AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 et al 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 similar symptoms. 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 et al suggested that these findings constituted glucagonoma syndrome.

Pathophysiology

Glucagon is a 29–amino acid polypeptide with a molecular weight of 3500 daltons that is produced by the alpha cells of the pancreatic islets. Produced as proglucagon, it then undergoes posttranslational processing to create glucagon and the major proglucagon fragment (MPGF). Posttranslational processing of proglucagon in the intestinal wall Langerhans cells creates the following:

• 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



• 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 the 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.

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

Glucagon mediates catabolism, and, along with the catecholamines (epinephrine, norepinephrine), cortisol, and growth hormone, it plays a key role in glucose counter-regulation in response to hypoglycemia. Indeed, the hyperglycemic actions of the other counter-regulatory hormones are mediated through increased production of glucagon.

Isolated deficiency of glucagon may cause hypoglycemia and impair response to both 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 physiological 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 to plasma glucose also is inhibited.

Glucagon promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Insulin and glucagon plasma levels vary in a reciprocal manner in healthy individuals. A small increase in glucagon level stimulates insulin secretion independent of hyperglycemia, and a relatively small increase in insulin level suppresses the secretion of glucagon.

Insulin inhibits glucagon release directly by binding to the insulin receptor on the alpha cell and having a suppressive effect on the function of the alpha cell. Glucagon, on the other hand, stimulates insulin secretion directly by binding to its receptor on the beta cell and indirectly through induction of hyperglycemia by glycogenolysis, gluconeogenesis, and by decreasing nonessential peripheral utilization of glucose.

In general, despite high glucagon levels associated with type 2 diabetes, diabetic ketoacidosis usually does not occur. Perhaps this is because the circulating insulin concentration, though not sufficient to suppress the hepatic glucose-producing effects of glucagon, is sufficient to inhibit lipolysis and ketogenesis. Both 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, and therefore is 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 and, therefore, causes 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.

Frequency

United States

Frequency is 1 case out of 20,000,000 population.

International

International frequency is 1 case out of 20,000,000 population.

Mortality/Morbidity

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

Race

No definite race predilection exists.

Sex

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

Age

The median age at presentation is 55 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

This section will limit the discussion of hyperglucagonemia to the glucagonoma syndrome. This syndrome is rare. It is caused by a tumor of the alpha cells of the pancreatic islets, most commonly located at the body or tail of the pancreas and rarely at the head of the pancreas. It can occur as part of the multiple endocrine neoplasia (MEN) I syndrome.

The tumor usually grows slowly and has an indolent course. An estimated 50-60% of these tumors are malignant. At diagnosis, the average size of the tumor is 5 cm or more, and 50% of the tumors are metastatic, usually to the liver. Less common sites of metastases include the lymph nodes, bone, kidney, adrenal gland, and lung. The median age at presentation is 55 years, with equal incidence in men and women. The benign glucagonomas usually are small and asymptomatic.

The most common clinical features of glucagonoma syndrome are weight loss, NME, and diabetes. The presence of diabetes and NME usually heightens the index of suspicion for the syndrome and leads to an early diagnosis. Glucagonomas can be diagnosed with reasonable accuracy on clinical criteria alone.

A brief discussion of the more common clinical features follows.

• Weight loss: This is one of the most prominent and common features of the glucagonoma syndrome. It is due to the accelerated rates of protein and fat turnover from the catabolic effects of glucagon. The nonspecific symptoms of nausea, anorexia, and general ill health could very well lead to poor food intake and contribute to weight loss. Although diarrhea may occur in some patients, malabsorption is rare.
• Necrolytic migratory erythema
• • NME typically is described as a superficial erythema with a moving edge associated with the formation of bullae, which sequentially rupture, form a crust, and then heal in areas with hyperpigmentation. This sequence recurs over 7-14 days, with a waxing and waning pattern, and tends to involve the buttocks, perineum, groin, and lower extremities. Extensive skin involvement can occur and may be complicated by secondary bacterial or fungal infection. All mucous membranes are involved, causing cheilosis, angular stomatitis, glossitis, and inflammation of the buccal mucosa. On histologic examination, NME tends to resemble toxic epidermal necrolysis.

  • The typical skin appearance and obtaining a skin biopsy help in diagnosis. However, several biopsies may be needed in order to visualize the characteristic diagnostic histologic changes. NME usually follows the diabetes in manifestation. The cause of NME is not clear, but postulated causes include the direct effect of glucagon, amino acid deficiency, fatty acid deficiency, and zinc deficiency. Indeed, the cause may be multifactorial.

  • Improvements have been noted with tumor resection and normalization of the glucagon levels, amino acid therapy, and zinc supplementation.

• Diabetes mellitus
• • The diabetes associated with glucagonoma syndrome tends to be mild and usually can be controlled with diet and/or oral hypoglycemic agents. Some patients may require insulin for optimal glycemic control. Hyperglycemia is due to the glycogenolytic and gluconeogenic actions of glucagon occurring in the context of an altered insulin-to-glucagon ratio and tends to correlate poorly with the plasma glucagon levels. Insulin resistance is not a feature of diabetes in glucagonoma syndrome.

  • Unless a preexisting state of insulin resistance exists, the diabetes resolves with surgical removal of the tumor or treatment with octreotide.

  • No evidence exists of an increased tendency to develop diabetic ketoacidosis or any of the long-term complications of diabetes.

• Anemia: The anemia in glucagonoma syndrome usually is mild. However, a correlation exists between the severity of the hyperglucagonemia and the extent of the anemia. Typically, the anemia is normochromic normocytic, although macrocytic anemia has been described in some patients. The cause is not certain but is thought to be due to the catabolic action of glucagon on the bone marrow, perhaps coupled with the chronic disease state. Bone marrow biopsy results are normal, with normal iron stores.
• Venous thrombosis: This is thought to occur in as many as 30% of patients with glucagonoma syndrome. It most commonly affects deep veins, such as the iliac veins and the splenic vein, and may affect the pulmonary artery. Venous thrombosis has a high mortality rate. Test results of coagulation function usually are normal, and the cause is not clear. Venous thrombosis tends to be a common problem with other types of pancreatic islet cell tumors, as well.
• Neuropsychiatric manifestations: Depression, dementia, insomnia, ataxia, proximal muscle weakness, and optic atrophy all have been described in patients with glucagonoma syndrome. Neuropsychiatric manifestations tend to respond to improvement in glucagon levels.
• Other symptoms
• • Nonspecific symptoms can include weakness, constipation, diarrhea, abdominal pain, and peptic ulcer disease.

  • Diarrhea may be due in part to other hormones, including gastrin, vasoactive intestinal peptide (VIP), 5-hydroxytryptamine (5-HT), or calcitonin, secreted from mixed cell populations within the tumor.

  • Peptic ulcer disease may occur from the effects of gastrin.

  • Features of hypercalcemia and/or anterior pituitary dysfunction may be present when glucagonoma syndrome is part of the MEN 1 syndrome.

  • Dystrophic nails are another dermatologic manifestation of glucagonoma syndrome.

Physical

Typical findings on examination of a patient with glucagonoma syndrome include the following:

• Most patients are middle-aged and may appear wasted and ill.
• The characteristic necrolytic migratory erythematous rash affecting the groin, perineum, and lower extremities could be generalized and associated with inflammation of the mucous membranes.
• The liver may be enlarged in cases of hepatic metastatic disease.
• When present, features of deep venous thrombosis or pulmonary embolism may be evident.

Causes

Glucagonoma syndrome occurs as a result of either a benign or malignant tumor of the alpha cells of the pancreatic islets. The glucagon levels usually are in excess of 500 pg/mL (normal levels are <60 pg/mL).

Other causes of hyperglucagonemia include pathophysiologic states in which loss of the normal restraining influence of insulin on the alpha cell function occurs. This occurs in circumstances of relative or absolute insulin deficiency. The glucagon levels in these situations usually are less than 500 pg/mL. Additional causes of hyperglucagonemia include the following:

• Diabetes mellitus and acute diabetic complications
• • These complications can include diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic state.

  • In type 2 diabetes with relative hyperinsulinemia, the cause of hyperglucagonemia is not clear, but suppression of glucagon secretion is impaired despite high insulin levels.

  • Persons who are obese and have type 2 diabetes are reported to have an exaggerated glucagon response both to a protein meal and to increased arginine levels. This exaggerated response is not corrected by restoration of normoglycemia or even by insulin infusion.

• Pancreatitis
• Trauma
• Burns: The mechanism of hyperglucagonemia in burns, as in any other stressful situation, is secondary to increased production of catecholamines.
• Infection and sepsis
• Myocardial infarction
• Increased cortisol (as in Cushing syndrome): Cortisol leads to hyperglucagonemia by increasing glucagon production. It also potentiates the actions of glucagon on the liver.
• Increased catecholamine or growth hormone levels
• Renal failure: Glucagon is metabolized and excreted in the liver and kidney.
• Hepatic cirrhosis: This is due to impaired metabolism and excretion of glucagon.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acrodermatitis enteropathica
Pellagra
Pemphigus
Pustular psoriasis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The diagnosis of glucagonoma syndrome depends on the presence of the clinical features of disease and elevated plasma glucagon levels. The NME, diabetes, and hyperglucagonemia may be present in as many as 70-90% of patients with glucagonoma syndrome. This should be confirmed by demonstration of a pancreatic islet cell tumor mass and by tissue biopsy or surgical specimen.
• The presence of a pancreatic islet cell tumor is necessary to exclude other nonspecific causes of hyperglucagonemia.
• Glucagonomas usually demonstrate immunoreactivity to antiglucagon antibody staining. Large tumors may be inefficient at glucagon production and, therefore, may produce negative results on glucagon immunostaining.
• Glucagon should be tested by RIA of a fasting plasma sample. The normal plasma glucagon level is less than 60 pg/mL. 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. Other causes of hyperglucagonemia usually result in glucagon levels in the range of 120-500 pg/mL.
• Hormones that may be elevated in glucagonoma syndrome include the following:
• • Insulin

  • VIP

  • Gastrin

  • Pancreatic polypeptide (PP): Fifty percent of the pancreatic islet cell tumors secrete PP, and the presence of elevated PP levels in association with other endocrine tumor syndromes indicates a pancreatic tumor source. PP on its own has no recognized physiologic activity.

  • 5-HT

  • Calcitonin

  • Adrenocorticotropic hormone (ACTH)

• Other nonspecific laboratory studies include the following:
• • CBC: The common finding is a normochromic normocytic anemia, but a macrocytic anemia may be present in some patients.

  • Serum or urine amino acid levels: These levels demonstrate hypoaminoacidemia. A general decrease of gluconeogenic and nongluconeogenic amino acids occurs, especially alanine and glutamine levels. The cause of the hypoaminoacidemia is thought to be the increased hepatic extraction of amino acids for gluconeogenesis and increased ureagenesis combined with decreased protein synthesis.

  • Fasting plasma glucose: This is used to diagnose diabetes mellitus.

  • Glycosylated hemoglobin (HbA1c): This assesses the level or degree of hyperglycemia in the preceding 2-3 months.

  • Comprehensive metabolic panel (CMP): Hypokalemia may occur in cases of protracted diarrhea. Hypercalcemia indicates the presence of hyperparathyroidism and, therefore, of MEN 1 syndrome.

  • Zinc levels: Zinc deficiency is postulated to be one of the causes of the NME that occurs in the glucagonoma syndrome.

Imaging Studies

• Transabdominal ultrasound is noninvasive and may be the initial imaging modality of choice in detection of pancreatic tumors. However, it has obvious limitations in obese patients and after surgery of the upper abdomen when air may be present in the peritoneal cavity and obscure accurate imaging.
• CT scan of the abdomen has a sensitivity and specificity similar to that of the transabdominal ultrasound and can be used in obese persons. This scan reliably can detect small tumors and is useful for tumor staging.
• MRI of the abdomen may be superior to both transabdominal ultrasound and CT scan. MRI is most helpful in pancreatic evaluation after surgery and for staging of pancreatic tumors.
• Selective angiography: The characteristic feature of islet cell tumors is their hypervascularity. Both primary and metastatic glucagonomas are reported to have a dense circumscribed homogeneous capillary blush appearance that persists into the parenchymal phase.
• Additional studies may be helpful.
• • Endoscopic retrograde cholangiopancreatography (ERCP) may help detect distortion of the pancreatic duct in pancreatic tumors, but it is more useful in diagnosis of ductal carcinomas.

  • Endoscopic ultrasonography is reported to provide a better-quality assessment of pancreatic configuration and to have the highest rate of detection of pancreatic tumors. It also can be combined with guided fine-needle aspiration biopsy for tissue diagnosis.

  • Transhepatic portal venous sampling is another option; however, it is highly invasive.

Procedures

• Fine-needle biopsy of a pancreatic tumor mass
• Biopsy of the skin lesions

Histologic Findings

NME is not specific to glucagonoma syndrome. It affects the upper one third of the epidermis, which shows necrolysis, mild lymphocytic infiltration around the blood vessels, and edema and pallor. It may appear as a nonspecific dermatitis in the early stages.

Glucagonomas are alpha cell tumors, which demonstrate neurosecretory granules on electron microscopy and have positive immunoreactivity to antiglucagon stains. Benign glucagonomas show more granules than malignant glucagonomas do. Some tumors, however, can have mixed cell types, and large tumors can have negative immunoreactivity to antiglucagon immunostains.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical treatment of glucagonoma syndrome includes the following:

• Therapy for the necrolytic migratory erythema
• • NME has been documented to respond to surgical resection of the glucagonoma or therapy with octreotide and chemotherapy, all of which lead to reduction in the levels of glucagon.

  • Amino acid supplementation and total parenteral nutrition, even in the presence of elevated glucagon levels, are shown to lead to dramatic improvement of NME.

  • NME is reported to respond to omega-3 triglyceride therapy.

  • Response of NME to zinc supplementation and to topical zinc has been described, but the role of zinc deficiency in the etiology of NME remains unclear.

  • Other agents used in the treatment of NME include tetracycline and hydrocortisone topical creams.

• Treatment for diabetes: The control of diabetes in glucagonoma syndrome usually can be achieved with diet, oral hypoglycemic agents, or, in some cases, insulin.

• Treatment for hyperglucagonemia
• • Octreotide is the therapeutic agent of choice used alone, in combination with chemotherapy, or in conjunction with hepatic artery embolization. This drug can be used preoperatively prior to surgical resection or debulking of large metastatic tumors.

  • Octreotide is a long-acting analogue of somatostatin with a half-life of 3 hours. The drug acts by blocking the secretion and the effects of glucagon and is particularly effective in the treatment of NME and diarrhea.

• Treatment of islet cell tumor
• • The most commonly used treatment modality is combination chemotherapy with streptozocin and 5-fluorouracil, which is reported to cause tumor shrinkage in as many as 10% of patients. Other chemotherapy agents used in combination include doxorubicin, dacarbazine, cisplatin, etoposide, lomustine, cyclophosphamide, and interferon. Occasionally, chemotherapy agents are used in combination with octreotide.

  • In rapidly progressive disease, a multimodality approach has been advocated, with use of surgery or hepatic artery embolization, octreotide, and chemotherapy.

Surgical Care

Surgery is the treatment of choice for glucagonoma syndrome. Surgical treatment includes the following:

• Resection of a localized tumor
• Cytoreduction or debulking of large and nonresectable metastatic tumors
• Hepatic artery embolization, either alone or in combination with somatostatin analogue (octreotide) or chemotherapy for unresectable hepatic metastases: Hepatic artery embolization works on the principle that most of the blood supply to the tumor is derived from the hepatic artery, whereas the blood supply to the healthy liver parenchyma comes from the portal vein. Embolization of the hepatic artery leads to tumor necrosis.
• Liver transplantation
• Preoperatively, patients may require the following:
• • Total parenteral nutrition with amino acid, fatty acid, and zinc supplementation

  • Blood transfusion - In cases of severe anemia

  • Proper treatment and control of diabetes

  • Heparin - For prophylaxis of deep venous thrombosis

  • Treatment with octreotide

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Somatostatin analogues

Inhibit secretion and action of glucagon.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Total parenteral nutrition with amino acid, fatty acid, and zinc supplementation
• Deep vein thrombosis prophylaxis

Further Outpatient Care

• Nutrition supplementation
• Management of diabetes
• Monitoring of recurrence with periodic fasting plasma glucagon levels

In/Out Patient Meds

• Octreotide

Deterrence/Prevention

• No known preventive measures exist.

Complications

• Deep venous thrombosis
• Hypercalcemia when glucagonoma syndrome occurs as part of MEN 1 syndrome
• Adverse effects of therapy, such as gallstone formation from octreotide
• Complications of diabetes mellitus

Prognosis

• Glucagonomas are slow-growing tumors with an indolent course.
• Approximately 50-60% of the tumors are malignant, with metastasis to the liver at the time of diagnosis.
• 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.

Patient Education

• Patient education should center around informing the patient of the nature of the disease and what to expect.
• Offer the patient dietary counseling to ensure adequate nutrition.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• No legal pitfalls are specific to the care of patients with the glucagonoma syndrome.
• Issues common to the care of all other patients apply in these cases as well.
• Exercise care and recognize the importance of explaining to the patient and family, as clearly as possible, the nature of the diagnosis, the available modes of investigation and therapy, and the possible side effects of therapy in order to obtain not only an informed consent but also compliance.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Aguilar-Parada E, Eisentraut AM, Unger RH. Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes. Nov 1969;18(11):717-23. [Medline].
• Almdal TP, Heindorff H, Bardram L. Increased amino acid clearance and urea synthesis in a patient with glucagonoma. Gut. Aug 1990;31(8):946-8. [Medline].
• Barnes AJ, Bloom SR. Pancreatectomised man: A model for diabetes without glucagon. Lancet. Jan 31 1976;1(7953):219-21. [Medline].
• Bloom SR, Polak JM. Glucagonoma syndrome. Am J Med. May 29 1987;82(5B):25-36. [Medline].
• Gerich JE, Lorenzi M, Bier DM. Prevention of human diabetic ketoacidosis by somatostatin. Evidence for an essential role of glucagon. N Engl J Med. May 8 1975;292(19):985-9. [Medline].
• Haga Y, Yanagi H, Urata J. Early detection of pancreatic glucagonoma. Am J Gastroenterol. Dec 1995;90(12):2216-23. [Medline].
• Mallinson CN, Bloom SR, Warin AP. A glucagonoma syndrome. Lancet. Jul 6 1974;2(7871):1-5. [Medline].
• McGavran MH, Unger RH, Recant L. A glucagon-secreting alpha-cell carcinoma of the pancreas. N Engl J Med. Jun 23 1966;274(25):1408-13. [Medline].
• Muller WA, Faloona GR, Aguilar-Parada E. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. Jul 16 1970;283(3):109-15. [Medline].
• Nurjhan N, Campbell PJ, Kennedy FP. Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes. Dec 1986;35(12):1326-31. [Medline].
• Raskin P, Unger RH. Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. N Engl J Med. Aug 31 1978;299(9):433-6. [Medline].
• Rossi P, Allison DJ, Bezzi M. Endocrine tumors of the pancreas [published erratum appears in Radiol Clin North Am 1989 May;27(3):following xii]. Radiol Clin North Am. Jan 1989;27(1):129-61. [Medline].
• Samols E, Marri G, Marks V. Promotion of insulin secretion by glucagon. Lancet. August;1965:415-416.
• Schade DS, Eaton RP. Dose response to insulin in man: differential effects on glucose and ketone body regulation. J Clin Endocrinol Metab. Jun 1977;44(6):1038-53. [Medline].
• Smith AP, Doolas A, Staren ED. Rapid resolution of necrolytic migratory erythema after glucagonoma resection. J Surg Oncol. Apr 1996;61(4):306-9. [Medline].
• Starke AA, Erhardt G, Berger M. Elevated pancreatic glucagon in obesity. Diabetes. Mar 1984;33(3):277-80. [Medline].
• Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (first two parts). N Engl J Med. Jun 18 1981;304(25):1518-24. [Medline].
• Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (second of two parts). N Engl J Med. Jun 25 1981;304(26):1575-80. [Medline].
• Vidnes J, Oyasaeter S. Glucagon deficiency causing severe neonatal hypoglycemia in a patient with normal insulin secretion. Pediatr Res. Sep 1977;11(9 Pt 1):943-9. [Medline].
• Wermers RA, Fatourechi V, Wynne AG. The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine (Baltimore). Mar 1996;75(2):53-63. [Medline].
• Wilmore DW, Lindsey CA, Moyland JA. Hyperglucagonaemia after burns. Lancet. Jan 19 1974;1(7847):73-5. [Medline].

Article Last Updated: Jun 20, 2006