Glucagon

Glucagon consists of 29 amino acids in a single-chain polypeptide with a molecular weight of 3485. It is produced by the alpha cells of the exocrine part of the pancreas and is removed by the liver and kidneys. Because glucagon has a half-life of just 3-6 minutes, collection of serum glucagon needs to occur in a chilled collecting tube with the immediate addition of a proteolytic enzyme inhibitor.

The reference ranges for glucagon can be found in the table below. ^[1]

Table 1. Glucagon Reference Ranges

Table. (Open Table in a new window)

Additional information on glucagon and glucose levels is as follows:

• For basic reference, the interval for glucagon is 50-100 pg/mL or 50-100 ng/L (SI units) ^[2]
• Blood glucose levels are measured in mg/dL
• Hypoglycemia is considered when the glucose value is less than 70 mg/dL
• The normal glucose range is 80-100 mg/dL
• The glucose range for prediabetes is 100-125 mg/dL

Glucagon works along with insulin to balance glucose distribution in the serum for transport to body tissues. The serum level of glucose is the driving force through which these two hormones are either being activated or inhibited. Insulin stimulates glucose and amino acid uptake from the blood to tissues for functional use. During a meal, glucose levels initially rise due to intake; in normal, healthy subjects, insulin’s job is to bring the levels back down to normal limits. The result of a lack of this hormone is especially seen in persons with diabetes after a meal in which glucose values elevate extremely high, unless endogenous insulin can inhibit glucagon’s effect for producing more glucose through the process of glycogenolysis. ^{[3, 4]}

Normal levels of fasting glucose (80-100 mg/dL) mean that a balance exists and that both insulin and glucagon are adequately produced.

Pancreatic glucagon employs gluconeogenesis and glycogenolysis to regulate plasma glucose levels. Excess glucagon levels contribute to the development of hyperglycemia in type 1 and type 2 diabetes. In cases of hypoglycemia, however, increased glucagon secretion is the primary counterregulatory mechanism through which normal levels of plasma glucose are restored. Patients who have had type 1 diabetes for 1-5 years suffer impairment of the glucagon response, with this response becoming almost undetectable in those who have had the disease for 14-31 years. A syndrome of hypoglycemic autonomic failure can result when diabetes control intensifies and repeated episodes of hypoglycemia occur. ^[5]  In a state of hypoglycemia (blood glucose less than 70 mg/dL), a patient will experience autonomic dysfunction (shaking, palpitations, sweating, nervousness) and central nervous system dysfunction (confusion, unresponsiveness, seizures). Persistent hypoglycemia can be associated with an insulinoma, overmedication of insulin or oral hypoglycemia drugs, or prolonged fasting.

Glucagonomas

A glucagonoma is a glucagon-secreting tumor associated with mild diabetes, stomatitis, anemia, malnutrition, hypoproteinemia, and characteristic dermatitis (necrolytic migratory erythema). The diagnosis is confirmed via the presence of a fasting glucagon level elevated to over 150 pg/mL, hyperglycemia, and hypoproteinemia. The tumors are usually solitary and located in the tail of the pancreas. At the time of diagnosis, up to 70% of these tumors have a metastatic presentation; surgery offers the only potential cure. ^{[1, 6, 7, 8]}

Multiple endocrine neoplasia type 1 includes glucagonoma as a component. The tumors of this syndrome occur in the parathyroid glands, the pancreas, and the anterior pituitary gland. ^[9]

Requirements for collection and transport include the following:

• Collect in lavender (ethylenediamine tetraacetic acid [EDTA]) or pink (dipotassium EDTA [K2EDTA]) plus aprotinin tube; collect in chilled container ^[10]

• Condition - Overnight fasting ^[10]

• Storage/transport temperature - Critical frozen; when multiple tests have been ordered, separate specimens must be submitted ^[10]

• Unacceptable conditions - Specimens transported in glass tubes; specimens must not be grossly hemolyzed ^[10]

• 3 mL of specimen; 1.1 mL minimum ^[11]

Stability (collection to initiation of testing; after separation from cells) is as follows:

• Ambient - Unacceptable

• Refrigerated - Unacceptable

• Frozen - 3 months ^[10]

Glucagon promotes energy storage in different types of tissues in response to feeding. The liver represents the major target organ for glucagon. The result of this can be seen in Table 2. Glucagon signaling occurs by way of glucagon receptors located on the surface of hepatocytes. Binding of glucagon and its receptor activates adenylyl cyclase and results in the generation of cyclic adenosine monophosphate (cAMP). Release of available energy stores from the liver—in the form of glucose (gluconeogenesis) and ketones (ketogenesis)—occurs via the glucagon signaling pathway. ^[1]

In cardiac tissue, glucagon has a potent inotropic and chronotropic effect mediated by cAMP. In the small intestine, glucagon has been known to relax smooth muscle in large amounts. ^[12]

A study by Edgerton et al indicated that glucagon has an impact on the brain resulting in a slight reduction in net hepatic gluconeogenic flux. This effect was determined by increasing brain glucagon via infusion of the hormone into the vertebral and carotid arteries or into a peripheral leg vein. According to the investigators, however, autoregulation in the liver led to a rise in net hepatic glycogenolysis and thus no net change in the liver’s glucose production. The study also reported that brain glucagon suppressed plasma free fatty acid and glycerol levels, apparently through a decrease in lipolysis. ^[13]

Different amino acids have different effects on glucagon. Arginine promotes the release of both glucagon and insulin. Alanine mainly stimulates glucagon release. Leucine stimulates the release of insulin but not glucagon. Other substances like catecholamines, gastrointestinal hormones, gastrin, gastric inhibitory polypeptide, and glucocorticoids stimulate glucagon release. Glucagon secretion is suppressed by high fatty acid levels. ^[1]

The most important clinical use of glucagon is as a drug that, in its recombinant form, is employed to treat severe hypoglycemic reactions in diabetic patients. A glucagon pen, or GlucaPen, contains 1 mg of the recombinant hormone that should be injected intramuscularly when oral feedings are not possible or patients are completely unresponsive. Glucagon is also sometimes useful for reversing the cardiac effects of a beta-blocker overdose. ^[12]

In 2019, nasal glucagon powder received approval from the US Food and Drug Administration (FDA) for adults and children (aged 4 years or older) with diabetes who need emergency treatment for severe hypoglycemia. It was the first such treatment that requires no injection. ^[14]

Table 2: Metabolic Actions of Insulin and Glucagon  ^[3]

Table. (Open Table in a new window)