Glucagon Like Peptide -1 : A New Era In Treatment Of Type - 2 Diabetes Mellitus

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Abstract

Therapies based on the incretin hormone glucagon-like peptide 1 (GLP-1) are novel treatment options for type 2 diabetes that act through a variety of complementary mechanisms. GLP-1 is produced by the proglucagon gene in L-cells of the small intestine in response to nutrients. It stimulates glucose-dependent insulin release from the pancreatic islets. In addition to its insulinotropic effects, it is thought to exert ant hyperglycemic effects by slowing gastric emptying, inhibiting inappropriate glucagon release, stimulating v-cell proliferation and differentiation, and improving satiety. GLP-1 secretion is decreased in type 2 diabetes, thus making it a logical target for novel treatments of type 2 diabetes. In clinical trials, GLP-1 effects are evident regardless of the duration or severity of diabetes. Thus, modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogs, and mimetics or by inhibiting its degradation has become a major focus of investigation for treating type 2 diabetes over the past decade.

Keywords: Diabetes Mellitus, GLP-1, Insulin, Incretin, Antihyperglycemic, DPP-IV inhibitor

Introduction

Diabetes mellitus is a group of metabolic diseases which is characterized by hyperglycemia, glycosuria, polydypsia, polyphagia that result from defects in insulin secretion, or action, or both. There are many antihyperglycaemic agents which are used for the treatment of diabetes; act on different sites as shown in figure 1.

Incretin hormones cause an increase in the amount of insulin released from beta cells in the pancreas following ingestion of food.1 Incretin hormones act to increase glucose-dependent insulin secretion from beta cells in the pancreas2; this action helps to ensure an appropriate insulin response after eating.1 glucagon-like peptide-1 (GLP-1) is the most well-characterized incretin hormone, which is considered to be the most important incretin released by the gut into the bloodstream in response to meal.3 In addition to its effects on insulin secretion after eating, GLP-1 also has additional effects that can help in the management of diabetes.3-5 The primary function of GLP-1 is to enhance insulin secretion only in the presence of elevated blood sugar (glucose) concentrations.3 GLP-1 also suppresses the release of glucagon from the pancreas.4 Glucagon stimulates glucose release from the liver6; so decreasing the amounts of glucagon helps to improve glucose control.3,4 It is postulated that GLP-1 acts in the brain to absorbed too quickly into the reduce appetite4 and in the stomach to slow the rate of gastric emptying so that nutrients are not bloodstream.5 GLP-1 has been shown to improve acute beta-cell function in humans.3

Role Of GLP-1 In Glucose Homeostasis

GLP-1 exerts multiple effects that contribute to the maintenance of glucose homeostasis as shown in table 1.3-5 GLP-1 enhances glucose-dependent insulin secretion; suppresses inappropriate glucagon secretion; reduces appetite, leading to reduction of food intake; regulates the rate of gastric emptying, so that nutrients are not absorbed as quickly into the bloodstream.

GLP-1 and Type 2 Diabetes

People with type 2 diabetes often have inappropriately elevated levels of glucagon.7 The elevated glucagon, which is produced in pancreatic alpha cells, causes the liver to release an excessive amount of glucose into the bloodstream, which then contributes to high blood glucose seen in type 2 diabetes.8 Many people with diabetes may also have an accelerated rate of gastric emptying, which leads to increased nutrient delivery to the intestine resulting in an abnormally rapid rise in glucose following a meal.9 The levels and actions of GLP-1 appear to be deficient in many people with type 2 diabetes, thus creating an opportunity for antidiabetes medications that act directly on the GLP-1 receptor or inhibit the breakdown of GLP-1 in the bloodstream.7 Metabolic actions of GLP-1 are summarized in figure 2; which shows the importance of GLP-1 in diabetes management.10

Administration of GLP-1 by continuous subcutaneous infusion (CSI) for 6 weeks in patients with T2DM caused a significant decrease in hemoglobin A1C (A1C) and reduced hyperglycemia significantly over the course of 8 hours, during which the patients ate breakfast and lunch. The effect of GLP-1 was noted at 1 week of treatment and was maintained over 6 weeks.11

GLP-1 concentrations in the picomolar range induce insulin secretion from pancreatic b-cells in vitro and in vivo when elevated glucose concentrations (> 5 mmol/l) are present. In patients with non-insulin-dependent diabetes mellitus (NIDDM) parenteral (i.v. and s.c.) administration of GLP-1 led to reconstitution of the early phase insulin secretion and reduction of postprandial glucose excursions. Even in insulin-deficient type-1 diabetic patients GLP-1 reduced the insulin requirements, suggesting additional peripheral activities.12

Drugs Under Development

Exendin-4

To compensate for the rapid and robust metabolism of GLP, several peptide analogues with extended action have been developed. The 39 amino acid peptide exendin-4 (exenatide) is homologous to GLP-1 and binds avidly to the GLP-1 receptor,13 but is resistant to the actions of DPP-IV. Because of this, exendin-4 has a greatly extended duration of insulinotropic activity compared with GLP-1.14 The effectiveness of repeated dosing with exendin-4 was recently demonstrated in patients with T2DM. Bedtime glucose levels were reduced from 15.5 to 9.2 mmol/L, and A1C decreased from 9.1% to 8.3% over just 1 month14. These results were corroborated by another recent placebo-controlled trial of exendin-4 in T2DM.15 The major side effect of exendin-4 in humans is nausea and vomiting, which seems to occur in a dose-dependent fashion.

Liraglutide

A second long-acting derivative was made by covalently linking GLP-1 to a fatty acid. This fatty acyl-GLP-1 binds to serum albumin, which greatly increases the duration of action of GLP-1 by: (1) limiting metabolism by DPP-IV; (2) delaying/prolonging absorption from the injection site; and (3) reducing renal clearance. The half-life of this compound, previously designated NN2211 and now called liraglutide, is approximately 12 hours in healthy volunteers;16 therefore, a single daily injection can deliver biologically active amounts of GLP-1 for an entire 24-hour period. In patients with T2DM, a single subcutaneous injection of liraglutide at bedtime reduced glucose levels during the night, greatly reduced the glucose excursions during a standardized lunch, and increased meal-stimulated insulin secretion.15 Suppression of meal-stimulated glucagon levels and delay of gastric emptying were also observed. However, as with exendin-4 or native GLP-1, nausea and vomiting are dose-limiting side effects.

CJC-1131

An alternative approach to overcome the short half-life of GLP-1is to form a constant bond of GLP-1 with albumin--as in the case with CJC-1131.17 This DPP-IV-resistant human GLP-1analog binds to and activates the GLP-1 receptor. This agent has a 10-day half-life in humans.18

DPP-IV Inhibitors

DPP-IV degrades active glucagonlike peptide (GLP)-1 and abolishes all the effects of GLP-1. An alternative to using exogenously administered GLP-1 receptor agonists is to increase the effect of endogenously secreted GLP-1 by blocking its degradation (Figure 3). There are several inhibitors of DPP-IV currently under investigation. These agents have the advantages of being active in an orally available form and having minimal gastrointestinal side effects. A theoretical problem with blocking DPP-IV is that this enzyme metabolizes a wide range of regulatory peptides and plays a role in the modification of antigens for immune recognition, so other physiologic systems could be affected. Sitagliptin, Vildagliptin, Saxagliptin, LAF237, SRY-322, PHX1149 and GRC-8200 are the agents which inhibit the DPP-IV and prevent degradation of GLP-1.Another potential limitation is that plasma levels of GLP-1 that can be achieved using DPP-IV inhibitors are a function of normal GLP-1 secretion rates and are not likely to reach the levels that can be obtained with GLP-1 analogues.19.20,21,22,23

Future Prospects

GLP-1 has emerged as a key glucoregulatory hormone, exerting several physiologic actions that lower blood glucose levels. In acute and short-term studies, GLP-1 is effective in controlling the hyperglycemia of T2DM. Several promising agents are under development as treatments for diabetes that are based on activation of the GLP-1 signaling system. Encouraging early results with these drugs strengthen the possibility of new treatment option for diabetic patients.

References

  1. Drucker D. The role of gut hormones in glucose homestasis, J Clin Invest 2007, 117, 24-32.
  2. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes, Diabetologia 1986, 29(1), 46-52.
  3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans, Am J Physiol Endocrinol Metab 2004, 287.
  4. Zander M, Christiansen A, Madsbad S, Holst JJ. Additive Effect of Glucagon-Like Peptide 1 and Pioglitazone in Patients with Type 2 Diabetes, Diabetes Care 2004, 27, 1910-1914.
  5. D'Alessio D, Sandoval D, Seeley R. New ways in which GLP-1 can regulate glucose homeostasis, J Clin Invest. 2007, 115(12), 3406-3408.
  6. Mallette L E, Exton J H, Park C R. Control of Gluconeogenesis from Amino Acids in the Perfused Rat Liver, Journal of Biological Chemistry 1969, 244(20), 5713-5723.
  7. Toft-Nielsen M-B, Damholt MB, Madsbad S. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients, J Clin Endocrinol Metab 2001, 86(8), 3717-3723.
  8. Diao J, Asghar Z, Chan C, Wheeler M. Glucose-Regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic a-Cells, Journal of Biological Chemistry 2005, 280(39), 33487-96.
  9. Nowak T V, Johnson C P, Kalbfleisch J H, Roza A M, Wood C M, Weisbruch J P, Soergel K H. Highly variable gastric emptying in patients with insulin dependent diabetes mellitus, Gut 1995, 37, 23-29.
  10. Drucker DJ. Therapeutic Strategies Based On GLP - 1 Pathways, Proceedings 2005, 5(10E), S1070-S1073.
  11. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet 2002, 359, 824-830.
  12. Anath Shalev. The role of glucagon-like peptide 1 in the regulation of glucose homeostasis and satiety, Eup. J. of End.1997, 137, 220-221.
  13. Thorens B, Porret A, Buhler L, Deng S-P, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor: Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor, Diabetes 1993, 42, 1678-1682.
  14. Egan JM, Meneilly GS, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes, Am J Physiol Endocrinol Metab 2003, 284, E1072-E1079.
  15. Juhl CB, Hollingdal M, Sturis J. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes, Diabetes 2002, 51, 424-429.
  16. Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men, Diabetologia 2002, 45, 195-202.
  17. http://www.faqs.org/patents/app/20090181887 accessed on 11/04/2010.
  18. http://care.diabetesjournals.org/content/27/10/2554.full accessed on 11/04/2010.
  19. Ahren B, Simonsson E, Larsson H. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes, Diabetes Care 2002, 25, 869-875.
  20. Aschner P, Kipnes M, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidylpeptidase-4 inhibitor Sitagliptin as monotherapy on glycemic control in patients with Type2 Diabetes, Diabetes Care 2006, 29, 2632!2637.
  21. Herman G, Stevens C, Van Dyck K. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses, Clin Pharmacol Ther 2005, 78, 675-688.
  22. Holst JJ, Gromada J, Nauck MA. The pathogenesis of NIDDM involves a defective expression of the GIP receptor, Diabetologia 1997, 40, 984-986.
  23. Brazg R, Xu L, DallaMan C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidylpeptidase-4 inhibitor, to metformin on 24-h glycemic control and beta-cell function in patients with type2 diabetes. Diabetes Obesity & Metabolism 2007, 9(2), 186-193.
Pancreas
  • Stimulates glucose-dependent insulin secretion (+)
  • Increases insulin gene transcription, mRNA stability, and biosynthesis (+)
  • Stimulates somatostatin secretion (+)
  • Enhances v cell response to glucose (+)
  • Induces v cell neogenesis and proliferation (+)
  • Inhibits v cell apoptosis (+)
  • Increases expression of key genes important for differentiated v cell function (+)
  • Gastrointestinal tract
    • Inhibits gastric emptying (+)
    • Inhibits gastric acid secretion (+)
    Central nervous system
    • Inhibits food and water intake (+)
    • Promotes satiety and weight loss (+)
    • Enhances memory and neuronal survival (+)
    • Activates aversive pathways leading to nausea/vomiting (+)
    Cardiovascular system
    • Improves cardiovascular function after ischemia (+)
    • Reduces the extent of cardiomyocyte death after experimental injury (+)
    Adipose tissue
    • Insulin-like lipogenic actions (-)
    • Lipid storage (-)
    "+" denotes that this action occurs; "-" denotes that this action does not occur.
    Table 1: Summary of GLP-1 actions relevant to glucose control and treatment of Type 2 Diabetes Mellitus

    Major sites of action of antihyperglycaemic agents

    GLP-1 Receptor Signaling Pathway

    Mechanism of DPP-IV inhibitor

    About Authors:

    Manmohan Singhal*, Rahul Dave

    Manmohan Singhal

    Manmohan Singhal

    School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India-302025

    Rahul Dave

    Rahul Dave

    School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India-302025

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    Comments

    Lakshmana Murthy's picture

    can you tell me what is DPP& its classes
    Kvpund's picture

    sir i read u r paper i like u r work but sir if i want evaluate the glucagon conc.then it is possible at lab level. I am also working on diabetes. If u provide me positive reply then its a very good for making my work easy. thank you.

    kvpund

    Pavan's picture

    hello sir, i have given 2 seminars about this topic in my college.. really GLP-1 is a break through in diabetes treatment...
    Tapanshah's picture

    Probably the newest class of OHA is SGLT-2 Inhibitors. BMS, J&J, BI and a few other MNCs have their SGLT-2 molecules in phase 3 studies right now. I am also working on one of these molecules. In addition to reducing blood glucose levels, the drugs of this class also reduce weight, and BP. Read about it. It is an interesting class of OHAs.

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