Insulinoma: How not to anger the beast

Tonya E. Boyle Brown, DVM, DACVIM
Port City Veterinary Referral Hospital, Portsmouth, NH

Insulinoma is a relatively uncommon condition in our canine and feline patients. Insulinoma is more common in dogs than cats, but it is important to remember that it does still occur in our feline patients.

Key points of this article

Whenever a patient is presented with a blood glucose below 60, seizing or not, with or without possible reason, draw a blood sample for insulin:glucose ratio before administering dextrose.
- Once dextrose therapy is initiated, the opportunity to get this blood sample may not present itself again without consequences.
If an insulinoma is suspected, give the smallest amount of dextrose to control the clinical signs – do not let the glucose numbers inﬂuence your medical therapy of the patient.
If clinically normal, a blood glucose of 47 may be very adequate for the patient.
Prognosis is signiﬁcantly improved with the addition of glucocorticoid therapy to medical management and may be implemented after surgical intervention or with dietary modiﬁcation, if surgery is not an option.

Pathology

The etiology of insulinoma remains unknown. The effects of growth hormone locally (levels not measurable in serum) on insulinoma cells is suspected. Canine pancreatic islets of Langerhans are composed of 70% beta cells, perhaps explaining why insulin-secreting beta cell neoplasia is the most common pancreatic endocrine neoplasia in dogs. The majority of insulinomas are found histologically to be carcinoma, with adenoma being a rare histological ﬁnding. Usually located in one of the limbs of the pancreas and not within the body, insulinomas are usually solitary tumors. The metastatic rate hovers around 50%, with regional lymph nodes and the liver being the most commonly affected organs, although any location is possible.

Pathophysiology

Neoplastic proliferation of insulin-secreting beta cells causing excessive insulin release into the body, causing hypoglycemia. As in other causes of hypoglycemia (Somogyi phenomenon), counter-regulatory mechanisms are initiated to counter-act and protect the brain from a hypoglycemic state. Glucagon and catecholamines are the most effective mechanisms to elevate the blood sugar. Other counter-regulatory hormones that are activated include growth hormone and glucocorticoids. Insulin secretion is mostly regulated by glucose. In a normal patient, a blood glucose level less than 80 mg/dL will completely inhibit insulin secretion. With insulinoma, neoplastic beta cells will continue to secrete insulin independent of the blood glucose. Therefore, insulinoma may be diagnosed when the blood insulin level is documented to be high or normal, when the blood glucose is below 80 mg/dL.

Signalment

Medium to large breed dogs are most commonly affected, but any breed may develop insulinoma. An age range of 3-15 years is reported with a mean of nine years of age. Sex or breed risk studies have been performed with no speciﬁc sex or breeds affected. Clinical signs are often attributable to neuroglycopenia (hypoglycemia of the central nervous system) and may include seizures, collapse, ataxia, weakness, mental dullness, disorientation and changes in vision. Hypoglycemia-induced release of catecholamines and stimulation of the sympathetic nervous system may cause clinical signs of nervousness, hunger and tremors. While clinical signs will increase as the severity of the hypoglycemia progresses, it is important to remember that they are also related to the duration and rate over which hypoglycemia develops. This rate and duration may be very gradual, and the patient may be very well compensated to a hypoglycemic state. Episodic clinical signs are possible as counter-regulatory mechanisms may effectively temporarily resolve neuroglycopenia. Excitement, exercise, fasting and even feeding may exacerbate hypoglycemia and clinical signs. Feeding may cause stimulation of insulin secretion and worsen signs; feeding may also resolve clinical signs with a temporary elevation in blood glucose levels.

Physical examination

The physical examination of a patient with insulinoma may be completely normal. A patient may be presented in an ictal or post-ictal state. The anabolic effects of insulin may cause a dog to be overweight. Tetraparesis and decreased, or absent, limb reﬂexes has been reported in dogs, and may be present due to a peripheral neuropathy of unknown etiology. This may be a paraneoplastic immune-mediated condition unrelated to metabolic changes from excessive insulin from the insulinoma.

Differentials

Decreased glucose production (Addison’s disease, liver disease, neonate, toy breed, hypopituitarism, growth hormone deﬁciency, glycogen storage disease), drug-associated hypoglycemia (insulin, oral anti-hyperglycemics, salicylates, acetaminophen, beta-blockers, among others) excessive glucose consumption (sepsis, extreme exercise) and excessive insulin or insulin-like factors, are the categories of differential diagnosis for insulinoma. Insulin or insulin-like factors include insulinoma, islet cell hyperplasia, or extra-pancreatic tumor. Spurious hypoglycemia may be caused when whole blood is not spun promptly (within 1 hour) to separate red blood cells from serum, or if leukocytosis or polycythemia are present.

Diagnostics

Deﬁnitive diagnosis of insulinoma is made based on histology and immunochemical staining of a pancreatic mass; visualization of a pancreatic mass with ultrasound or CT supportive of insulinoma; a serum insulin concentration of 20 pmol/L or greater with concurrent hypoglycemia (less than 60 mg/dL), along with appropriate clinical signs, substantiates the clinical suspicion for insulinoma. Minimum data base (CBC, Chemistry panel, urinalysis) may have no signiﬁcant abnormalities and some insulinoma patients may be euglycemic despite elevated insulin values. Mild increases in ALKP or ALT and a mild hypokalemia have been documented; thoracic radiographs and abdominal ultrasound may be normal. If a patient is suspected of insulinoma with euglycemia on presentation, fasting under observation with glucose sampling every hour is recommended. Most insulinoma patients will develop hypoglycemia within 12 hours of fasting. When the blood glucose falls to 60 mg/dL or below, a blood sample for insulin:glucose ratio is collected and the patient should be fed a small meal. If the patient does not become hypoglycemic and insulinoma is still suspected, several other diagnostic tests may be employed (serum fructosamine, glycosylated hemoglobin A1c, serial insulin measurements). Moreaggressive stimulation and tolerance tests are not recommended due to the potential of adverse effects such as seizure and death.

Treatment

Treatment strategies are two-fold for insulinoma: treatment of the acute crisis, and long term disease management. An acute hypoglycemic crisis may be resolved with conservative administration of dextrose (0.5 g/kg slowly IV, diluted on 0.9% NaCl at a ratio of 1:5) followed by a continuous rate infusion of 2.5% dextrose. Caution must be maintained as excessive dextrose administration will quickly cause insulin secretion and cause more severe hypoglycemia. Discontinuation of dextrose may occur when clinical signs have resolved, even if hypoglycemia is still present. Neurogylycopenia will resolve with this protocol in most patients, but if clinical signs remain despite conservative use of dextrose, dexamethasone (0.1 mg/kg slowly IV every 12 hours) and somatostatin analogue (10 to 50 mcg total SC every 8 to 12 hours) may be indicated. Seizure control may also be obtained with diazepam or propofol, if needed, to allow time for the neuroglycopenia to resolve. Glucagon may be administered as a continuous infusion as well, but may increase insulin secretion and worsen hypoglycemia. Long term disease management is best obtained with identiﬁcation of the pancreatic mass, and surgical removal of the mass and any identiﬁable metastatic disease. Complications of surgery include negative exploratory, transient post-operative hypoglycemia, diabetes mellitus, and pancreatitis among others. Medical management before surgery, or if surgery is not pursued, may be aimed at relieving the hypoglycemia or cytotoxic therapies against the insulin secreting beta cells. Hypoglycemia may be controlled with dietary modiﬁcation (small, frequent meals every 4-6 hours of a diet high in proteins, fats and complex carbohydrates is recommended). Glucocorticoid therapy with prednisone will increase the blood glucose by stimulating glucagon secretion and increasing gluconeogenesis. Oral dosing at 0.5-2 mg/kg/day, starting low and increasing as needed over time, is recommended. Diazoxide (a benzothiadiazine derivative) decreases the exocytosis of insulin-containing vesicles from the pancreatic beta cells and increases glycogenolysis, gluconeogensis and inhibits the uptake of glucose by tissues. It is given at an oral dose of 10-40 mg/kg/day divided and given every 8-12 hours, beginning at the lowest dose and increasing if needed. Side effects include anorexia, salivation and vomiting in dogs, but may be well-tolerated and it is reported that about 70% of dogs with insulinoma will respond to diazoxide therapy.

Prognosis

Dogs that undergo partial pancreatectomy may have a median survival time of 785 days in a recent study. A subgroup of dogs that additionally received prednisone therapy after partial pancreatectomy had a median survival time of 1316 dogs. Young dogs have a worse prognosis and dogs that are normo or hyperglycemic after surgery have a signiﬁcantly better prognosis than those that are hypoglycemic after surgery.

Feline insulinoma

Although rare, insulinoma has been reported in cats aged 12-17 years old. Of the six cats reported in the literature, ﬁve were neutered males and three were Siamese. Clinical signs, physical examination, differentials and diagnostics are similar to cats as dogs. An insulin radioimmunoassay validated for cats should be used when performing an insulin:glucose ratio. Therapy is similar, with surgical removal of the pancreatic mass if possible, followed by prednisolone therapy and frequent small meal administration.