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GLP-1 Agonists: Increasing Effective Insulin Release

By Wael Diab, RPh, PharmD Candidate University of Colorado College of Pharmacy

The pathophysiology of type 2 diabetes mellitus is complex, consisting of far more physiologic defects than simple insulin resistance and beta-cell dysfunction….

Our understanding of this progressive disease has moved from a "dual defect" to an "ominous octet" description. This multi-factor concept may explain the difficulty in achieving and maintaining glycemic goals with traditional therapies. Glucagon-like peptide-1 (GLP-1) agonists, which improve insulin secretion, decrease glucagon secretion, increase satiety (and therefore decrease food intake), and may have beneficial effects on beta-cell function, represent an important addition to treatment options. Their glucose-dependent mechanism limits the risk for hypoglycemia, and they are associated with weight loss. GLP-1 agonists may be used alone in patients intolerant of metformin or in combination with metformin, thiazolidinediones, and sulfonylureas (or in any combination thereof). Concomitant use of dipeptidyl-peptidase-4 inhibitors (DPP-4) is not recommended because they have a similar basis of action.


Incretins are peptide hormones secreted by entero-endocrine cells in the gastrointestinal tract. Incretins modulate pancreatic islet secretions as part of the "entero-insular axis," and their primary function is to regulate postprandial nutrient utilization and storage. There are several incretin hormones, but GLP-1 appears to be the major player in type 2 diabetes and is best understood. The primary actions are to regulate insulin and glucagon secretion only when plasma glucose exceeds normal fasting levels. Thus, a deficiency of GLP-1 is now considered as part of the pathophysiology of type 2 diabetes1.

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The pharmacologic effects of GLP-1 are noted in the next figure. The importance of GLP-1 is demonstrated in experiments showing that it accounts for up to 60% of postprandial insulin secretion in healthy individuals.


Strategies to correct the incretin defects in patients with type 2 diabetes include replacement of GLP-1 with a long-acting analog that resists degradation and development of drugs that inhibit the enzyme DPP-4, which breaks down GLP-1.

The first strategy, exenatide was the first GLP-1 analog introduced for the treatment of patients with type 2 diabetes. Liraglutide then became available, and several other GLP-1 analogs are in development. The administration of pharmacologic quantities of GLP-1 analogs result in plasma activities that are 5- to 7-fold higher than physiologic levels. At these levels, the effects on gastric emptying, satiety, and decrease in food intake are seen. Glucagon-like peptide-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. The half-life of exenatide necessitates twice-daily dosing, while the longer half-life of liraglutide allows once-daily dosing. Longer-acting GLP-1 analogs that can be administered once each month are currently in clinical trials.

Glucagon is synthesized and released from pancreatic alpha cells and from intestinal L cells of the ileum and colon. Pancreatic glucagon is a 29–amino acid peptide that regulates glucose homeostasis via gluconeogenesis, glycogenolysis, and lipolysis and is counter regulatory to insulin. The gene for glucagon encodes not only preproglucagon but also glucagon-like peptides (GLPs). This precursor peptide consists of a signal peptide, a glucagon-related polypeptide, glucagon, and GLP-1 and GLP-2. Tissue-specific peptide processing occurs through prohormone convertases that produce glucagon in the pancreas and GLP-1 and GLP-2 in the intestine2.

Glucagon and GLP-1 regulate glucose homeostasis. Glucagon is released from the endocrine pancreas in response to a meal and binds to G protein-coupled receptors on skeletal muscle and the liver to exert its glucoregulatory effects. GLP-1 stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta cell. GLP-1 analogs have been developed for the treatment of type II diabetes mellitus. A human GLP-1 analog improves beta cell function and can lower body weight in patients with type II diabetes2.

The enthusiasm for potential therapeutic use of GLP-1 derives from studies demonstrating that unlike GIP, the glucose-lowering actions of GLP-1 are preserved in patients with type 2 diabetes. Similarly, the actions of GLP-1 on inhibition of gastric emptying are also preserved in subjects with poorly controlled type 2 diabetes. Although the actions of GLP-1 on the beta-cell are preserved yet modestly diminished in T2DM, the diabetic alpha-cell retains near normal responsivity to low dose GLP-1 infusion, with inhibition of glucagon secretion seen to a similar extent in diabetic vs. non-diabetic subjects. Hence, modestly diminished GLP-1 action in diabetic subjects does not likely contribute to the defective glucose-stimulated glucagon suppression that remains a characteristic of diabetic subjects3.

Native GLP-1 has been infused by the subcutaneous route (4.8 pmol/kg/min) using a portable insulin pump in a non-randomized study of subjects with type 2 diabetes over the age of 40 (mean age 55) with mean initial HbA1c of about 9%, and mean fasting glucose ~14 mM. Oral antidiabetic medication was discontinued 3 weeks prior to the study. In GLP-1-infused subjects, plasma levels of GLP-1 rose from ~ 19 pM to 197 pM by week 1, and 282 pM at week 6. Six weeks of GLP-1 infusion resulted in significant improvements in fasting (decrease of 4.3 mM glucose) and 8 h mean glucose (decrease of 5.5 mM), fasting and mean 8h free fatty acids, a reduction in HbA1c from 9.2% to 7.9%, a decrease in fructosamine from 349 uM to 282 uM, and a reduction in gastric emptying3,4.

In one study5 where they assessed the efficacy of eight classes of diabetes medications used in current clinical practice [metformin, sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) analogues and insulin analogues] to reach the HbA1c target <7% in type 2 diabetes. The results were a total of 218 RCTs (339 arms and 77 950 patients) met the inclusion criteria. The proportion of patients who achieved the HbA1c goal ranged from 25.9% (95% CI 18.5–34.9) with alpha-glucosidase inhibitors to 63.2% (54.1–71.5) with the long-acting GLP-1 analogue. There was a progressive decrease of the proportion of patients at target for each 0.5% increase in baseline HbA1c, ranging from 57.8% for HbA1c ≤7.5% to 20.8% for HbA1c ≥10% (p for trend 9.0% with no further decrease, whereas for non-insulin drugs the relationship was continuous without any evidence of plateau5.

It is obvious from the information above that the use of GLP-1 analogs can make a great difference in diabetes management and that the effective lowering of postprandial glucose is directly related to the ability of these analogs to increase glucose dependent insulin secretion.

  1. J Am Osteopath Assoc February 1, 2011 vol. 111 no. 2. Accessed May 24,2012
  2. Liddle RA. Gastrointestinal Hormones and Neurotransmitters. In: Feldman: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th ed. 1(8). Accesses May 24,2012
  3. glucagon Accessed May 24,2012
  4. 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. Accessed May 24,2012
  5. Esposito, K. "Proportion of patients at HbA1c target <7% with eight classes of antidiabetic drugs in type 2 diabetes: systematic review of 218 randomized controlled trials with 78 945 patients". Diabetes, obesity & metabolism. November 2011. (1462-8902),14(3), p. 228. May 24, 2012

Written by Wael Diab, RPh, PharmD Candidate University of Colorado College of Pharmacy

Copyright © 2012 Diabetes In Control, Inc.