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Keresés:

Insulinoma (Linda Shell, DVM, DACVIM, Mark Rishniw, BVSc, DACVIM)

Contributors:
Mark Rishniw, BVSc, DACVIM (Small Animal Internal Medicine & Cardiology)
Linda Shell, DVM, DACVIM (Neurology)

Synonyms:
Insulin-secreting tumor
Beta-cell tumor

Disease description:
Insulinomas are tumors of the pancreatic beta cells that secrete excessive amounts of insulin leading to clinical signs of hypoglycaemia. They are considered rare in dogs and very rare in cats. 1-18 Secretion of insulin is typically episodic resulting in episodic clinical signs.

PATHOGENESIS
Insulin is a peptide secreted by beta cells in response to increased extracellular glucose. Glucose enters the beta-cell through the glucose transporter (insulin-independent), and is oxidized by glucokinase. This increases ATP, which closes the ATP-dependent K+ channel, leading to beta cell depolarization. The depolarization opens Ca2+ channels, resulting in an increase in intracelluar Ca2+, which results in exocytosis of “docked” insulin granules. Simultaneously, the increased Ca2+ triggers a series of responses that include increased production of insulin (translation), recruitment of “undocked” secretory granules, and increased insulin-associated gene activation.

Insulin is synthesized as preproinsulin, which is then directed to the endoplasmic reticulum, where the ER signal is cleaved to form proinsulin. Proinsulin is then packaged into secretory granules, where C-peptide is cleaved to produce insulin.

With insulinomas, the regulation of insulin production and secretion is independent of glucose concentration. The mechanism by which this occurs is unknown; in humans some cases of insulinoma are associated with multiple endocrine neoplasia type 1 (MEN1) and mutations in MEN1 gene (menin), which is a tumor suppressor. However, most cases have normal MEN1 expression. In one study, beta-cell lines that were transformed into “insulinoma” cells became hypersensitive to extracellular glucose and upregulated hexokinase activity and production.19 However, there is no evidence that hexokinase activity is altered with spontaneous disease.

A recent study has found that insulinomas drive the transcription of a splice variant of preproinsulin, which increases the efficiency of protein translation, thereby allowing the high demand for insulin to be met. This compensatory mechanism was also evident in animal models of insulin resistance and obesity.20,21

The unregulated insulin secretion results in hypoglycemia, and activation of gluconeogenic pathways, including glucagon and catecholamine secretion. Insulin interferes with the release of glucose from hepatic stores and increases the uptake of glucose by insulin sensitive tissues, such as muscle. Excessive insulin levels also inhibits enzymes necessary for metabolizing muscle amino acids and glycerol from adipose tissue. These effects of insulin lower blood glucose levels decreasing the necessary energy source for central nervous system function.

DIAGNOSIS

    • Persistent hypoglycemia is a strong clue to the diagnosis of insulinoma, especially if hypoglycemia is documented during clinical signs of weakness, collapse, tremors, or seizure activity. If hypoglycemia is suspected but not documented initially, multiple samples for plasma glucose concentration should be obtained q 1-2 hours during a fasting period. When the lowest glucose concentration (usually 30-60 mg/dl) is detected, plasma from the same sampling time should be submitted for insulin assay (see below).
    • Simultaneous fasting glucose and insulin concentrations are highly suggestive of an insulinoma when the insulin level is above normal and the blood glucose is below 60 mg/dl. However, if the insulin level is well within normal range in face of hypoglycemia, an insulinoma is possible. One study indicated that dogs with higher serum insulin levels preoperatively had shorter survival times. 1
    • The amended insulin: glucose ratio (AIGR) may be helpful when the insulin concentration is within normal range but inappropriately high for the degree of hypoglycemia. 22
    • Fructosamine or glycosylated hemoglobin should be decreased with insulinomas because of persistent hypoglycemia.14,23
    • Imaging: An insulinoma is usually so small and solitary of nodule that it isn’t often visualized with abdominal ultrasonography. However ultrasound is recommended because it may find signs of gross metastatic disease that may preclude surgery. One recent study suggested that CT was more sensitive in the diagnosis of insulinoma than ultrasound or single-photon emission computed tomography (SPECT), however the sample size was small.24 Thoracic metastases have not been reported but are often suggested as a means of evaluation for metastasis of other neoplasias that might cause a paraneoplastic hypoglycemic effect.
    • Scintigraphic evaluation using pentetreotide (a radioactive somatostatin analog) can help localize insulinomas, because they often express somatostatin receptors.25,26
    • Intrasurgical visualization and gentle palpation of the pancreas is still considered the gold standard for diagnosing a pancreatic mass such as an insulinoma. Visualization of neoplastic tissue can be enhanced by intravenous injection of 1 % methylene blue (3 mg/kg IV mixed into 250 ml isotonic saline solution) administered over 30-40 minutes. Methylene blue is preferentially absorbed by the tumor tissue. Adverse effects could include pseudocyanosis, decreased PCV, Heinz bodies, and blistering of red blood cells. 27,28

PATHOLOGY

Insulinomas are almost always malignant i.e. carcinoma or adenocarcinoma; tumors judged benign (adenoma) on histopathology usually metastasize later. Over 50% have metastases at the time of diagnosis in contrast to insulinomas in humans where over 90% are benign. Common sites of metastasis include regional lymph nodes, liver, duodenum, mesentery, omentum, and spleen.The histopathological diagnosis often requires immunostaining for insulin. In some cases, multiple pancreatic polypeptides can be identified.29-31 Localization can be enhanced by intravenous methylene blue injection prior to histological evaluation.26,27 Some authors have looked at advanced histological imaging to differentiate benign and malignant tumors.32Although insulinomas generally arise from pancreatic beta cells, reports exist in humans of insulin secretion from glucagonomas (because these tumors often secrete more than one peptide).

Disease description in this species:

The clinical signs of insulinoma are associated with both hypoglycemia and consequent release of catecholamines. Distinguishing between these mechanisms is very difficult. Both result in behavioral changes, shaking, trembling, and muscle fasciculations. Other neurological complications can develop, including seizures, collapse or episodic weakness, insomnia, and other behavioral changes.12,1 In some cases there is a tendency to gain weight due to the anabolic effects of insulin. If the pancreatic tumor is located near the biliary tree or if the mass becomes large enough, or if it metastasizes, biliary obstruction can occur resulting in jaundice. 33

Tetraparesis, muscle atrophy, and appendicular hyporeflexia or areflexia can occur in insulinoma cases because of a peripheral polyneuropathy. Nerve biopsy findings include extensive axonal degeneration of the peripheral nerves and secondary demyelination. Clinical signs may respond to glucocorticoid administration.17,18,34

There is a single report of osseous metastasis of an insulinoma.35

Some authors have used a staging system for insulinomas. Those that are restricted to the pancreas (primary tumor) have a better outcome than those that have metastasized. 1

Etiology:
Insulinoma

Breed predilection:
Boxer
Fox terrier
German shepherd dog
Irish setter
Standard poodle

Age predilection:
Middle-aged
Old

Diagnostic procedures: Diagnostic results:
Computed tomography (CT) or MRI, exploratory of tissues affected Pancreatic mass
Serum chemistry Bilirubin increased, hyperbilirubinemia
Glycosolated hemoglobin decreased
Hypoglycemia
Insulin:glucose ratio on serum Amended insulin:glucose ratio >30
Ultrasonography of abdomen Abdominal mass internal
Insulin assay Hyperinsulinemia

Treatment/Management/Prevention:
SPECIFIC
The goals of treating insulinomas is to limit or reverse the hypoglycemia and remove the tumor.

1) Surgical partial pancreatectomy has been recommended in most cases. One study compared effectiveness of medical or surgical management, and concluded that surgery should be performed in all possible cases.3 A recent study of 28 cases showed a median survival time of 785 days in dogs undergoing partial pancreatectomy and 196 days for those who received only medical treatment. 44 One study suggested that surgery did not affect outcome and those authors suggested surgery should be reserved for younger patients. 37

  • Hypoglycemia is controlled during surgery with dextrose 5% administered in an IV drip.
  • Postoperative pancreatitis can occur and may be fatal.
  • Persistent hypoglycemia is a poor prognostic finding post-op; this indicates functional remaining malignant tissue, and medical treatment is indicated.2) Medical management could be directed at chemotherapeutic destruction of the pancreas, a reduction in insulin secretion and/or antagonism of the hypoglycemia.
  • Prednisolone has gluconeogenic properties, and is a common adjunct therapy for insulinoma.
  • Diazoxide: 5 mg/kg PO q12h; increase to a maximum of 30 mg/kg PO q12h to control clinical signs. This is a benzthiazide analogue that inhibits insulin release from beta cella via stimulation of alpha-adrenergic receptors in addition to a lesser extra pancreatic effect, possibly through inhibition of cAMP phosphodiesterase leading to increased glycogenolysis. Side effects might include sodium retention, nausea, and edema (from the sodium retention).
  • Streptozocin is a naturally occurring nitrosourea that selectively destroys pancreatic beta cells. However its efficacy in controlling clinical signs of hypoglycemia and prolonging survival time has been variable. One study did not demonstrate a significant survival benefit associated with streptozocin treatment, but resolution or maintenance of normoglycemia and reduction in tumor size was noted in some dogs. 39 In another case it was been used successfully to reduce tumor burden.40 The treatment protocol involves a 0.9% saline diuresis for 7 hours with streptozotocin (500 mg/m2) administered over a 2 hour time period beginning three hours after initiating the diuresis. Antiemetics are administered immediately following streptozotocin administration to minimize vomiting. Streptozotocin treatment is repeated every 3 weeks until euglycemia is attained. Adverse reactions of streptozotocin treatment include vomiting, pancreatitis, diabetes mellitus and renal failure.
  • Octreotide (Sandostatin) is a stable somatostatin analog that antagonizes insulin by preventing it’s cleavage from the pro-hormone. Current information on the effectiveness of octreotide for insulinomas is conflicting. One study examining the efficacy of octreotide in management of hypoglycemia showed a reduction in insulin with a concommittent rise in glucose,41 while another study showed that it had no benefit over placebo, and also that it had little effect on circulating glucose and insulin concentrations despite clearly detectable plasma concentrations. 42A depot analog, Lanreotide, has not been investigated in animals.
  • Glucagon increases gluconeogenesis. A constant rate infusion has been used in refractory hypoglycemic patients to manage acute hypoglycemic crises. 43The initial infusion rate is 5 ng/kg/minute; this can be increased as needed (one patient received up to 13 ng/kg/minute). Reconstitute 1 mg of lyophilized glucagon with the diluent provided and add that solution to one liter of 0.9% NaCl. The resulting solution will have a 1 ug/ml concentration which will allow for convenient administration rates. 53) Surgical and medical treatment may be necessary in those cases who are hypoglycemic post surgery.SUPPORTIVE
    1) Some patients can be controlled with dietary management, feeding small non-glucose, high protein, complex carbohydrate meals frequently, although this therapy alone is generally insufficient for successful management.2) If animal is presented in hypoglycemic crisis, administer 1 to 10 mls 25-50 % dextrose IV using a large vein to prevent phlebitis. Such animals can be difficult to stabilize as glucose administration can increase insulin release from the tumor. Offer food when alert. Maintain on IV fluids with 5-10% dextrose. 53) Some dogs develop diabetes mellitus post surgery due to atrophy of normal β cells; these patients may need insulin therapy but only if hyperglycemia and glucosuria last > 2-3 days beyond when dextrose fluids are discontinued. Insulin is usually only needed temporarily. 5

References:

1) Caywood DD, Klausner JS, O’Leary TP, et al: Pancreatic insulin-secreting neoplasms: Clinical, diagnostic, and prognostic features in 73 dogs. J Am Anim Hosp Assoc 1988 Vol 24 (5) pp. 577-584.
2) Trifonidou MA, Kirpensteijn J, Robben JH: A retrospective evaluation of 51 dogs with insulinoma. Vet Q 1998 Vol 20 (Supp 1) pp. S114-S115.
3) Tobin RL, Nelson RW, Lucroy MD, et al: Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999 Vol 215 (2) pp. 226-30.
4) Leifer CE, Peterson ME, Matus RE: Insulin-secreting tumor: Diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986 Vol 188 (1) pp. 60-64.
5) Garrett LD: Insulinomas: A Review and What’s New. ACVIM Proceedings 2003.
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18) Bergman PJ, Bruyette DS, Coyne BE, et al: Canine clinical peripheral neuropathy associated with pancreatic islet cell carcinoma. Prog Vet Neurol 1994 Vol 5 (2) pp. 57-62.
19) Efrat S: Regulation of insulin secretion: Insights from engineered ß-cell lines. Ann NY Acad Sci 2004 Vol 1014 pp. 88-96.
20) Minn AH, Lan H, Rabaglia ME, Harlan DM, Peculis BA, Attie AD, Shalev A: Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance. Mol Endocrinol 2005 Vol 19 (3) pp. 794-803.
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38) Polton GA: Prognostic Factors in a Cohort of Canine Insulinoma Patients. Proceedings 14th ECVIM-CA Congress, Barcelona 2004.
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40) Bell R, Mooney CT, Mansfield CS, Jones BR: Treatment of insulinoma in a springer spaniel with streptozotocin. J Small Anim Pract 2005 Vol 46 (5) pp. 247-250.
41) Robben JH, van den Brom WE, Mol JA, van Haeften TW, Rijnberk A: Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma. Res Vet Sci. 2006 Vol 80 (1) pp. 25-32.
42) Simpson KW, Stepien RL, Elwood CM, Boswood A, Vaillant CR: Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs. J Small Anim Pract 1995 Vol 36 (4) pp. 161-165.
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