Glucagon, Plasma

Overview:

For use (1) when considering a glucagon-secreting tumor of the pancreas, (2) in the diagnosis and management of diabetes mellitus and other carbohydrate metabolism disorders, and (3) in the diagnosis of glucagon deficiency in patients with hypoglycemia.

The Millipore glucagon RIA kit employed by LabCorp has been shown to exhibit a small cross-reactivity with oxyntomodulin and glicentin.1

Results of this test are labeled for research purposes only by the assay's manufacturer. The performance characteristics of this assay have not been established by the manufacturer. The result should not be used for treatment or for diagnostic purposes without confirmation of the diagnosis by another medically established diagnostic product or procedure. The performance characteristics were determined by LabCorp.

Glucagon is produced by the alpha cells of the islets of Langerhans of the pancreas in response to a decrease in plasma glucose concentrations and in response to increased concentrations of specific amino acids.2 The glucagon precursor protein undergoes tissue-specific post-translation processing.2 Glucagon secretion is controlled by a number of factors. In nondiabetic individuals, secretion is stimulated by protein-rich meals, but inhibited by carbohydrate-rich meals. Hypoglycemia activates the autonomic nervous system which stimulates glucagon release into the portal circulation.3-5 Glucagon release is also regulated in a paracine manner by insulin, zinc and other factors secreted from neighboring β- and δ-cells within the islet of Langerhans.5 In healthy individuals, glucagon released is inhibited by hyperglycemia, mixed nutrient meals, and oral intravenously administered amino acids.

Glucagon is a counter-regulatory hormone opposing the actions of insulin in glucose homoeostasis. The intravenous administration of glucagon raises blood glucose substantially in nondiabetic individuals.6 Glucagon is thought to play an important role in the maintenance of fasting and postprandial glucose homeostasis.6,7 By stimulating hepatic glucose output, glucagon counterbalances the action of insulin and serves to maintain circulating glucose and prevent insulin mediated hypoglycemia.2,5 Blockade of endogenous glucagon secretion with somatostatin causes glucose concentrations to decrease.6

A highly specific glucagon receptor is abundantly expressed on hepatocytes.6 Glucagon binding to this receptor leads to increased hepatic glucose production, fatty acid oxidation and ketogenesis.6,7 Glucagon stimulates glycogenolysis and gluconeogenesis, changing the liver from an organ of glucose release.2,3 Glucagon secretion inhibits gastric emptying, increases gastric output, increases bile flow and increases cardiac muscle contraction. Glucagon also has lipolytic effects.2

Insulin treatment of diabetic patients can cause acute hypoglycemia which is often exacerbated by a deficient glucagon response.3,4,6,8,9 The exact pathophysiologic mechanisms for this dysregulation is not fully defined but has been attributed, in part, to a lack of intra-islet insulin effect.5,10

Alternatively, some patients with controlled type 1 diabetes experience inappropriately elevated plasma glucagon levels in the context of hyperglycemia.6 Both type 1 and type 2 diabetes frequently exhibit an inappropriately high glucagon response to a meal.10 The high levels of glucagon have been shown to contribute importantly to diabetic hyperglycemia and can result in ketoacidosis.3-7,11 Relative hyperglucagonemia, in the setting of deficient insulin secretion may contribute to the development of fasting and postprandial hyperglycemia in the patients.6-8

Increased plasma glucagon levels have been demonstrated in many forms of physiological stress that are not typically associated with hypoglycemia.9 Hyperglucagonemia has been documented in patients with trauma, burns, surgery, sepsis, hemorrhage, acute myocardial infarction, cardiac arrest and neonatal hypoxia.9

A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of glucagon.12,13 Serum glucagon concentrations in excess of 500 pg/mL are strongly suggestive of glucagonoma.12 These tumors are associated with glucagonoma syndrome. The raised glucagon concentrations produce hyperglycemia, diabetes mellitus and glucose intolerance. Excessive glucagon action produces a catabolic state resulting in weight loss.2,14 Glucagonomas frequently present with a specific dermatitis referred to as necrolytic migratory erythema (NME).15 Patients with NME develop erythematous blisters and swelling in areas subject to greater friction and pressure, including the lower abdomen, buttocks, perineum, and groin.1,13 In addition, these patients are prone to deep venous thrombosis that may be a significant cause of death. Other common symptoms of glucagonoma include depression,diarrhea and anemia.2,12,14 Because the symptoms of early disease are nonspecific, patients often present at a later stage with extensive metastatic disease.2

1. Bak MJ, Albrechtsen NW, Pedersen J, et al. Specificity and sensitivity of commercially available assays for glucagon and oxyntomodulin measurement in humans. Eur J Endocrinol. 2014 Mar 8; 170(4):529-538. PubMed 24412928

2. Ardill JE. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Ann Clin Biochem. 2008 Nov; 45(Pt 6):539-559. PubMed 18941127

3. Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003 Apr; 284(4):E671-E678. PubMed 12626323

4. Taborsky GJ Jr, Mundinger TO. Minireview: The role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology. 2012 Mar; 153(3):1055-1062. PubMed 22315452

5. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. 2007 Feb; 28(1):84-116. PubMed 17261637

6. D'Alessio D. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes Metab. 2011 Oct; 13(Suppl 1):126-132. PubMed 21824266

7. Cryer PE. Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012 Mar; 153(3):1039-1048. PubMed 22166985

8. Holst JJ, Christensen M, Lund A, et al. Regulation of glucagon secretion by incretins. Diabetes Obes Metab. 2011 Oct; 13(Suppl 1):89-94. PubMed 21824261

9. Jones BJ, Tan T, Bloom SR. Minireview: Glucagon in stress and energy homeostasis. Endocrinology. 2012 Mar; 153(3):1049-1054. PubMed 22294753

10. Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care. 2008 Jul; 31(7):1403-1404. PubMed 18594062

11. Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000 Nov; 85(11):4053-4059. PubMed 11095432

12. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec; 26(6):737-753. PubMed 23582916