5 (also known as BG37) which is coupled to stimulation of GLP-1 secretion in a cAMP-dependent manner, as described in Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-390. Subsequent studies have demonstrated that TGR5 agonists improve glucose homeostasis in mice, through mechanisms that are associated with enhanced GLP-1 secretion from gut endocrine L cells, and increased GLP-1 secretion in mice treated with TGR5 agonists, as described in TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009 Sep;10(3):167-77. Parker and  colleagues examined the mechanisms through which bile acids promoted GLP-1 secretion in enteroendocrine GLUTag cells in a TGR5-dependent manner. Bile acids stimulated GLP-1 secretion from GLUTag cells in a TGR5-dependent manner. The synthetic TGR5 agonist GPBAR-A increased levels of cAMP and potentiated glucose-stimulated signal transduction in GLUTag cells. Molecular mechanisms underlying bile acid stimulated glucagon-like peptide-1 secretion. Br J Pharmacol. 2011 Jun 30. doi: 10.1111/j.1476-5381.2011.01561.x. [Epub ahead of print

Furthermore, breakdown of fats is an essential upstream event, directly or indirectly, for subsequent stimulation of GLP-1 secretion in human subjects. Duodenal infusion of a triglyceride emulsion stimulated CCK and GLP-1 secretion; the same infusion carried out in the presence of the lipase inhibitor tetrahydrolipstatin resulted in attenuation of pyloric pressures, increased number of antral and duodenal pressure waves, and elimination of the fat-induced rise in circulating levels of CCK and GLP-1. Similarly, human diabetic subjects given the lipase inhibitor orlistat in the presence of an olive oil and glucose drink exhibit reduced gastric emptying, increased glycemic excursion, and decreased levels of circulating GLP-1, as shown in Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34.

Whether the stimulation of CCK/GLP-1 secretion is due directly to generation of fatty acids, or partly due to the complex integration of fatty acids and patterns of gut motility/pressure, warrants further investigation. See Effects of fat digestion on appetite, APD motility, and gut hormones in response to duodenal fat infusion in humans. Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G798-807

Experiments using murine GLUTag cells have identified a role for glutamine as a potential chemical mediator of GLP-1 secretion from enteroendocrine cells as described in Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells. Diabetologia. 2004 Sep 9. Acute oral administration of glutamine also increases plasma levels of GLP-1 in human subjects, with or without diabetes Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects Am J Clin Nutr. 2009 Jan;89(1):106-13. Further analysis of the effects of amino acids and glutamine on GLP-1 secretion in GLUTag cells and non-immortalized murine L cells was reported by Tolhurst and colleagues. Glutamine stimulated GLP-1 secretion from murine L cell cultures in a dose-dependent manner, similar to previous observations made using GLUTag cells. GLP-1 secretion was also stimulated by other amino acids, although glutamine produce the most potent effects. Glutamine increased intracellular calcium through mechanisms requiring extracellular calcium and Na+ transport. In contrast, the metabolic derivative glucosamine failed to stimulate GLP-1 release, and the mTOR pathway did not appear to be involved as the effects of Gln were not sensitive to rapamycin, nor inhibitors of PKC or thapsigargin. Notably, glutamine triggered cAMP accumulation. The precise membrane transporter/receptor mediating the stimulatory effects of Gln on the L cell remains to be determined Glutamine Triggers and Potentiates Glucagon-Like Peptide-1 Secretion by Raising Cytosolic Ca2+ and cAMP Endocrinology. 2011 Jan 5. [Epub ahead of print

Flock and colleagues identified robust expression of the classical progesterone receptor in GLUTag cells and showed that enteral progesterone stimulates GLP-1 secretion and lowers blood glucose in mice. Remarkably, membrane restricted ligands such as BSA-progesterone also stimulated GLP-1 secretion from GLUTag cells, and inhibition of classical PR signaling with RU486 had no effect on progestin-stimulated GLP-1 secretion and did not impair the ability of progesterone to improve glucose homeostasis in vivo. GLUTag cells also expressed membrane progesterone receptors Paqr5 and Paqr7, and knockdown of these receptors in GLUTag cells eliminated the progestin-dependent stimulation of GLP-1 secretion. Nevertheless, enteral progesterone was still capable of increasing insulin and lower glucose even in mice with disruption of both the Glp1r and Gipr. These findings raise the possibility that gut restricted membrane progestrone receptor agonists may be capable of enhancing incretin secretion and lowring glucose in vivo. Activation of Enteroendocrine Membrane Progesterone Receptors Promotes Incretin Secretion and Improves Glucose Tolerance in Mice Diabetes. 2012 Aug 29.

Studies in the rat identify an important role for muscarinic receptors in the control of meal-stimulated GLP-1 release. Both atropine, and pirenzepine, a M1 muscaranic receptor antagonist) block fat-induced GLP-1 secretion in vivo, and muscaranic receptors are expressed on rodent L cells. See Muscarinic receptors control postprandial release of glucagon-like Peptide-1: in vivo and in vitro studies in rats. Endocrinology. 2002 Jun;143 (6): 2420-6. The importance of the sympathetic (inhibitory) and cholinergic (stimulatory) nervous system for control of gut PGDP secretion was further illustrated in studies employing the isolated perfused pig intestine together with specific agonist and antagonists of the respective neurotransmitters. See Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E939-47

Panaro and colleagues localized the MCR4 receptor to CCK+ and GLP-1+ mouse enteroendocrine cells. In fact relative MCR4 abundance was the second highest amongst almost 400 other GPCRs in mouse L cells. MCR4 ligands stimulated GLP-1 secretion from GLUTag cells and from perfused murine small bowel, but not from mouse colonic crypt preparations and no stimulatory effect was detected in rats. Basolateral MCR4 agonists also reduced epithelial chloride secretion through mechanisms requiring the Y1 receptor likely mediated indirectly via PYY released from L cells. Peripheral administration of LY2112688 robustly increased plasma levels of PYY, and produced a more modest but significant rise in GLP-1 in vivo. These findings delineate a novel role for peripheral melanocortin signaling via MCR4 in the control of mucosal electrolyte transport via regulation of L cell secretion. The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-Like Peptide 1 In Vivo Cell Metabolism doi:10.1016/j.cmet.2014.10.004

 

GPR119 was originally described as an orphan G protein coupled receptor that was subsequently demonstrated to be expressed in human and rodent gut endocrine cells, and in GLUTag cells. Activation of GPR119 signaling, presumably in enteroendocrine cells in vivo, leads to increased secretion of gut hormones such as GIP and GLP-1 as demonstrated by Chu and colleagues A Role for Intestinal Endocrine Cell-Expressed GPR119 in Glycemic Control by Enhancing GLP-1 and GIP Release Endocrinology. 2008 Jan 17; [Epub ahead of print]. Although GPR119 agonists stimulate the secretion of both GLP-1 and GIP in mice, the actions on GIP secretion may be indirect, as GPR119 receptors have not yet been detected on GIP+ gut enteroendocrine K cells. For more about receptors like GPR119, see Gut endocrine cells

The levels of intracellular cAMP appear to be important for regulation of intestinal GLP-1 synthesis and secretion. Studies using primary rat intestinal cell cultures Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. Proc Natl Acad Sci U S A. 1989 Jun;86(11):3953-7 and intestinal enteroendocrine cell lines Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol. 1994 Dec;8(12):1646-55 and Multiple cis-acting domains mediate basal and adenosine 3',5'-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line. Endocrinology. 1993 Mar;132(3):1055-62 have shown that activation of the adenylate cyclase pathway induces proglucagon gene transcription and GLP-1 biosynthesis. This pathway also co-regulates the expression of the enzyme, PC1, that plays an important role in liberation of GLP-1 from proglucagon in gut L cells Coregulation of Glucagon-Like Peptide-1 Synthesis with Proglucagon and Prohormone Convertase 1 Gene Expression in Enteroendocrine GLUTag Cells. Endocrinology. 2001 Jan 1;142(1):37-42

The local production of somatostatin-28 may also regulate, via inhibition, the tonic release of GLP-1 and GLP-2 from gut L cells, as illustrated by immunoneutralization studies in the perfused porcine ileum Am J Physiol 2000 ;278(6):E1010-E1018. As GLP-1 stimulates SMS release from intestinal cells Endocrinology. 1998 Jan;139(1):148-55, and Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E311-7, it appears that SMS and GLP-1 may constitute an autoregulatory loop, with GLP-1 secretion attenuated following stimulation of intestinal SMS release. The somatostatin receptor subtype 5 seems to be particularly important for control of intestinal GLP-1 secretion in rat intestinal cell cultures. See Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E311-7. Insulin may play a role in the tonic stimulation of GLP-1 secretion, as preclinical studies demonstrate that insulin may stimulate GLP-1 secretion, raising the possibility that insulin resistance may contribute to defective GLP-1 secretion, as suggested in Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology. 2008 Sep 25. [Epub ahead of print]. Leptin was also shown to be important for the control of GLP-1 secretion by Brubaker and colleagues Role of leptin in the regulation of glucagon-like Peptide-1 secretion. Diabetes. 2003 Feb;52(2):252-9

The available data in rodents supports a role for GPR40 (FFA1) as an enteroendocrine fatty acid GPCR linked to GLP-1 secretion. Original studies carried out by Edflak, Edlund and colleagues Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion Diabetes. 2008 Sep;57(9):2280-7 in mice have since been confirmed by others. Xiong and colleagues identified co-localization of a FFA reporter gene andGLP-1 immunoreactive GLP-1 in mouse small bowel enteroendocrine cells. Corn oil administration (enteral) stimulated an increase in plasma GLP-1 levels in GPR120-/- but not in FFA1-/- mice and glycemic excusrion was higher after corno oil in Glp1r-/- mice. Long chain fatty acids and synthetic FFA1 ligands directly increased GLP-1 secretion from FMIC cultures and GLUTag cells in vitro. Evidence using partial and full agonists supports a mechanism involving alloesteric interactions necessary for full glucoregulatory potential in murine systems. Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1 Mol Cell Endocrinol. 2013 Feb 9. doi:pii: S0303-7207(13)00032-4. Whether activation of GPR40/FFA1 increases GLP-1 secretion in humans requires more study.

Prostaglandins are locally synthesized in the gastrointestinal tract and Coskun and colleagues demonstrate the expression of the EP4 prostanoid receptor in enteroendocrine GLUTag cells. Prostaglandin E1 and E2 as well as more selective EP4 receptor agonists stimulated GLP-1 secretion from GLUTag cells in vitro, and in mice in vivo. Surprisingly however, the EP4 agonists also raised blood glucose in acute glucose tolerance tests, despite increasing plasma levels of GLP-1 in mice.  Activation of Prostaglandin E Receptor 4 Triggers Secretion of Gut Hormone Peptides GLP-1, GLP-2, and PYY Endocrinology. 2012 Nov 9. [Epub ahead of print]

The bone-derived hormone osteocalcin (uncarboxylated form) has also been shown to increase GLP-1 secretion from STC-1 cells through its 'putative' receptor Gprc6a at most but not all doses in vitro, and plasma active GLP-1 levels increased following injection of 7 but not 10 ug/kg of recombinant u-osteocalcin protein in fasted mice in the presence of co-administered sitagliptin. Remarkably, oral administration of various osteocalcin proteins also increased GLP-1 levels in mice. Osteocalcin also increased serum insulin levels in fasted mice through mechanisms sensitive to the GLP-1R antagonist exendin(9-39). Osteocalcin induces release of glucagon-like Peptide-1 and thereby stimulates insulin secretion in mice PLoS One. 2013;8(2):e57375

Emery and colleagues used microarray analysis of murine enteroendocrine cells and STC-1 and GLUTag cell lines to profile the expression of trpa1, trpc1, trpc3 and trpm7, but not trpc4 and trpc5 in enteroendocrine cells and selected TRPA1 for functional analysis due to availability of ligands and related reagents. Trpa1 was much more abundant in small bowel L cells, and weakly expressed or absent in colonic L cells. Functional TRPA1 activity (increased depolarisation-dependent voltage-gated Ca2+ entry) was demonstrated in isolated L cells, and the TRPA1 agonist AITC increased GLP-1 secretion from GLUTag cells independent of the ambient glucose concentration. In contrast, TRPV1 agonists such as capsaicin had no effect on GLP-1 secretion Stimulation of glucagon-like peptide-1 secretion downstream of the ligand-gated ion channel TRPA1 Diabetes. 2014 Oct 16. pii: DB_140737

Drugs and plasma levels of GLP-1

Acarbose

Several studies using the drug acarbose have shown increased circulating levels of GLP-1 in association with short or longer term acarbose use in human subjects. Acarbose inhibits the action of glucosidases, thus diminishing carbohydrate absorption in the proximal intestine, and increasing delivery of complex carbohydrates to the distal intestine. Acarbose ingestion along with sucrose prolongs the kinetics of "second phase" GLP-1 secretion in human subjects, as demonstrated in Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol. 1995 Sep;30(9):892-6. Acarbose administration also prolongs time to gastric emptying, possibly due in part to enhanced GLP-1 release. See Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect. Diabet Med. 1998 Feb;15(2):120-4 and Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G752-63. 

Similar elevations in circulating GLP-1 following acarbose ingestion have also been observed in some but not all studies of patients with Type 2 diabetes-Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in Type 2 diabetic patients. Diabet Med. 1998 Jun;15(6):485-91. Nevertheless, it should not be assumed that acarbose administration is always associated with enhanced GLP-1 release, as no significant evidence for enhanced GLP-1 release in the setting of acarbose administration was detected in subjects over the age of 65 with Type 2 diabetes. See Glucagon-like peptide-1 response to acarbose in elderly type 2 diabetic subjects. Diabetes Res Clin Pract. 2002 May;56(2):101-6. In contrast, acute and prolonged treatment with acarbose was not associated with increased plasma levels of GLP-1 in studies of 10 patients with Type 2 diabetes before and after single and repeat 2 week dosing (100 mg t.i.d) as described alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7-36 amide) and to delay gastric emptying in Type 2 diabetic patients. Diabet Med. 2005 Apr;22 (4): 470-6

Metformin

Patients receiving metformin have also been noted to exhibit additive glucose lowering benefits following institution of GLP-1 therapy. See Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care. 2001 Apr;24(4):720-5. In a study of 10 obese non-diabetic male patients, metformin administration was associated with increased levels of circulating GLP-1 following oral glucose-loading, and in experiments using pooled human plasma, metformin (0.1-0.5 ug/ml) significantly inhibited degradation of GLP-1(7-36)amide after a 30-min incubation at 37 degrees C, in the presence or absence of DPP-4. The authors of this study raised the possibility that metformin may inhibit the enzymatic breakdown of GLP-1 both in vitro and in vivo. See Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001 Mar;24(3):489-94

A subsequent study examined the interaction between metformin, DPP-4, and GLP-1 degradation using biochemical analyses in vitro. Demuth and colleagues found no effect of metformin on the DPP-4-mediated degradation of GLP-1 using a variety of sources of human DPP-4. See Metformin Effects on Dipeptidylpeptidase IV Degradation of Glucagon-like Peptide-1. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1302-8. Nevertheless, the observation that administration of metformin and related biguanides increases plasma levels of GLP-1 has also been made in wildtype rats or Fischer rats with inactivating DPP-4 mutation, as shown in Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.

Similarly, combination therapy with both metformin and the DPP-4 inhibitor Val-Pyr produces a synergistic anti-diabetic effect, including increased levels of plasma GLP-1, and a reduction in food intake and weight loss, beyond that seen with either agent alone when administered to Zucker fa/fa rats for 14 days. See Metformin causes reduction of food intake and body weight gain, and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats. J Pharmacol Exp Ther. 2004 Mar 23 [Epub ahead of print]

Migoya and colleagues examined GLP-1 synthesis and secretion in mice with diet-induced obesity and plasma levels of GLP-1 and GIP were also assessed in non-diabetic human subjects following acute metformin administration. Metformin administered to high fat fed mice by oral gavage acutely increased total GLP-1 immunoreactivity in both fasted and fed mice within 1 hr post dosing and increased levels of proglucagon mRNA transcripts were detected in the mouse large bowel even 1 hr after metformin administration, whereas no effect of metformin on pancreatic proglucagon mRNA transcripts was observed. Similarly, metformin increased plasma GLP-1 levels (total GLP-1 immunoreactivity) in healthy non-diabetic subjects whereas sitagliptin alone decreased total GLP-1 levels but increased active GLP-1 levels. In contrast, metformin had no effect on circulating GIP levels in human subjects Dipeptidyl Peptidase-4 Inhibitors Administered in Combination With Metformin Result in an Additive Increase in the Plasma Concentration of Active GLP-1 Clin Pharmacol Ther. 2010 Nov 3.

Similar findings in rodents were reported by Maida et al who demonstrated acute increases in plasma levels of GLP-1 following metformin administration to fasted mice, but no effect on circulating levels of GIP. Although the AMPK activator AICAR also acutely and markedly increased GLP-1 levels in mice, the mechanism through which metformin promotes GLP-1 secretion appears indirect and has not yet been precisely elucidated. Notably metformin also increased islet incretin receptor expression via a PPARa-dependent mechanism in both cells and mice and directly enhanced the insulinotropic actions of incretin hormones. The actions of metformin to induce islet incretin receptor expression were absent in PPARa-/- mice. See Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice Diabetologia 2011 Feb;54(2):339-49. and the commentary New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser Diabetologia 2011 Feb;54(2):219-22

The actions of metformin to acutely stimulate GLP-1 secretion in rats appear to be indirect, requiring M3 muscarinic receptors and GRP. In contrast, Mulherin and colleagues did not find any direct effect of metformin to stimulate GLP-1 secretion from GLUTag, NCH-H716, or rat FRIC cultures. Mechanisms Underlying Metformin-Induced Secretion of Glucagon-Like Peptide-1 from the Intestinal L Cell Endocrinology October 4, 2011, doi: 10.1210/en.2011-1485

Gastric bypass surgery, GLP-1, and weight loss

As many patients with obesity experience rapid weight loss together with striking amelioration of their diabetes often within days of gastric bypass surgery, a role for GI hormones such as GLP-1 has been invoked to explain these impressive clinical improvements. Valverde and colleagues studied plasma levels of GLP-1, together with serial analysis of glucose tolerance in two groups of patiets; after Larrad's pancreaticobiliary diversion (BPD) or following vertical banded gastroplasty (VBG). Basal and glucose-stimulated plasma GLP-1 increased after surgey, with GLP-1 levels comparatively greater in subjects following BPD. See Changes in glucagon-like peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obes Surg. 2005 Mar;15(3):387-97 Similarly, the GLP-1, PYY, Hunger and Satiety Following Gastric Bypass Surgery In Morbidly Obese Subjects. J Clin Endocrinol Metab. 2006 Feb 14; [Epub ahead of print] and Incretin levels and effect are markedly enhanced one month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 2007 Apr 6; [Epub ahead of print]

The observation that some patients treated with gastric bypass exhibit hypoglycemia and neuroglycopenia has raised the questions as to whether exaggerated incretin responses underlie this problem in some patients. Goldfine and colleagues have reported a cross-sectional analysis of incretin secretory profiles in patients post gastric bypass with and without symptoms of hypoglycemia. Plasma levels of GLP-1 are clearly very significantly increased in some patients with hypoglycemia post GBP. Patients with Neuroglycopenia Post Gastric Bypass Surgery Have Exaggerated Incretin and Insulin Secretory Responses to Mixed Meal. J Clin Endocrinol Metab. 2007 Sep 25; [Epub ahead of print

                                                                                          Glucocorticoids

Glucocorticoids are known to induce insulin resistance and impair b-cell function. Hansen et al administered a high fat diet and prednisolone 37.5 mg/day for 12 days, then examined incretin secretion and glucose responses. Plasma glucose responses to a test meal increased modestly,with increases in glucagon, insulin, and GIP, but no changes in plasma GLP-1 observed in response to a test meal. Increased postprandial GIP and glucagon responses, but unaltered GLP-1 response after intervention with steroid hormone, relative physical inactivity, and high-calorie diet in healthy subjects J Clin Endocrinol Metab. 2011 Feb;96(2):447-53

                                                                                               Resveratrol

Administration of the Sirt1 activator resveratrol has been shown to increase GLP-1 synthesis and GLP-1 secretion and improve glucose homeostais via a GLP-1R-dependent manner in mice. Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control PLoS One. 2011;6(6):e20700. The explanation for these findings, confirmed by Park and colleagues, appears to reflect the ability of resveratrol to increase cAMP via inhibition of phosphodiesterase activity, consistent with the potent properties of cyclic AMP to stimulate PGDP biosynthesis and GLP-1 secretion from L cells. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases Cell 10.1016/j.cell.2012.01.017

GLP-1 clearance

There appear to be 2 principal mechanisms responsible for regulating the levels of intact GLP-1 in the circulation, namely N-terminal cleavage at the position 2 alanine by DPP-4, and renal elimination. For an overview of the importance of DPP-4, see DPP-4. There are several studies demonstrating the importance of the kidney in GLP-1 clearance. The clearance of both GLP-1 is significantly altered in nephrectomized dogs Renal catabolism of human glucagon-like peptides 1 and 2. Can J Physiol Pharmacol. 1990 Dec;68(12):1568-73 and studies in human subjects with chronic renal failure demonstrate the importance of the kidney for clearance and degradation of both GLP-1 and GIP as shown in Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects. Diabetes. 2004 Mar;53(3):654-662.