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Diagnosis and follow-up of glucagonomas and other glucagon-producing tumors
Assessing diabetic patients with problematic hyper- or hypoglycemic episodes (extremely limited utility)
Glucagon is routinely measured along with serum glucose, insulin, and C-peptide levels, during the mixed-meal test employed in the diagnostic workup of suspected postprandial hypoglycemia. However, it plays only a minor role in the interpretation of this test.
Glucagon is a single-chain polypeptide of 29 amino acids that is derived from a larger precursor peptide (big plasma glucagon), which is cleaved upon secretion. The main sites of glucagon production are the hypothalamus and pancreatic alpha-islet cells. The function of hypothalamic glucagon is incompletely understood and currently no clinical disorders of hypothalamic glucagon function have been defined. Pancreatic islet glucagon is secreted in response to hypoglycemia, with resultant increases in blood glucose concentration. Glucagon's hyperglycemic effect is produced by stimulating hepatic glycogenolysis and gluconeogenesis; it has no effect on muscle glycogen. Once blood-glucose levels have normalized, glucagon secretion ceases.
Excessive glucagon secretion can lead to hyperglycemia or aggravate preexisting hyperglycemia. Excessive and inappropriate glucagon secretion can sometimes be observed in diabetes, in particular during ketoacidosis, and can complicate management of the disorder. In rare cases, it also can occur in tumors of the pancreatic islets (glucagonoma); carcinoid tumors and other neuroendocrine neoplasms and hepatocellular carcinomas. Patients with glucagon-secreting tumors may present with classic glucagonoma syndrome, consisting of necrolytic migratory erythema, diabetes, and diarrhea, but also can have more subtle symptoms and signs.
Decreased or absent glucagon response to hypoglycemia can be seen in type I diabetes (insulin-dependent diabetes) and can contribute to severe and prolonged hypoglycemic responses.
< or =6 hours: 100-650 pg/mL
1-2 days: 70-450 pg/mL
2-4 days: 100-650 pg/mL
4-14 days: declining gradually to adult levels
>14 days: < or =80 pg/mL (range based on 95% confidence limits)
Glucagon levels are inversely related to blood glucose levels at all ages. This is particularly pronounced at birth and shortly thereafter, until regular feeding patterns are established. This explains the higher levels immediately after birth, which then first fall as the glucagon release mobilizes the infant's glucose stores, then rise again as stores are depleted, finally normalizing towards adult levels as regular feeding patterns are established.
Elevated glucagon levels in the absence of hypoglycemia may indicate the presence of a glucagon-secreting tumor. Successful treatment of a glucagon-secreting tumor is associated with normalization of glucagon levels.
Inappropriate elevations in glucagon levels in hyperglycemic type I diabetic patients indicate that paradoxical glucagon release may contribute to disease severity. This can be observed if insulin treatment is inadequate and patients are ketotic. However, glucagon measurement plays little, if any, role in the diagnostic workup of diabetic ketoacidosis, which is based on demonstrating significantly elevated plasma or serum glucose (>250 mg/dL), circulating ketones (beta-hydroxy butyrate), and acidosis (typically with increased anion gap).
In diabetic patients, low glucagon levels (undetectable or in the lower quartile of the normal range) in the presence of hypoglycemia indicate impairment of hypoglycemic counter-regulation. These patients may be particularly prone to recurrent hypoglycemia. This can be a permanent problem due to islet alpha-cell destruction or other, less well understood processes (eg, autonomous neuropathy). It can also be functional, most often due to over tight blood-glucose control, and may be reversible after decreasing insulin doses.
Results obtained with different glucagon assays can differ substantially. This can be caused by use of different calibration standards. Different glucagon assays may also exhibit variable cross-reactivity with different isoforms of glucagon, not all of which are biologically active. Some assays, including this one, remove biologically inactive isoforms before measurement, while others do not. All these factors contribute to the differences between different assays. Serial measurements should, therefore, always be performed using the same assay.
Precise reference ranges for appropriate glucagon responses for given blood glucose ranges are not well established and vary widely from assay to assay. Expert advice should be sought when interpreting inappropriately low glucagon levels or when interpreting glucagon, insulin, and C-peptide levels obtained during mixed-meal testing.
Tumor marker tests, including glucagon, are not specific for malignancy. All immunometric assays can, on rare occasions, be subject to hooking at extremely high analyte concentrations (false-low results), heterophilic antibody interference (false-high results), or autoantibody interference (unpredictable effects). If the laboratory result does not fit the clinical picture, these possibilities should be considered.
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