Practice Essentials
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). Most patients are middle-aged and may appear wasted and ill. [1, 2, 3, 4, 5, 6, 7, 8, 9]
The glucagon levels usually are in excess of 500 pg/mL (normal levels are < 60 pg/mL).
Hyperglucagonemia is caused by a tumor of the alpha cells of the pancreatic islets, most commonly located at the body or tail of the pancreas or, in rare cases, at the head of the pancreas. [10, 11] It can occur as part of the multiple endocrine neoplasia (MEN) type 1 syndrome. [12, 13] The tumor usually grows slowly and has an indolent course.
Additional causes of hyperglucagonemia include diabetes mellitus and acute diabetic complications, pancreatitis, trauma, burns, infection and sepsis, myocardial infarction, increased cortisol levels, increased catecholamine or growth hormone levels, renal failure, and hepatic cirrhosis. [14, 6, 7, 9]
The most common clinical features of glucagonoma syndrome are weight loss, necrolytic migratory erythema (NME), and diabetes. [15, 16, 17, 18, 19, 20, 1] The diabetes mellitus associated with glucagonoma syndrome tends to be mild and usually can be controlled with diet and/or oral hypoglycemic agents. Typically, the associated anemia is normochromic normocytic, although macrocytic anemia has been described in some patients. Venous thrombosis is thought to occur in as many as 30% of patients with glucagonoma syndrome.
Diagnosis is aided by the typical skin appearance of patients with NME and by the evaluation of a skin biopsy.
Glucagon should be tested by RIA of a fasting plasma sample. Hormones that may be elevated in glucagonoma syndrome include insulin, VIP, gastrin, pancreatic polypeptide, 5-HT, calcitonin, adrenocorticotropic hormone, and adrenocorticotropic hormone (ACTH). In glucagonoma syndrome, glucagon levels are well in excess of 500 pg/mL and are reported to increase even further with the administration of intravenous tolbutamide.
Transabdominal ultrasonography is noninvasive and may be the initial imaging modality of choice for the detection of pancreatic tumors, but it has limitations in obese patients and after surgery of the upper abdomen (when air may be present in the peritoneal cavity and obscure accurate imaging). Computed tomography (CT) scanning of the abdomen has a sensitivity and specificity similar to that of transabdominal ultrasonography and can be used in obese persons. CT scanning can reliably detect small tumors and is useful for tumor staging.31 Magnetic resonance imaging (MRI) of the abdomen may be superior to transabdominal ultrasonography and CT scanning. MRI is most helpful in pancreatic evaluation after surgery and in pancreatic tumor staging.
Surgery is the treatment of choice for glucagonoma syndrome. Surgical treatment includes the following:
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Cytoreduction or debulking of large and nonresectable metastatic tumors
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Hepatic artery embolization
Medical treatment of glucagonoma syndrome includes therapy for NME, treatment of diabetes, treatment of hyperglucagonemia, and treatment of islet cell tumor. Improvements have been noted with tumor resection and normalization of the glucagon levels, as well as with amino acid therapy and zinc supplementation. [21, 22] NME has been documented to respond to surgical resection of the glucagonoma, to therapy with octreotide, and to chemotherapy, all of which lead to reduction in glucagon levels. [15, 16, 18, 19, 20, 1, 21, 22, 24] The control of diabetes in glucagonoma syndrome usually can be achieved with diet, oral hypoglycemic agents, or, in some cases, insulin. Octreotide is the therapeutic agent of choice for hyperglucagonemia. The most commonly used treatment for islet cell tumor is combination chemotherapy with streptozocin and 5-fluorouracil, which is reported to cause tumor shrinkage in as many as 10% of patients.
Complications include deep venous thrombosis, hypercalcemia when glucagonoma syndrome occurs as part of MEN type 1 syndrome, [12, 13] adverse effects of therapy (eg, gallstone formation from octreotide), and complications of diabetes mellitus.
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). [25] In the pancreatic α-cells, glucagon is stored as amyloidlike fibrils. [26] In the intestinal wall's Langerhans cells, proglucagon undergoes post-translational processing to create the following products:
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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
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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 [27]
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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. [28]
The secretion of glucagon is increased by hypoglycemia, increased sympathetic activity, catecholamines, and alanine. It is inhibited or decreased by hyperglycemia, insulin, and somatostatin. [29, 30]
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. [31] To this end, glucagon analogues have been synthesized and are life-saving medications used in the treatment of hypoglycemia. [32, 33]
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. [34, 35] 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. [36] 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. [37]
Epidemiology
The frequency of glucagonoma syndrome is 1 case out of 20,000,000 population. The international frequency is 1 case out of 20,000,000 population. For persons with glucagonoma syndrome, the median age at presentation is 55 years. Mortality related to glucagonoma syndrome most commonly is due to the complication of deep venous thrombosis.
Glucagonomas are slow-growing tumors with an indolent course. Approximately 50-60% of the tumors are malignant and have, by the time of diagnosis, metastasized to the liver. Even with liver metastases, some patients live over 20 years without therapy. [38] Metastasis to the liver, complications of deep venous thrombosis, and the catabolic effects of the tumor are the usual causes of death and shortened survival.
