How Important is Glucagon in the Pathophysiology of Diabetes?

Q: What is glucagon and how does it impact glucose metabolism?

A: Glucagon is a hormone, produced by the alpha cell of the pancreas, which increases blood glucose by stimulating hepatic glycogenolysis, gluconeogenesis, and inhibiting insulin-stimulated glycogen synthesis.^1,2 In contrast to individuals without diabetes, glucagon increases in response to oral glucose in patients with both type 1and type 2 diabetes.^3,4 Glucagon has negligible effects on muscle glucose disposal.^1,5

Glucagon also is important in the counterregulatory response to hypoglycemia by way of its potent stimulation of hepatic glucose production.^1,6
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Q: What affects glucagon secretion in type 2 diabetes and why is this important?

A: Oral glucose (carbohydrate) ingestion stimulates production of glucagon-like peptide-1 (GLP-1), a protein which increases insulin and inhibits glucagon secretion, delays gastric emptying, and directly stimulates hepatic glucose uptake.⁵ Deficiency of GLP-1, both in secretion and potency of effect⁷ is the major factor responsible for increased postprandial glucagon secretion, which contributes substantially to higher glucose levels in patients with type 2 diabetes.⁴ 

High intra-islet cell insulin normally suppresses basal glucagon secretion¹ but persons with low beta-cell function, and low intra-islet cell insulin, may have relative basal hyperglucagonemia. Insulin-induced hypoglycemia causes increased alpha cell glucagon production by way of direct sympathetic and parasympathetic autonomic stimulation and circulating epinephrine.¹ This protective feedback mechanism is largely related to neural mechanisms in the brain and can be inhibited by repeated hypoglycemia causing the syndrome of hypoglycemia-associated autonomic failure.^1,6 When intra-islet insulin is fully absent, such as in type 1 or advanced type 2 diabetes, there is a loss of the compensatory rise in glucagon secretion in response to hypoglycemia, thereby placing these individuals at much greater risk for serious hypoglycemia.

Q: How do newer diabetes medications affect glucagon in type 2 diabetes?

A: Several medications for diabetes now target the bioavailability of GLP-1, which lowers postprandial glucose levels. After dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, sitagliptin, alogliptin, linagliptin) block the enzyme that degrades endogenous GLP-1, local concentration is increased.⁸ Exogenous GLP-1 agonist analogs (eg, exenatide, liraglutide, albiglutide) provide an even greater, more sustained GLP-1 effect.

Q: What role does glucagon have in type 1 diabetes?

A: Oral glucose intake also increases glucagon in persons with type 1 diabetes,³ which causes postprandial hyperglycemia. However, these results are independent of GLP-1 as levels of this hormone remain unchanged. DPP-4 inhibitors and GLP-1 agonists are not currently approved for use in type 1 diabetics, but many studies are ongoing to assess their clinical applicability.

Glucagon secretion also contributes greatly to hyperglycemia, ketosis, and acidosis in the setting of diabetic ketoacidosis.¹

Q: How can glucagon therapy benefit patients with diabetes?  

A: Because of potent effects on glycogenolysis and gluconeogenesis, exogenous glucagon may be used by diabetes patients to rapidly treat hypoglycemia. Persons prone to hypoglycemia should carry an emergency glucagon rescue device at all times (Glucagon Emergency Rescue Kit or GlucaGen HypoKit). ■

Kim A. Carmichael, MD, FACP, is an associate professor of medicine, department of internal medicine, division of endocrinology, diabetes, and lipid research at Washington University School of Medicine in St. Louis, MO.

Dr Carmichael discloses that he is on the speaker’s bureaus for Merck and Janssen that may be relevant to the content of this manuscript.

References:

1. Taborsky GJ Jr. The physiology of glucagon. J Dibetes Sci Technol. 2010;(6):1338-1344.

2. Dineen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycemia in IDDM. Diabetologia. 1995;38(3):337-343.

3. Hare KJ, Vilsboll T, Holst JJ, Knop FK. Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab. 2010;298(4):E832-E837.

4.  Shah P, Vella A, Basu A, et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85(11):4053-4059.

5.  Edgerton DS, Cherrington AD. Glucagon as a critical factor in the pathology of diabetes. Diabetes. 2011;60(2):377-380.

6.  Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. NJEM. 2013;369(4):362-372.

7.  Knop FK, Vilsbol T, Hojberg PV, et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 207;56(8):1951-1959.

8.  Freeman JS.  Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus.  Cleve Clin J Med. 2009;76(Suppl 5):S12-S19.