Insulinoma is a tumour of the beta cells of the pancreas which causes an excessive production of insulin; in its turn the hyperinsulinaemia causes signs of disease, by inducing hypoglycaemia. In patients with insulinoma the neoplastic beta cells do not respond to the negative feedback of the hypoglycaemia, which normally blocks the production of insulin, thus resulting in an excessive amount of insulin. The beta cells are found in the islets of Langerhans, which are scattered throughout the pancreatic tissue; insulinomas can, therefore, occur in any part of the pancreas.
The lesions may consist of hyperplasia, adenoma or adenocarcinoma; the signs are the same in all cases, independently of the type of lesion. Animals with insulinoma usually have several neoplastic nodules disseminated in the pancreatic parenchyma; the sizes of these insulinomas vary considerably, from lesions invisible to the naked eye to a few centimetres (Fig. 1). Recurrences are common, but the incidence of metastases outside the pancreas is low. If metastasis does occur, it mainly involves the regional lymph nodes, the liver and the spleen. The causes of insulinoma are unknown, but genetic and dietary factors are suspected to be involved (excess of carbohydrates in the diet and consequent overstimulation of the beta cells of the pancreas).
Insulinoma is a very common neoplasm in ferrets; according to one study carried out in the USA, it accounts for 25% of all the tumours in this species. Most of the affected ferrets are aged over 5 years old (range, 2 to 7 years old). Insulinoma often occurs together with adrenal gland disease; there is no difference in prevalence between the two genders.
CLINICAL SIGNS
The disease has an inconspicuous onset and the first, rather vague signs sometimes escape observation; more attentive owners sometimes note that the ferret appears “absent” for a few seconds, staring into an empty space without reacting, and then becomes normal again, or has difficulty in waking up completely after being asleep.
The signs worsen gradually. The animal may develop periodic attacks of nausea (manifested as hypersalivation and nose rubbing), ataxia and hind leg weakness which mimics paresis and seizures; these signs tend to become more frequent and more severe as time passes. Prolonged episodes of severe hypoglycaemia can cause permanent brain damage. Sometimes the animal loses weight.
The ferret adapts well to a chronic state of very low blood glucose levels; it is not unusual to find ferrets with values around 30 mg/dl which are perfectly conscious.
DIAGNOSIS
The diagnosis of insulinoma is based mainly on fasting blood glucose levels. Normal values are in the range of 90-110 mg/dl; values below 60 mg/dl are diagnostic if accompanied by compatible signs which disappear when glucose is administered. In the case of suspected insulinoma the period of fasting should be 4 hours, during which the ferret must be kept under observation so that if a hypoglycaemic crisis occurs, it can be picked up and treated immediately. After taking a blood sample, the animal is given food. In the case of hypoglycaemia the differential diagnosis includes liver diseases, septicaemia, prolonged fasting and laboratory artefacts. It is important to evaluate or process the blood sample immediately, because the level of the glucose in the blood decreases progressively with time (7% every hour).
The other blood test values in animals with insulinoma are usually normal. Sometimes the levels of alanine transaminase and aspartate transaminase are increased, which can indicate damage to the liver due to chronic hypoglycaemia (lipidosis), hepatic metastases of malignant insulinoma or concomitant diseases. The levels of insulin in the blood are not measured in the ferret.
Insulinomas are usually too small to be detected by radiography or ultrasound studies.
TREATMENT
Insulinomas can be treated medically, surgically or with a combination of the two approaches.
The surgical intervention may be limited to simple nodulectomy (excision of the tumour nodules detected during laparotomy), or to partial pancreatectomy (asportation of the left lobe of the pancreas – to reduce the tumour burden – as well as any nodules present in the right lobe). Surgical treatment is rarely curative (being so in about 15% of cases). Indeed, by the time of diagnosis, microscopic metastases, which are impossible to detect, are almost always disseminated throughout the liver. Although the ferrets are, therefore, still hypoglycaemic after the surgical intervention, their life expectancy is prolonged. According to one study, the mean survival of rats with insulinoma was 668 days after a partial pancreatectomy, 456 days after nodulectomy alone and 186 days after medical therapy alone.
Medical treatment has the purpose of controlling symptoms and maintaining the ferret euglycaemic as much as possible; nevertheless, it is not possible to control the progression of the tumour and medical treatment gradually loses its efficacy until the animal becomes completely refractory. Medical treatment may be used alone or together with and after surgery.
Treatment is commenced with the administration of prednisolone, which has gluconeogenic properties. The dose ranges from 0.25 to 2 mg/kg per os every 12 hours, starting from the lowest dose and gradually increasing it when the dose is no longer sufficient to control the signs. The minimum effective dose is usually at least 1 mg/kg/day. The ferret tolerates chronically high levels of cortisone very well, with minimal side effects. The periodic control of the glycaemia can be carried out in the outpatient clinic, using strips for diabetics and the appropriate readers.
Subsequently, depending on the severity of the hypoglycaemia and related signs, treatment with diazoxide can be added. Diazoxide inhibits the release of insulin, stimulates glycogenolysis and hepatic gluconeogenesis and inhibits the cellular uptake of glucose. If added at a later time, the dose of prednisolone is lowered to 1-1.25 mg/kg. The starting dose of diazoxide is 5-10 mg/kg per os every 12 hours and the dose is then increased gradually up to a maximum of 30 mg/kg every 12 hours; possible side effects include nausea, vomiting, anorexia, lethargy and obesity. Since anorexia can be rapidly fatal in ferrets with insulinoma, the side effects should be evaluated with care.
The toxic effects on beta cells of some chemotherapeutic drugs (streptozocin and alloxane) are being studied in the treatment of insulinoma in dogs. These drugs have considerable side effects and their use in ferrets has not yet been evaluated. Studies on doxorubicin treatment in the ferret are underway.
The management of the animal’s diet is of paramount importance for controlling the glycaemia. Small meals should be administered frequently; the food should be of excellent quality and have a high protein content and little or no carbohydrate. Food should always be left available. Food and snacks containing sugars or other carbohydrates should be avoided completely. Meat, eggs and homogenised meat can be given as treats.
The ferret should be monitored periodically by measuring fasting (1-3 hours at most) blood glucose levels every 2 or 3 months. It is good practice to perform a full blood count and urinalysis, including urine cultures, once or twice a year.
The owner should be instructed on observing the ferret’s behaviour with a view to picking up signs of hypoglycaemia. The owner should also be taught how to treat any severe hypoglycaemic crises (collapse, seizures) by applying honey or glucose syrup to the gums of the animal and administering food as soon as the ferret recovers.
Hypoglycaemic ferrets having convulsions should be administered a 2-4 ml bolus of 50% glucose by slow intravenous infusion and then given maintenance treatment with an infusion of 5-10% glucose. Seizures can also be controlled by the administration of diazepam, if necessary. The disease has a chronic, progressive course and gradually becomes refractory to drug treatment, to the point that the hypoglycaemic crises can no longer be controlled. In this case, euthanasia is advised.