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GLP-1 Synthesis, Secretion, and Degradation

David Joffe, BSPharm, CDE
Brittany Davis, Pharm D Candidate, Presbyterian College School of Pharmacy

This is the first of a two-part series that examines some of the current research and unanswered questions about how GLP-1 is made in the body, what factors are involved in the release and quantity of this hormone and how diabetes and other problems affect this release. We will also include how other medications and procedures affect Plasma Levels and what happens to cause the breakdown of the hormone and why.

See more GLP-1 Agonist Resources

GLP-1 and GLP-2 are produced in the same gut endocrine cells and liberated, following posttranslational processing of a single pro-glucagon precursor.1 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 manner2 and that 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.3

Is There a Defect in GLP-1 Release Associated with Human Diabetes? 

Although some studies document a significant reduction in meal-stimulated GLP-1 levels from 60 minutes to 2 hrs after meal ingestion, the available evidence, summarized by Nauck and colleagues, suggest that inter-individual differences in GLP-1 secretion, age of patients, duration of diabetes, concomitatnt drug therapy, and other variables, preclude definitive conclusions that diabetes is invariably associated with reduced GLP-1 secretion.4

Consistent with the lack of evidence supporting a consistent 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 groups5,6

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. 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.7

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.8

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.9

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.10

Is there a defect in clearance of GLP-1 in human diabetic subjects that explains the decreased levels of plasma GLP-1?

This possibility has been examined by infusing GLP-1 in association with a meal test in normal and diabetic human subjects. No difference in the elimination t1/2 of GLP-1 was noted in the different study subjects.11

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.12

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.13 

Direct Vs. Indirect Control of GLP-1 Secretion

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).14

The rapid increase in plasma gut hormone levels within 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.

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.15,16

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.17

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.18

Fatty acids stimulate both insulin secretion and enhance GLP-1 release in human subjects. 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-1.19

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 20

As you can see, GLP-1 is more than just a hormone that is made in the small intestines when we eat a meal.

In the next part of this series we will look at the “Mechanisms and Receptors Controlling Intestinal GLP-1 Secretion,” as well as “Drugs and Plasma Levels of GLP-1 and GLP-1 Clearance from the Body.”

References:
  1. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing.  J Biol Chem. 1986 5;261:11880-9
  2. 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.
  3. 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
  4. 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.
  5. 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
  6. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001 Mar;50(3):609-13
  7. 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
  8. 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
  9. 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.
  10. 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.
  11. Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care. 2001 Sep;24(9):1640-5.
  12. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients Diabetes. 2007 Dec 27;
  13. Endocrinology 1999: 140(4):1687-94
  14. 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
  15. 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.
  16. 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
  17. 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]
  18. 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.
  19. Incretin Hormone and Insulin Responses to Oral Versus Intravenous Lipid Administration in Humans J Clin Endocrinol Metab. 2011 May
  20. 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

 

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