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. 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. These findings have 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

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

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.  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

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

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

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

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

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.

Leptin was 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 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

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

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-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]

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 DP IV. 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 ant-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]

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 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]

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.