INSULINOMA (PANCREATIC NEUROENDOCRINE CARCINOMA)

Author: Michelle Brunton (March 2021)

What is Insulinoma?

Insulinoma is a disease that commonly affects middle-aged to older ferrets. Insulinoma causes tumours to form in the pancreas. An insulinoma can be either an insulin-producing adenoma (benign) or an insulin-producing adenocarcinoma (malignant). Insulinoma cause an increase in secretions of a hormone called insulin (Insulin is the hormone that the body uses to convert the sugar in food to glucose for energy). As insulin levels rise, blood sugar or blood glucose levels fall, which in turn, leads to severely low blood sugar (hypoglycemia).

Blood sugar or glucose is essential to allow the brain and muscles to function normally. The brain is the biggest user of glucose in a body and when the blood sugars lower the ferret starts to exhibit symptoms which can include lethargy, collapse, hind limb weakness, and, in severe cases, seizures. Too much insulin in the body “starves” the brain of fuel and causes the most severe symptoms.

Ferrets have a high metabolism, which means they burn a lot of energy. They need regular food intake to keep their blood glucose levels balanced. Anything that interferes with their eating, such as dental disease, can cause problems. Hypoglycemia (low blood glucose) can be a temporary condition, or it can be a recurring problem.

Why Ferrets Develop Insulinoma?

Like most forms of abnormal cellular growth, the causes are unknown. It is thought that the food, medications and lifestyle of domestic ferrets may contribute to the condition.

Diet

The pancreas plays a big role in the digestive process. During digestion, the pancreas makes pancreatic juices called enzymes which break down sugars, fats, and starches. The pancreas also aids the digestive system by making hormones that travel through the blood to help regulate the blood sugar levels and appetite, stimulate stomach acids, and tell the stomach when to empty. In the wild, mustelid species are carnivorous and designed to subsist on whole prey. Wild European ferrets (polecats) consume a diet of rodents and small animals that consist of approximately 50% protein and 28% fat and very minimal carbohydrate. Rodent flesh is about 80% water and low in fibre.

 

Domesticated ferret diets differ and include dry kibble that contain carbohydrate (starchy) ingredients such as corn, wheat, potato or peas. Insulinoma is very rarely noted in wild populations however the life span of wild animals is far lower and there is no way of knowing if pancreatic tumours would have developed had the animals lived longer.

Another contributing factor could be how you present the food to your ferret. Mustela are grazers and in nature they never consume large meals. Large meals make the pancreas work harder and for longer to digest the meal.

Housing

Outdoor housing is also said to lessen the chances of the ferret developing Insulinoma as they have more natural light and normal day / night cycles.

Providing a healthy, balanced diet, plenty of exercise and regular vet checks throughout the ferrets life is best for preventing insulinoma however it is impossible to eliminate the risk of developing the disease.

 

Clinical Signs of Insulinoma in Ferrets

 

Most ferrets with insulinoma will begin to exhibit symptoms at around four to five years of age; however, ferrets as young as 2 years of age have been diagnosed with insulinoma.

 

In the early stages of insulinoma the clinical signs may not be specific and can be easy overlooked. Periodically, your ferret may have an absent look or be uncharacteristically inactive and deep in thought (stargazing). Healthy ferrets rarely sit still unless they are asleep.

 

Commonly, ferrets with insulinoma experience gradually progressive weakness and lethargy over a period of weeks to months. The severity of symptoms depends on how low the blood glucose gets and will often improve if the ferret has just eaten. Signs of the disease may appear suddenly as an episode of collapse lasting from minutes to hours.

 

Low blood sugar symptoms (increasing in severity)

  • Stargazing “Staring” into space

  • Weakness or drunken walking (mostly seen in the hind legs)

  • Weight loss

  • Lethargy (Extreme weakness)

  • Ptyalism (excessive salivation or foaming at the mouth))

  • Pawing at the mouth (unique to ferrets with insulinoma). Some ferrets violently and repeatedly scrape the roof of their mouth and owners perceive this as ingestion of a foreign body or foul-tasting substance

  • Collapse

  • Depression

  • Confusion

  • ataxia (i.e., neuroglycopenic manifestations)

  • Moaning or screaming

  • Clenched teeth/locked jaw

  • Twitching/seizures

In serious cases symptoms can progress to include seizures and hypoglycemic (low blood sugar) coma. Prolonged, severe hypoglycemia can lead to convulsions and even irreversible brain damage and death.

Ferrets that have not eaten due to illness or neglect may present similar symptoms and although prolonged anorexia or starvation, sepsis, liver disease, and other neoplasms can result in a low blood glucose concentration, insulinoma is most likely in a well-cared for ferret.

 

 

Diagnosis

A consultation with a veterinarian familiar with ferrets is essential. During the consultation, the veterinarian will ask about the normal behaviour of the ferrets and any symptoms that are presenting. They will conduct a physical examination and collect blood samples for diagnostic testing. It is recommend to have a complete blood count and clinical chemistry tests performed as this will give the vet a full picture of the ferrets’ health. Your veterinarian may recommend insulin testing as an additional test if the ferret is displaying any symptoms during the examination.

Diagnosis for insulinoma is based on history, suggestive clinical signs, and hypoglycemia (<60 mg/dl).

In ferrets showing clinical signs during presentation, blood glucose concentration can be quickly assessed with a digital glucometer but all too often ferrets with insulinoma have normal insulin levels at the time of sampling, due to the episodic nature of this condition.  If the ferret is behaving normal during examination but shows signs of low blood sugars at home, blood samples should be collected after a 3- to 4-hour fast. Fasting blood glucose in normal ferrets is 90 to 125 mg/dl. The ratio of insulin to glucose is a more useful test. If there is a high level of insulin in the face of a low glucose level, the diagnosis is definitively made.

Insulinoma signs are characterized clinically by the Whipple triad:

  • Episodic hypoglycaemia (low blood sugar)

  • Neurologic dysfunction temporally related to hypoglycaemia (symptoms caused by low blood sugar)

  • Dramatic reversal of neurologic abnormalities by administering glucose or feeding (Improvement of symptoms after treatment to raise blood sugar levels)

X-rays can be performed but pancreatic tumours are not usually big enough to be seen. The spleen however, may be incidentally enlarged. Definitive diagnosis of insulinoma is made by histologic examination of pancreatic biopsy specimens. 

 

Treatment Options

There are two main treatment options available for this disease, medical or surgical.

 

The most common medical management treatment of insulinoma is the use of corticosteroids such as Prednisone and Diazoxide to increase blood glucose levels. Prednisone acts by increasing both hepatic gluconeogenesis and peripheral blood glucose concentration by inhibiting glucose uptake by peripheral tissues. Diazoxide can be used alone or added to the treatment regimen when prednisone alone is not effective. Diazoxide also exhibits hyperglycemic activity by directly inhibiting pancreatic insulin secretion.

These treatments do not stop the progression of the tumours, but will minimize the symptoms. For this reason, regular blood glucose monitoring is essential to help determine if the dose needs to be changed. Medical therapy alone is usually effective in controlling signs of the disease for 6 – 18 months.

Surgery is a second option for treatment of insulinoma. The procedure involves removal of a portion of the pancreas, and is usually combined with medical treatment. Unfortunately there is no way to remove all tumour cells surgically. Typically, there are microscopic metastases throughout the entire pancreas by the time a ferret is showing clinical signs of the disease and even if entire sections of the pancreas are removed, signs of insulinoma will eventually recur.

Diet must also be well managed at home. Ferrets with insulinoma will need 4-6 small meals daily to provide a more consistent food intake throughout the day and the last meal should be just before bed to help the ferret get through the night without the blood sugars dropping too much. Convalescence foods can be used or a diet containing high quality protein and moderate levels of fat is preferred. Which helps level out the blood glucose levels.

If a ferret experiences a sudden collapse, seizure or a hypoglycemic coma, emergency treatment is needed immediately for the ferret to survive. Immediately rub honey or corn syrup onto the gums using a finger or cotton bud (be careful if the ferret is having a seizure, as there is a danger of being bitten.) Once the ferret is stabilised they need immediate veterinary treatment. Rush your ferret to the veterinarian for further supportive care and diagnostics.