Basics Actions Mechanism Regulators Diabetes Analogues Enhancers
GLP-1 and Acarbose
Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1. Acarbose an alpha glucosidase inhibitor while increasing GLP-1 secretion in normal subjects, Scand J Gastroenterol. 1995 Sep;30(9):892-6 does not seem to have a similar beneficial effect in type 2 diabetics. Diabet Med. 2005 Apr;22(4):470-6. In contrast, Miglitol, a second generation Alpha glucosidase inhibitor, produces a significant post prandial GLP-1 response in diabetic patients following an ordinary meal. Diabetes Obes Metab. 2002 Sep;4(5):329-35. Note that GIP is predominantly secreted from the upper intestines while GLP-1 is secreted mainly from the lower intestines which have a higher concentration of L cells. Hence while Acarbose diverts nutrients rapidly to the lower intestine with resultant increased GLP-1, it also reduces concomitant GIP secretion. Scand J Gastroenterol. 1995 Sep;30(9):892-6.
GLP-1 and Lipase Inhibition
Orlistat, a gastrointestinal lipase inhibitor, has been reported to produce an increase in GLP-1 in the post prandial period with increased C-peptide responses and improved postprandial glycaemic control as shown in a study in type 2 diabetics.Diabetes Care 27:1077–1080, 2004. although this has not been consistently demonstrated. J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34. It is possible that accelerated gastric emptying brought about by inhibition of fat-digestion might have produced an increased secretory response of insulin although an effect on GLP-1 degradation cannot be ruled out. Un-digested fat being delivered to the distal ileum is thought to be less likely to stimulate GLP-1 secretion from the ileal L cells.Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G798-807.
GLP-1 and Metformin
Metformin has been shown to have effects on GLP-1 levels. A study in 10 obese non-diabetic patients treated with 2.5 gms metformin daily for 2 weeks, showed a significant increase of active GLP-1 in response to an oral glucose load at 30 and 60 minutes compared to controls. Diabetes Care. 2001 Mar;24(3):489-94. Basal GLP-1 levels were unchanged. Although Metformin was initially thought to produce this increased GLP-1 levels through DPP-IV inhibition, Biochem Biophys Res Commun. 2004 Nov 5;324(1):92-7. further studies seemed to suggest a lack of effect of metformin on DPP-IV Biochem Biophys Res Commun. 2002 Mar 15;291(5):1302-8. although a later study has shown that metformin inhibits DPP-IV without altering GLP-1 or insulin levels in type 2 diabetics. Diabet Med. 2005 May;22(5):654-7. Also, a study in rats has shown that the metformin induced GLP-1 rise is not associated with changes in glycaemia! Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.
A single dose of metformin does not seem to raise GLP-1 levels in diabetic patients, but longer therapy (2 weeks) seems to increase GLP-1 levels in the fasting and postprandial state. Diabetes Nutr Metab. 2004 Dec;17(6):336-42. A randomised crossover study in 7 obese diabetic patients using metformin (1.5 gms od), GLP-1 infusion or a combination alternating with each other for 48 hours during fixed energy intake revealed additive effects of the combination on glycaemic control compared to either alone. Diabetes Care. 2001 Apr;24(4):720-5. GLP-1 infusion and metformin independently improved glycaemia to similar degrees. Interestingly, Insulin levels and C-peptide were not different in those on metformin or GLP-1. But mean glucagon levels in a 24 hour period was significantly lower in the GLP-1 treated group which could explain the improved glycaemia in this group. Glucagon levels were lowered further on combining GLP-1 with Metformin. Lack of an incretin effect in the study was attributed to probable glucotoxicity in the "untreated" patients in the GLP-1 treated group! Metformin has been shown to increase postprandial GLP-1 levels in obese non diabetic patients. Diabetes Nutr Metab. 2004 Dec;17(6):336-42.
A 2 week study in Zucker fa/fa rats (rat models for DM and IGT) using bd metformin or a DPP-IV inhibitor or a combinationdemonstrated that the combination caused a significant GLP-1 rise , with reduction in food intake and body weight gain. Separately neither of them had effects on appetite or body weight gain. J Pharmacol Exp Ther. 2004 Aug;310(2):614-9.
Pioglitazone (a thiazolidinedione- PPAR gamma agonist) treatment of Zucker diabetic rats has been shown to produce increased GLP-1 levels which correlated with decreased serum DPP-IV activity in serum. Biochem Biophys Res Commun. 2004 Nov 5;324(1):92-7.
Special groups:
Glucose tolerant first degree relatives of type 2 patients seem to have similar incretin effects compared to control subjects, Regul Pept. 2004 Nov 15;122(3):209-17. although a reduced insulin response to GIP infusion has been noted. 24 hour hormone profiling in glucose-tolerant but insulin-resistant relatives of type 2 diabetics and controls show similar endogenous GLP-1 response to glucose although endogenous GIP responses to glucose were higher in the relatives of type 2 diabetics. Diabetologia. 1999 Nov;42(11):1314-23.
Subjects with Impaired Glucose Tolerance seem to have incretin responses to glucose which is intermediate between normals and type 2 diabetics. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23.
The incretin (GLP-1) response in glucose tolerant BMI matched young men who had normal or Low birth weight seem to be similar and does not seem to directly contribute to the higher risk of later onset of type 2 diabetes in the latter group. J Clin Endocrinol Metab. 2005 Aug;90(8):4912-9
Women with previous Gestational diabetes mellitus do not seem to have a defect in GLP-1 or GIP secretion, Diabetologia.2005 Jul 12 and insulin resistance seems to be the major player in this subgroup.
GLP-1 infused intravenously at doses as low as 0.4 pmol/kg/mt has been shown to be effective in patients withpancreatitis with improved C-peptide levels and glucagon suppression. Pancreas. 2000 Jan;20(1):25-31.
Normoglycaemic lipodystrophic HIV-infected patients have been shown to have impaired glucose and lipid metabolism in multiple pathways involving the liver, muscle as well as beta-cell function. Eur J Endocrinol. 2005 Jan;152(1):103-12. HIV patients with impaired glucose tolerance seem to have increased GLP-1 secretion compared to HIV infected normoglycaemics, HIV Med. 2005 Mar;6(2):91-8. probably as a compensatory mechanism for deteriorating glycaemia produced by other mechanisms.
Acromegalic patients and patients with non functioning pituitary adenomas treated with octreotide show abolishment of the initial GLP-1 and insulin response during an OGTT, with a reduced late response. But these hormones escape at least partially from this suppressive effect despite ongoing therapy.
Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1. Acarbose an alpha glucosidase inhibitor while increasing GLP-1 secretion in normal subjects, Scand J Gastroenterol. 1995 Sep;30(9):892-6 does not seem to have a similar beneficial effect in type 2 diabetics. Diabet Med. 2005 Apr;22(4):470-6. In contrast, Miglitol, a second generation Alpha glucosidase inhibitor, produces a significant post prandial GLP-1 response in diabetic patients following an ordinary meal. Diabetes Obes Metab. 2002 Sep;4(5):329-35. Note that GIP is predominantly secreted from the upper intestines while GLP-1 is secreted mainly from the lower intestines which have a higher concentration of L cells. Hence while Acarbose diverts nutrients rapidly to the lower intestine with resultant increased GLP-1, it also reduces concomitant GIP secretion. Scand J Gastroenterol. 1995 Sep;30(9):892-6.
GLP-1 and Lipase Inhibition
Orlistat, a gastrointestinal lipase inhibitor, has been reported to produce an increase in GLP-1 in the post prandial period with increased C-peptide responses and improved postprandial glycaemic control as shown in a study in type 2 diabetics.Diabetes Care 27:1077–1080, 2004. although this has not been consistently demonstrated. J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34. It is possible that accelerated gastric emptying brought about by inhibition of fat-digestion might have produced an increased secretory response of insulin although an effect on GLP-1 degradation cannot be ruled out. Un-digested fat being delivered to the distal ileum is thought to be less likely to stimulate GLP-1 secretion from the ileal L cells.Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G798-807.
GLP-1 and Metformin
Metformin has been shown to have effects on GLP-1 levels. A study in 10 obese non-diabetic patients treated with 2.5 gms metformin daily for 2 weeks, showed a significant increase of active GLP-1 in response to an oral glucose load at 30 and 60 minutes compared to controls. Diabetes Care. 2001 Mar;24(3):489-94. Basal GLP-1 levels were unchanged. Although Metformin was initially thought to produce this increased GLP-1 levels through DPP-IV inhibition, Biochem Biophys Res Commun. 2004 Nov 5;324(1):92-7. further studies seemed to suggest a lack of effect of metformin on DPP-IV Biochem Biophys Res Commun. 2002 Mar 15;291(5):1302-8. although a later study has shown that metformin inhibits DPP-IV without altering GLP-1 or insulin levels in type 2 diabetics. Diabet Med. 2005 May;22(5):654-7. Also, a study in rats has shown that the metformin induced GLP-1 rise is not associated with changes in glycaemia! Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.
A single dose of metformin does not seem to raise GLP-1 levels in diabetic patients, but longer therapy (2 weeks) seems to increase GLP-1 levels in the fasting and postprandial state. Diabetes Nutr Metab. 2004 Dec;17(6):336-42. A randomised crossover study in 7 obese diabetic patients using metformin (1.5 gms od), GLP-1 infusion or a combination alternating with each other for 48 hours during fixed energy intake revealed additive effects of the combination on glycaemic control compared to either alone. Diabetes Care. 2001 Apr;24(4):720-5. GLP-1 infusion and metformin independently improved glycaemia to similar degrees. Interestingly, Insulin levels and C-peptide were not different in those on metformin or GLP-1. But mean glucagon levels in a 24 hour period was significantly lower in the GLP-1 treated group which could explain the improved glycaemia in this group. Glucagon levels were lowered further on combining GLP-1 with Metformin. Lack of an incretin effect in the study was attributed to probable glucotoxicity in the "untreated" patients in the GLP-1 treated group! Metformin has been shown to increase postprandial GLP-1 levels in obese non diabetic patients. Diabetes Nutr Metab. 2004 Dec;17(6):336-42.
A 2 week study in Zucker fa/fa rats (rat models for DM and IGT) using bd metformin or a DPP-IV inhibitor or a combinationdemonstrated that the combination caused a significant GLP-1 rise , with reduction in food intake and body weight gain. Separately neither of them had effects on appetite or body weight gain. J Pharmacol Exp Ther. 2004 Aug;310(2):614-9.
Pioglitazone (a thiazolidinedione- PPAR gamma agonist) treatment of Zucker diabetic rats has been shown to produce increased GLP-1 levels which correlated with decreased serum DPP-IV activity in serum. Biochem Biophys Res Commun. 2004 Nov 5;324(1):92-7.
Special groups:
Glucose tolerant first degree relatives of type 2 patients seem to have similar incretin effects compared to control subjects, Regul Pept. 2004 Nov 15;122(3):209-17. although a reduced insulin response to GIP infusion has been noted. 24 hour hormone profiling in glucose-tolerant but insulin-resistant relatives of type 2 diabetics and controls show similar endogenous GLP-1 response to glucose although endogenous GIP responses to glucose were higher in the relatives of type 2 diabetics. Diabetologia. 1999 Nov;42(11):1314-23.
Subjects with Impaired Glucose Tolerance seem to have incretin responses to glucose which is intermediate between normals and type 2 diabetics. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23.
The incretin (GLP-1) response in glucose tolerant BMI matched young men who had normal or Low birth weight seem to be similar and does not seem to directly contribute to the higher risk of later onset of type 2 diabetes in the latter group. J Clin Endocrinol Metab. 2005 Aug;90(8):4912-9
Women with previous Gestational diabetes mellitus do not seem to have a defect in GLP-1 or GIP secretion, Diabetologia.2005 Jul 12 and insulin resistance seems to be the major player in this subgroup.
GLP-1 infused intravenously at doses as low as 0.4 pmol/kg/mt has been shown to be effective in patients withpancreatitis with improved C-peptide levels and glucagon suppression. Pancreas. 2000 Jan;20(1):25-31.
Normoglycaemic lipodystrophic HIV-infected patients have been shown to have impaired glucose and lipid metabolism in multiple pathways involving the liver, muscle as well as beta-cell function. Eur J Endocrinol. 2005 Jan;152(1):103-12. HIV patients with impaired glucose tolerance seem to have increased GLP-1 secretion compared to HIV infected normoglycaemics, HIV Med. 2005 Mar;6(2):91-8. probably as a compensatory mechanism for deteriorating glycaemia produced by other mechanisms.
Acromegalic patients and patients with non functioning pituitary adenomas treated with octreotide show abolishment of the initial GLP-1 and insulin response during an OGTT, with a reduced late response. But these hormones escape at least partially from this suppressive effect despite ongoing therapy.