Hyperglucagonemia 

  • Author: George T Griffing, MD; Chief Editor: George T Griffing, MD   more...
 
Updated: Jul 13, 2011
 

Background

Hyperglucagonemia is a state of excess glucagon secretion. In healthy individuals, insulin has a suppressive effect on alpha-cell function and on glucagon secretion. The most common cause of hyperglucagonemia is an absence or deficiency of the restraining influence of insulin on glucagon production. Although rare, hyperglucagonemia can be caused by an autonomous secretion of glucagon by a tumor of pancreatic alpha cells (glucagonoma syndrome).

In 1942, Becker and colleagues described the first case report of what, in retrospect, appears to have been a classic presentation of glucagonoma syndrome. The patient presented with diabetes mellitus, weight loss, severe depression, and an unusual erythematous migratory skin rash associated with a malignant tumor of the pancreas of an unknown cell type. The patient later died, following an acute thrombosis of the left iliac vein.

In 1965, glucagon was positively identified by radioimmunoassay (RIA) in the tumor and plasma of a patient who presented with symptoms similar to those of the patient from 1942. The patient also had a tumor of the pancreas, with metastasis to the liver. In 1974, in a review of a series of 9 patients who had necrolytic migratory erythema (NME), normochromic normocytic anemia, and diabetes mellitus, with markedly elevated glucagon levels (among other features), Mallinson and colleagues suggested that these findings constituted glucagonoma syndrome.[1, 2, 3, 4, 5, 6, 7, 8]

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Pathophysiology

Glucagon is a 29–amino acid polypeptide with a molecular weight of 3500 daltons; it is manufactured by the alpha cells of the pancreatic islets. Produced as proglucagon, it undergoes posttranslational processing that turns it into glucagon and the major proglucagon fragment (MPGF).[9] In the pancreatic α-cells, glucagon is stored as amyloidlike fibrils.[10] In the intestinal wall's Langerhans cells, proglucagon undergoes post-translational processing to create the following products:

  • Glicentin - A 69-amino acid polypeptide that contains the amino acid sequence of glucagon but does not bind to glucagon receptors or have any of the actions of glucagon
  • Oxyntomodulin – Stimulates gastric acid production and acts via the glucagonlike peptide I receptors in the arcuate nucleus to induce satiety; the administration of oxyntomodulin to animals and humans causes weight loss by reducing food intake in combination with increasing energy expenditure[11]
  • Glucagonlike peptide (GLP) I and II - GLP I (also known as incretin) is a potent stimulator of insulin secretion. It is thought to play an important role in early, anticipatory insulin secretion during a meal, before the increase in arterial blood glucose causes glucose-stimulated insulin secretion (GSIS), which usually occurs about 15 minutes from the start of a meal.[12]

The secretion of glucagon is increased by hypoglycemia, increased sympathetic activity, catecholamines, and alanine. It is inhibited or decreased by hyperglycemia, insulin, and somatostatin.[13, 14]

Glucagon mediates catabolism, and along with cortisol, growth hormone, and the catecholamines (epinephrine, norepinephrine), it plays a key role in glucose counterregulation in response to hypoglycemia. Indeed, the hyperglycemic actions of the other counterregulatory hormones are mediated through the increased production of glucagon.[15] To this end, glucagon analogues have been synthesized and are life-saving medications used in the treatment of hypoglycemia.[16, 17]

Isolated deficiency of glucagon may cause hypoglycemia and impair response to spontaneous and induced hypoglycemia. Hypoglycemia is a powerful stimulator of glucagon secretion. Glucagon secretion increases when blood glucose concentration falls below 50-60 mg/dL and decreases to a nadir at a blood glucose concentration of about 150 mg/dL, usually within 45-90 minutes following a meal. However, hyperglycemia does not suppress glucagon production without the accompanying physiologic increase in insulin secretion.

Insulin and glucagon are the 2 main hormones involved in fuel metabolism. Insulin primarily is anabolic in its actions and is involved in glycogen and protein synthesis, incorporating triglycerides into adipose tissue, increasing glucose uptake and utilization in insulin-sensitive tissues, and promoting glycolysis. Insulin inhibits gluconeogenesis, ketogenesis, and lipolysis. Conversion of the glycerol released from lipolysis into plasma glucose also is inhibited.

Glucagon promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Glucagon agonism has also been shown to exert effects on lipid metabolism, energy balance, and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity.[18, 19] Insulin and glucagon plasma levels vary in a reciprocal manner in healthy individuals. A small increase in the glucagon level stimulates insulin secretion independent of hyperglycemia, and a relatively small increase in the insulin level suppresses the secretion of glucagon.

Insulin directly inhibits glucagon release by binding to the insulin receptor on an alpha cell and having a suppressive effect on the cell's function. Glucagon, on the other hand, not only stimulates insulin secretion directly, by binding to its receptor on the beta cell, but also stimulates secretion indirectly, through induction of hyperglycemia by glycogenolysis, by gluconeogenesis, and by decreasing nonessential peripheral utilization of glucose.

Despite the high glucagon levels associated with type 2 diabetes, diabetic ketoacidosis usually does not occur. Perhaps this is because the circulating insulin concentration, although not sufficient to suppress the hepatic glucose–producing effects of glucagon, is sufficient to inhibit lipolysis and ketogenesis. Hepatic glucose production and lipolysis are known to be more sensitive to insulin than the stimulation of peripheral glucose utilization. However, less insulin is required to suppress lipolysis than to suppress hepatic glucose production.

The role of glucagon in the development of diabetic ketoacidosis is through suppression of malonyl coenzyme A (CoA) levels. Malonyl CoA is an inhibitor of carnitine palmityltransferase (CPT-I), an enzyme that catalyses the rate-limiting step in the transfer of fatty acids across the mitochondrial membrane for beta oxidation; malonyl CoA is therefore an inhibitor of ketogenesis.

CPT-I transesterifies fatty acyl CoA to fatty acyl carnitine, allowing it to cross the mitochondrial membrane and undergo beta oxidation. By decreasing malonyl CoA levels, glucagon indirectly disinhibits CPT-I, causing ketosis. In the absence of glucagon, ketone production is minimal. However, diabetic ketoacidosis does not occur, as a rule, in glucagonoma syndrome, perhaps because the available insulin is sufficient to suppress lipolysis and ketogenesis.

A syndrome of marked hyperglucagonemia and pancreatic α-cell hyperplasia without a tumor has been described. Genetic studies shown the glucagon gene to be normal, but the glucagon receptor sequence showed a homozygous missense mutation (P86S) in the extracellular domain.[20]

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Epidemiology

Frequency

United States

The frequency of glucagonoma syndrome is 1 case out of 20,000,000 population.

International

The international frequency is 1 case out of 20,000,000 population.

Mortality/Morbidity

Mortality related to glucagonoma syndrome most commonly is due to the complication of deep venous thrombosis.

Race

No definite race predilection exists for glucagonoma syndrome.

Sex

No significant differences exist in the incidence of glucagonoma syndrome between the sexes. Earlier reports seemed to favor a female preponderance, but this has not been borne out in subsequent reports.

Age

For persons with glucagonoma syndrome, the median age at presentation is 55 years.

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Contributor Information and Disclosures
Author

George T Griffing, MD  Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Coauthor(s)

Sylvester Odeke, MD, FACE  Clinical Assistant Professor of Medicine, Division of Endocrinology and Metabolism, The Brody School of Medicine at East Carolina University

Sylvester Odeke, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, and North Carolina Medical Society

Disclosure: Nothing to disclose.

Steven B Nagelberg, MD  Clinical Professor, Department of Medicine, Division of Endocrinology and Metabolism, Drexel University College of Medicine

Steven B Nagelberg, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Medical Association, Endocrine Society, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Frederick H Ziel, MD  Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Yoram Shenker, MD  Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison

Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society

Disclosure: Nothing to disclose.

Mark Cooper, MBBS, PhD, FRACP  Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD  Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgments

This chapter is dedicated to the memory of the late James C. Melby, MD.

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