Saturday , November 18 2017
Home / Resources / Articles / GLP-1 Agonist Effects on Glucagon Suppression

GLP-1 Agonist Effects on Glucagon Suppression

Alan Mathis, PharmD Candidate 2013, University of Florida College of Pharmacy

The pathophysiology of type-2 diabetes is characterized by insulin resistance and beta-cell dysfunction.

In addition, the presence of high levels of glucagon in the blood also seems to play an important role in the disease. Glucagon-like peptide-1 (GLP-1) is a part of a family of peptide hormones known as incretins. Incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are secreted by entero-endocrine cells of the gastrointestinal tract to stimulate glucose-dependent insulin secretion and beta-cell proliferation. Native GLP-1 is rapidly cleared by the body, either through the kidneys or by an enzymatic process involving dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of only 1-2 minutes. Therefore, the native peptide cannot be used therapeutically. However, GLP-1 analogs have been manufactured to be resistant to the effects of DPP-4 and renal clearance and are shown to be effective in the treatment of type-2 diabetes. GLP-1 agonists have been shown to improve insulin secretion, decrease glucagon production, increase satiety, and help decrease food intake. GLP-1 agonists have also been shown to help patients lose weight and may have cardiovascular benefits as well.1

See more GLP-1 Agonist Resources.


In addition to traditional therapies for type-2 diabetes, incretin mimetics are valuable new options that help target patients that may have GLP-1 deficits. Two strategies that accomplish this are replacement of GLP-1 with long-acting analogs or inhibition of DPP-4, the enzyme responsible for GLP-1 degradation. By inhibiting DPP-4, the patients endogenous GLP-1 is able to have longer effect. This can increase beta-cell production but does not have any effect on gastric emptying or weight loss. On the other hand, the addition of a long acting GLP-1 analog creates plasma levels 5-7 times higher than normal physiologic levels which allow the effects of decreased gastric emptying, increased satiety, and weight loss to be seen. Exenatide was the first GLP-1 analog to be produced followed by liraglutide. Exenatide is a twice daily injection that should be administered one hour before breakfast and supper while liraglutide is once daily and can be injected anytime during the day. Most recently, a once weekly injection formulation of exenatide has been produced.

Proglucagon, a precursor to both glucagon and GLP-1 is synthesized in alpha-cells of the pancreas, intestinal L-cells, and specific neurons in the hindbrain. Glucagon and GLP-1 are important regulators for glucose homeostasis. Eating an amino acid rich meal, being in a state of hypoglycemia, or stimulation from the autonomic nervous system can stimulate the pancreas to release glucagon which binds to G protein coupled receptors on skeletal muscle and the liver. In the liver, glucagon stimulates hepatic glucose production by stimulating the breakdown of glycogen and gluconeogenesis. Glucagon is counter regulatory to the glucose lowering effects of insulin. Therefore the role of glucagon in the body is to maintain an adequate supply of glucose even in the fasting state. About one-half of the hepatic glucose production in the fasting state has been attributed to the effects of glucagon on the liver.2


As mentioned above, mechanisms responsible for hyperglycemia found in type-2 diabetes include not only a decline in beta-cell function and insulin resistance, but also increased levels of glucagon found in the blood. Because of elevated amounts of glucagon in the blood, type-2 diabetic patients have increased production in hepatic glucose and therefore significantly higher postprandial and fasting plasma glucose levels. GLP-1 has been shown to counter the effects of both mechanisms responsible for type-2 diabetes by stimulating glucose dependent pancreatic beta-cell function as well as inhibiting the effects of pancreatic alpha-cells.3

Interestingly, in patients with type-2 diabetes, some studies showed GLP-1 analogs to lower glucose levels and HbA1c without affecting the patients’ insulin or C-peptide levels. These unchanged insulin levels most likely reflect the GLP-1 agonist’s ability to help glucose stimulate beta-cell production leading to a decreased work load thereby creating a more normal ratio of glucose and insulin. This also shows that GLP-1 agonists have a role at suppressing glucagon production which allows lower postprandial and fasting glucose levels.4

Hare et al studied ten patients with type-2 diabetes with mean HbA1c of about 7% and ten healthy subjects by giving stepwise increasing GLP-1 infusions on day one or saline on day two with plasma glucose levels clamped at fasting level. On day three, plasma glucose levels were normalized overnight using a variable insulin infusion. Then this was followed by a three hour GLP-1 infusion. The healthy subjects were given the same protocols for days one and two. In both the patient and control groups, a similar dose dependent stepwise suppression of glucagon was observed. In patients with type-2 diabetes, glucagon AUC was significantly reduced on days one and three when compared to day two (1096 ± 109 (day 1) and 1116 ± 108 (day 3) 3h · pmol/liter vs. 1733 ± 193 (day 2) 3h · pmol/liter; P < 0.01). In the healthy subjects control group, a similar reduction in AUC for glucagon was observed (1122 ± 186 (day 1) vs. 1733 ± 312 3h · pmol/liter (day 2); P< 0.001)5. GLP-1 has very significant glucagon suppressive effects at normal plasma glucose levels and at elevated plasma glucose levels.

Dupre’ et al also studied the effects of GLP-1 on glucagon suppression by administering exenatide to patients with type-1 diabetes. Nine type-1 diabetics with little to no endogenous insulin production were administered exenatide 15 minutes before breakfast, along with usual insulin, and acetaminophen was taken with the meal as an indicator of gastric emptying. The study found plasma glucose was reduced 90% after the meal and reached normal levels when compared to healthy volunteers. While insulin levels were not affected, plasma pancreatic peptide, glucagon, and acetaminophen levels were all reduced. GLP-1 receptor agonists still suppress alpha-cell function even if beta-cell function is already impaired and can bring glucagon levels down to normal levels seen in healthy individuals6.

As evidenced above, GLP-1 analogs are a great option for type-2 diabetics to help control postprandial and fasting plasma glucose levels not only through sensitizing beta-cells to plasma glucose and its effects on satiety and gastric emptying but also suppressing glucagon production to decrease hepatic glucose production.


  1. Powers AC, DAlessio D. Chapter 43. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Chabner BA, Brunton LL, Knollman BC, eds.Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. Accessed August 21, 2012.
  2. Nolte Kennedy MS. Chapter 41. Pancreatic Hormones & Antidiabetic Drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. Accessed August 21, 2012.
  3. 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.
  4. Hansen, Morten, Kristine Hare, Jens Holst, and Filip Knop. “Inhibition of Glucagon Secretion by GLP-1 Agonists and DPP4 Inhibitors.” JCMD 2 (2011): 7-13.
  5. Hare, KJ, FK Knop, M Asmar, et al. “Preserved Inhibitory Potency of GLP-1 on Glucagon Secretion in Type 2 Diabetes Mellitus.” The Journal of Clinical Endocrinology & Metabolism 94.12 (2009): 4679-4687.
  6. Dupre´ J, Behme MT, McDonald TJ. Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab. 2004;89:3469_3473.

Copyright © 2012 Diabetes In Control, Inc.