Diet Recommendations for Dogs with Metastatic Insulinoma

My patient is “Ben,” a 10-year old, male Lab weighing 35 kg that presented with a 2-month history of having strange episodes, which included signs of disorientation and ataxia lasting from 10 minutes to 2 hours. The episodes were initially intermittent, but became much more frequent (2-3 times per day), so that the owner (finally) brought him in for an evaluation.

On physical exam, the dog was clinically normal. On our routine chemistry profile, the serum glucose value was very low (28 mg/dl; 1.56 mmol/l). We collected another blood sample for paired serum insulin and glucose concentrations. These test results showed an extremely low serum glucose concentration (25 ng/dl; 1.39 mmol/l) with a high serum insulin value (439 pmol/l; reference interval, 36-287 pmol/l).

An abdominal ultrasound showed a solitary 7-9 mm hypoechoic nodule on the pancreatic body between the pyloris and the proximal duodenal flexure. Unfortunately, multiple, small, very discrete solitary hypoechoic masses or nodules were also found throughout the liver, suggesting metastatic disease.

Based upon the hypoglycemia, hyperinsulinemia, and ultrasound findings, my presumptive diagnosis is insulinoma with metastasis to the liver. His owners have declined surgical exploration or biopsy.

We started Ben on oral prednisone (5 mg three times daily), and the owners have been feeding him small frequent meals. His improvement has been dramatic— no further episodes of disorientation or ataxia have been noted. I'm planning on keeping Ben on long-term, daily prednisone, but have some questions about the best diet to feed.

My understanding is that these dogs do best when fed frequent meals with high complex carbohydrates and low simple carbohydrates. I’ve also read that puppy diets are best, whereas others have said that a diabetic diet is better. But I was also concerned that a lower carbohydrate diet may not keep the blood glucose high enough. Which diets do you recommend?

My Response:

Unfortunately, there are no published studies to help us decide which is the best nutritional approach for management of dogs with insulinoma. This is not a very common endocrine tumor (1,2), so it’s difficult to do randomized trials that would evaluate the glucose response to different diets in dogs with insulinoma.

In my experience, there is not a single type of diet that will work well in all dogs. This is likely related to what stimulates that dog’s insulinoma to secrete insulin. In most dogs, hypoglycemia occurs most often during periods of fasting or exercise, whereas other dogs appear to develop the most severe signs of hypoglycemia after feeding (1,2).

Low carbohydrate, high protein diets?
Dogs with insulinomas should be fed every 4 to 8 hours, with a diet containing moderate to high levels of protein and fat and low amounts of simple carbohydrates (3). By avoiding simple sugars, an appropriate diet can dramatically reduce the stimulus for tumor insulin release, thereby controlling the clinical signs of hypoglycemia. The only exception is when a dog is actively exhibiting signs of hypoglycemia. In those cases, a rapidly absorbed source of sugar (such as honey, corn syrup, or maple syrup) may be administered orally at home pending further veterinary consultation (1,2).

Some dogs do well on a low-carbohydrate, high-protein diet, similar to what is commonly recommended for the diabetic cat. Most “young dog diets" fit reasonably well into this category. Since these diets are higher in fat, however, they can lead to weight gain in some dogs. Again, such low-carb diets reduce the stimulus for insulin secretion since these diets lessen postprandial hyperglycemia. During the metabolism of protein to glucose, glucose is liberated slowly into the blood stream, thus avoiding excessive production of insulin but providing a source of glucose over a prolonged period of time (4,5).

High-fiber, complex carbohydrate diet?
If a higher carbohydrate diet is fed, one containing complex carbohydrate and/or high fiber is ideal, since the digestion and absorption of carbohydrates should be slower and the rise in blood glucose more sustained over time (2). However, as opposed to the lower carbohydrate, higher fat diets, these high fiber diets tend to be low in energy density; therefore, if the dog is underweight or starts to lose weight, this type of diet might not be the best choice.

Bottom line
A number of different types of diets can be used to help manage the signs of hypoglycemia in dogs with insulinoma. Some dogs will do best on low carb diets, whereas others may respond better to a higher fiber diet. Whatever type of diet is chosen, multiple small feedings a day are indicated.

But remember: diet therapy generally plays only a minor role in management of dogs with insulinoma. Surgical resection of gross pancreatic disease is the treatment of choice and should always be considered, even in dogs with known metastatic disease. If surgery is not possible or it fails to control hypoglycemia, glucocorticoids (prednisone) and diazoxide are two drugs commonly used in conjunction with diet for the long-term management of dogs with insulinoma (1,2,6,7).

Overall, the combination of surgical and medical therapy, together with proper dietary management, offers the greatest chance to control clinical signs and prolong survival time (8,9) in dogs with this malignant islet-cell pancreatic tumor.

References:

1. Kintzer PP. Insulinoma and other gastrointestinal tract tumours. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:148-155.
2. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163.
3. Bell SJ, Forse RA. Nutritional management of hypoglycemia. Diabetes Educ 1999;25:41-47.
4. Conn JW. The advantage of a high protein diet in the treatment of spontaneous hypoglycemia. Preliminary report J Clin Invest 1936;15:673-678.
5. Blumberg S. Should hypoglycemia patients be prescribed a high-protein diet? J Am Diet Assoc 2005;105:196-197.
6. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
7. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64.
8. Rychel J, Worley DR, Hardy CS, et al. Prolonged survival in an aged labrador retriever with a metastatic insulinoma. J Am Anim Hosp Assoc 2013;49:224-229.
9. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156.

Top Endocrine Publications of 2013: Insulinoma and Other Causes of Hypoglycemia

Insulinoma in a dog, showing a solitary pancreatic nodule

In my fourth compilation of the canine and feline endocrine publications of 2013, I’m going back to disorders of the pancreas. But now let’s move on to islet cell tumors (e.g., insulinoma) and other causes of hypoglycemia.

Listed below are 9 research papers written in 2013 that review endocrine hypoglycemia in dogs and cats.

Most of these papers concentrate on canine insulinoma and include the following: New aspects in gene expression profiling of primary canine insulinomas and their metastases (1,8), an investigation of the use of medetomidine as an adjunct to the anesthetic management of dogs with insulinoma (2), evaluation of a new biweekly streptozotocin protocol for treatment of dogs with insulinoma (4), and finally, a case report of a dog that had an unusually prolonged, asymptomatic, disease-free interval after surgical treatment of insulinoma despite hepatic metastasis (6).

One of these 2013 papers describes a cat with insulinoma, a relatively rare feline endocrine tumor (7). This geriatric cat presented for evaluation of weakness and trembling associated with mild hypoglycemia. Ultrasound revealed a single pancreatic nodule (benign insulinoma), which was surgically excised, resulting in complete and prolonged resolution of all clinical signs associated with hypoglycemia.

Other papers include a review of the use of continuous glucose monitoring in dogs and cats (9), a study of the comparison of glucose fluctuations between day- and night-time measured using a continuous glucose monitoring system in diabetic dogs (3), and finally, a review of the hypoglycemia and liver toxicosis associated with xylitol toxicosis in dogs (5).

References:

1. Buishand FO, Kirpensteijn J, Jaarsma AA, et al. Gene expression profiling of primary canine insulinomas and their metastases. Vet J 2013;197:192-197. 
2. Guedes AG, Rude EP. Effects of pre-operative administration of medetomidine on plasma insulin and glucose concentrations in healthy dogs and dogs with insulinoma. Vet Anaesth Analg 2013;40:472-481. 
3. Mori A, Kurishima M, Oda H, et al. Comparison of glucose fluctuations between day- and night-time measured using a continuous glucose monitoring system in diabetic dogs. J Vet Med Sci 2013;75:113-117. 
4. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490. 
5. Peterson ME. Xylitol. Top Companion Anim Med 2013;28:18-20. 
6. Rychel J, Worley DR, Hardy CS, et al. Prolonged survival in an aged labrador retriever with a metastatic insulinoma. J Am Anim Hosp Assoc 2013;49:224-229. 
7. Schaub S, Wigger A. Ultrasound-aided diagnosis of an insulinoma in a cat. Tierarztliche Praxis Ausgabe K, Kleintiere/Heimtiere 2013;41:338-342. 
8. Schermerhorn T. Canine insulinoma as a model for studying molecular genetics of tumorigenesis and metastasis. Vet J 2013;197:126-127. 
9. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 

Seizures and Bilateral Adrenal Enlargement in an Older Boxer: Insulinoma, Cushing's Disease, or Something Else?

I'm looking for some advice for Alex, a 10-year old M/N Boxer who has been a long-term patient of mine. Alex's serious medical problems started a year ago, when he had his first seizure event. Blood work following this seizure was unremarkable aside from a mild elevation in the serum alkaline phosphate activity (219 IU/L; reference range, 5-131 IU/L). Alex's owner began keeping a seizure log, and Alex had further neurological issues until 7 months ago when he suffered another tonic-clonic seizure event, which lasted approximately 3 minutes.

Following this second seizure, Alex was examined by a neurologist, who found no abnormalities on his examination. Routine blood work again showed a mild elevation in the serum alkaline phosphate with all other serum chemistry values being normal. Due to Alex's age and breed, one obvious rule-out was a brain tumor or other intracranial disease, so an MRI was performed. Fortunately, the results of Alex's MRI was normal, with no brain or pituitary masses found.

Alex did well until about 4 months ago, when he had a severe seizure lasting about 5 minutes. A week later, Alex had multiple episodes of severe weakness and disorientation. His physical examination the following day was normal, but blood work revealed a further increase in the serum alkaline phosphate activity (382 IU/L), as well as a slightly low blood glucose concentration (58 mg/dl). Alex had not eaten since the night before, but in light of his clinical signs over the past few days, we sent out a serum insulin:glucose panel, which came back as follows:

• Glucose: 61 mg/dl (reference range, 70-140 mg/dl)
• Insulin: 32.2 µU/ml (reference range, 520 µU/ml)

In light of these findings, we referred Alex for an abdominal ultrasound looking for an insulinoma. No pancreatic nodules were seen. However, bilateral adrenal enlargement was noted, and the radiologist recommended a workup for Cushing's disease. Needless to say, Alex's owners were upset and frustrated with the results and recommendations, although they were told beforehand that there was a fair chance that an insulinoma would not be visible on an ultrasound examination (even if a pancreatic islet cell tumor was there).

Despite the lack of clinical signs consistent with Cushing's disease, we performed both an ACTH stimulation test as well as a low-dose dexamethasone suppression test, both of which came back completely normal. However, at the time of this same visit, Alex's blood glucose again read low (58 mg/dl) on our glucometer so we repeated a insulin:glucose panel. The serum results again came back in the borderline range for insulinoma:

• Glucose: 64 mg/dl (reference range, 70-140 mg/dl)
• Insulin: 29.2 µU/ml (reference range, 5-20 µU/ml)

By now, I'm sure that you're thanking every deity you've ever heard of that you have reached the bottom of this case history! My question is this—do we have enough evidence to make a diagnosis of insulinoma in this dog and initiate therapy? I know most specialists require a lower blood glucose (i.e., below 60 mg/dl) before they begin to interpret glucose:insulin ratios. However, in Alex, he has had a number of slightly low glucose values with slightly high insulin readings; in light of his clinical signs, insulinoma still remains my primary differential.

As I was writing this post, I just got a call from the owner — Alex had another episode of severe weakness this morning that seemed to respond to Karo syrup applied to his gums.  As you can see, we've been through the ringer with this dog and are just hoping to get the owners some answers at this point so they can sleep a little more soundly.

Thanks very much in advance for your help and very sorry for the length of this post!

My Response:

In the face of hypoglycemia, the serum insulin level should be low, so this dog's high-normal to slightly high insulin value is inappropriate given the low blood glucose values (1-4). Many dogs suffering from insulinoma can be difficult to diagnose, since many have borderline glucose and insulin values similar to what you are describing in this dog.

Could this dog have Cushing's disease?
Hyperadrenocorticism (Cushing's disease) is a clinical diagnosis and is based primarily on the finding of compatible signs (e.g., polydipsia, polyphagia hepatomegaly, hair loss, pot-belly). In a dog suspected of suffering from Cushing's syndrome, we confirm the diagnosis by using one or more of the adrenal function tests (e.g, ACTH stimulation or low-dose dexamethasone suppression tests) (5-7).

One should never make a diagnosis of hyperadrenocorticism based on the finding of large adrenal gland size alone. Remember that the stress of any nonadrenal illness commonly leads to an overactive hypothalmic-pituitary-adrenal axis. Therefore, any dog with chronic stress or illness can develop bilateral adrenocortical hyperplasia as a physiological response. I know that some radiologists like to diagnose Cushing's disease based on adrenal gland size, but this just cannot be done using this criteria alone (5,6). Dogs with Cushing's disease certainly tend to have larger adrenal glands, but large adrenal glands alone are not diagnostic for this disease.

The way I see it, it's highly unlikely that this dog has Cushing's disease. First of all, this dog doesn't have any of the classical signs associated with glucocorticoid excess (5-7). The slightly high serum alkaline phosphatase could be secondary to Cushing's disease, of course, but there is a long list of reasons what that enzyme could be high, including primary liver or bone disease, neoplasia, and other endocrine disease (8).  The history of seizures could go along with a macrotumor of the pituitary gland, but your MRI excluded a CNS or pituitary mass as the cause of the seizures. So the obvious question is this— if this dog has Cushing's disease, how do we explain the seizures and low blood glucose values, which have NOTHING to do with Cushing's syndrome! If anything, the glucocorticoid excess associated with Cushing's can lead to mild to moderate hyperglycemia, with overt diabetes developing in 5-10% of Cushing's dogs (5,6).

So let's not get sidetracked. Let's get back to why this dog has periodic weakness and seizures. Working up and treating Alex for Cushing's syndrome, even if he does have that disease, will not help the dog's main clinical problems.

Confirming or excluding insulinoma as the cause of hypoglycemia
Insulinoma is more likely in this dog, but your blood glucose values have not been very low and your insulin levels are just above reference range limits. It would be great to collect samples during a seizure episode but that's not always possible.

This is what I would recommend: I'd fast the dog overnight at home and have the owners drop the dog off at your clinic in the morning. Then collect samples for glucose and insulin every 1-2 hours throughout the day, stopping when the blood glucose falls to below 45 mg/dl, or when the dog has signs of hypoglycemia. Then submit the sample or samples that have a low glucose for insulin determination.

Ideally, we would see clinical signs of hypoglycemia, document significant hypoglycemia (less than 55
and the lower the better) together with significant hyperinsulinemia, and then give glucose (or feed) and see the signs resolve.

If you are monitoring him and you get a blood glucose of 55 mg/dl on your in-house machine, I'd go another hour (if not symptomatic) and get another sample. If that one isn't lower, I'd continue to sample through the day but monitor closely. You don't want to do this again if possible.

If the dog isn't becoming hypoglycemic by the middle of the day, it's sometimes helpful to take the dog for a brisk walk of 5 to 10 minutes and then check a blood glucose (and insulin) concentration. This exercise can help induce hypoglycemia and hyperinsulinemia in some dogs and therefore, increasing the diagnostic yield of this prolonged fast.

Follow-up Testing and Response to Treatment on Alex:

We performed fasted "glucose curve" in our hospital as you suggested. Alex's serum glucose concentration continued to decrease throughout the day, bottoming out at 42 mg/dl (glucometer reading) after a short afternoon walk. He had minimal clinical signs but did start hypersalivating, so we stopped the test at that point. We collected blood samples for serum insulin and glucose to send out to our lab, and fed the dog. Alex ate well and the hypersalivating resolved almost immediately thereafter.

The serum results came back as follows:

• Glucose: 39 mg/dl (reference range, 70 - 140 mg/dl)
• Insulin: 52 µU/ml (reference range, 5 - 20 µU/ml)

Based on these results — severe symptomatic hypoglycemia that responding to feeding together with overt hyperinsulinemia, we made a diagnosis of insulinoma.

I am happy to report that Alex has been doing well on treatment with prednisone and an adjusted feeding schedule (many smaller meals throughout the day). To this point our spot checks in the hospital have been very normal, and the seizure episodes have resolved.

We know that we are only controlling signs of hypoglycemia in this dog and growth and metastasis of Alex's insulinoma is likely within the next few months, Due to his age, the owners have declined exploratory surgery for now and just want to control the hypoglycemia medially at this time.  

References:

1. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms:  Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612. 
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;188:60-64. 
5. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clin Tech Small Anim Pract 2007;22:2-11. 
6. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
7. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. Vet Clin North Am Small Anim Pract 2010;40:259-267. 
8. Fernandez NJ, Kidney BA. Alkaline phosphatase: beyond the liver. Vet Clin Pathol 2007;36:223-233. 

My Other Blog Posts that Discuss Insulinoma and Hypoglycemia:

• http://endocrinevet.blogspot.com/search/label/Hypoglycemia

Medical Treatment of Insulinomas

Dietary or medical management of insulinoma is recommended for animals that are showing signs of hypoglycemia and have previously undergone surgery and in those whose owners have declined surgery (1-6).

Specific chemotherapy can also be considered in animals in which all of the tumor cannot be resected and in those that have undergone previous surgery and again are showing signs of hypoglycemia. Just over half of dogs with insulinoma have metastases at the time of diagnosis (1-4), so it is reasonable to discuss the possibility of follow-up chemotherapy after surgery. Chemotherapy should be given only to patients with a confirmed histologic diagnosis of insulinoma.

Dietary management of hypoglycemia
Animals with insulinoma should be fed a diet that is high in protein, fat, and complex carbohydrates. Simple sugars, often contained in semimoist pet foods, should be avoided. Dogs should be fed small meals three to four times daily. Cats and ferrets may be fed free choice if they do not become obese. Exercise should be controlled and owners should attempt to limit excitement in these pets.

Glucocorticoids
Glucocorticoids are recommended when frequent feedings are no longer successful in controlling clinical signs of hypoglycemia. These drugs raise blood glucose by inhibiting glucose uptake in the peripheral tissues (creating insulin resistance) and stimulating hepatic glucose production (7-9).

Oral prednisone (or prednisolone) is started at the dosage of 0.25 mg/kg, twice daily (1-6). This dosage may be increased gradually as needed to control clinical signs or may be decreased if the disease is well controlled at the initial dosage. We should remember, however, that dosages of 1.1 mg/kg or higher given twice daily are considered immunosuppressive.

Diazoxide
Diazoxide (Proglycem, Teva Pharmaceuticals) is a nondiuretic benzothiadiazide that decreases insulin secretion, promotes gluconeogenesis and glycogenolysis, and inhibits the cellular uptake of glucose (10-12). Diazoxide can be difficult to obtain in the United States; however, reputable compounding pharmacies can often supply this drug.

The recommended starting dosage of diazoxide is 5 mg/kg, given orally twice daily (1-6,13). As with prednisone, the dosage may be increased as needed to control clinical signs. The maximal recommended dosage is 30 mg/kg twice daily.

The most common side effects of diazoxide are anorexia, vomiting, and diarrhea (1-6,13). These signs may be avoided or lessened by giving the medication with food. Ferrets find the diazoxide suspension distasteful, but because only small volumes are required, owners usually are able to administer it. Other potential side effects of diazoxide are hyperglycemia, bone marrow suppression, and sodium retention.

Octreotide acetate
Somatostatin is a polypeptide hormone that inhibits the secretion of insulin, glucagon, gastrin, secretin, and motilin. Octreotide acetate (Sandostatin, Novartis) is a long-acting somatostatin analogue that can be used in the management of patients with insulinoma (14).

Reports on the use of octreotide acetate in veterinary patients are limited and the response is mixed (4,12,15). About half of dogs with refractory hypoglycemia will show a response to octreotide acetate.  Ferrets refractory to other forms of treatment may show improvement in clinical signs in some, but certainly not all, cases.

The recommended dosage is 1 to 2 μg/kg given subcutaneously two to three times daily. This drug is relatively expensive, but may be practical for use in small dogs, cats, or ferrets due to their small size.

Currently, there is no way of predicting which patients will respond to octreotide acetate. Metastatic lesions may express fewer somatostatin receptors than the primary mass, so octreotide may be less effective in patients with advanced disease. This agent does appear to be safe and can be administered by owners at home. Thus, it should be considered for the treatment of animals with insulinoma that are refractory to or unable to tolerate traditional medical or surgical therapy (4,12).

Streptozotocin
Streptozotocin (Zanosar, Teva Pharmaceuticals) is a chemotherapeutic drug that selectively destroys pancreatic beta cells (16-19). When given alone, this drug may cause severe, acute renal failure in dogs. However, the drug can be administered safely if given with aggressive saline diuresis (17-19). Treatment is discontinued if there is clear tumor progression, resistant or recurrent hypoglycemia, or drug toxicity.

Streptozotocin may induce diabetes in some dogs, but the chemotherapy drug may be given along with appropriate insulin therapy if gross disease is still present.  No reports have described the use of streptozotocin in cats or ferrets with insulinoma. Further study of this agent is needed in all species.

Prognosis

The short-term prognosis for dogs with insulinoma is good, although most will eventually die of this disease. While survival time depends on the stage of the disease and the success of surgery, it also depends on the owners’ willingness to treat aggressively and follow up with symptomatic therapy once signs of hypoglycemia return.

Approximately two-thirds to three-quarters of dogs survive 6 months or longer after surgery (often over a year) before intractable hypoglycemia recurs. Reported median survival time is much longer in dogs initially treated with surgery than in those treated with medical management alone (1-5,20,21). Individualizing therapy with the use of combinations of medical and surgical therapy based on the stage and extent of disease may improve prognosis and survival time in any given patient.  

References:

1. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
2. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
6. Nelson RW, Foodman MS. Medical management of canine hyperinsulinism. J Am Vet Med Assoc 1985;187:78-82. 
7. Olefsky JM, Kimmerling G. Effects of glucocorticoids oncarbohydrate metabolism. Am J Med Sci 1976;271:202-210. 
8. Chap Z, Jones RH, Chou J, et al. Effect of dexamethasone onhepatic glucose and insulin metabolism after oral glucose in conscious dogs. J Clin Invest 1986;78:1355-1361. 
9. Moore GE, Hoenig M. Effects of orally administeredprednisone on glucose tolerance and insulin secretion in clinically normal dogs. Am J Vet Res 1993;54:126-129.
10. Tabachnick, II, Gulbenkian A. Mechanism of diazoxide hyperglycemia in animals. Ann N Y Acad Sci 1968;150:204-218. Koch-Weser J. Diazoxide. N Engl J Med 1976;294:1271-1273. 
11. Paulissian R. Diazoxide. Int Anesthesiol Clin 1978;16:201-237. 
12. Meleo K. Management of insulinoma patients with refractory hypoglycemia. Prob Vet Med 1990;2:602-609. 
13. Parker AJ, Musselman EM, O'Brien D. Diazoxide treatment of canine insulinoma. Vet Rec 1981;109:178-179. 
14. Maton PN. The use of the long-acting somatostatin analogue,octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am 1989;18:897-922. 
15. Simpson KW, Stepien RL, Elwood CM, et al. Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs. J Small Anim Pract 1995;36:161-165. 
16. Meyer DJ. Temporary remission of hypoglycemia in a dog with an insulinoma after treatment with streptozotocin. Am J Vet Res 1977;38:1201-1204. 
17. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). J Am Vet Med Assoc 2002;221:811-818. 
18. Bell R, Mooney CT, Mansfield CS, et al. Treatment of insulinoma in a springer spaniel with streptozotocin. J Small Anim Pract 2005;46:247-250. 
19. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490. 
20. 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;215:226-230. 
21. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156. 

Surgical Treatment of Insulinomas

Surgery is the initial treatment of choice for the long-term management of animals with insulinoma. Exploratory celiotomy is useful in confirming the diagnosis, staging the patient, and removing all identifiable pancreatic nodules (1-4). When possible, these pancreatic masses should be removed by partial pancreatectomy to ensure a more complete resection.

Preoperative Management
The serum glucose concentration should be stabilized before induction of anesthesia and surgery. While it is not necessary for the serum glucose to be in the normal range, the measured levels should be stable and the patient should be seizure-free for a few days prior to surgery.

Frequent feedings, continuous intravenous infusion of dextrose solution (5% dextrose or higher), or both, are the best ways to control symptomatic hypoglycemia (1-4). In some cases, use of prednisone or prednisolone may be helpful to help increase the low blood glucose concentrations. If these methods are unsuccessful, more aggressive medical management should be considered. In dogs, a constant rate infusion of glucagon can be considered to stabilize refractory patients (5). For more information, see my last post on Emergency management of hypoglycemia.

Identifying the Pancreatic Nodule(s)
Careful palpation of the entire pancreas and visualization of the liver and mesenteric lymph nodes is critical (4,6). Insulinomas are typically firmer than the normal parenchyma and may be small and obscured by the normal pancreatic tissue. Therefore, it can be difficult to localize a pancreatic nodule at time of surgery, especially in dogs (4,6-9).

When a nodule cannot be identified intraoperatively, biopsy specimens should be taken from the pancreas, liver, and mesenteric lymph nodes. In dogs, insulinoma develops within the right and left pancreatic lobes with equal frequency, and occult nodules are most common in the body of the pancreas. In addition, multiple nodules are seen in approximately 15% of dogs.  Thus, random removal of an entire pancreatic lobe offers no advantage and is not recommended (1-4,6).

In contrast to dogs, occult insulinoma appears to be rare in the ferret, making the pancreatic nodules less challenging to find. However, as compared to dogs and cats, multiple pancreatic nodules are more common than solitary nodules in ferrets. Full abdominal exploratory celiotomy is strongly recommended in ferrets, since concurrent nonpancreatic neoplasia (e.g., adrenal tumors) are not uncommon in this species (3,10,11).

Surgical Techniques for Partial Pancreatectomy
Surgical technique is similar in both the dog and cat (4,6,9). During surgery, the pancreas should be handled gently, and the surgeon should pay special attention to preserving the blood supply to the pancreas when performing a partial pancreatectomy. Any identifiable pancreatic nodules should be removed by partial pancreatectomy if possible, as this has been reported to result in longer survival times than simple excision of the tumor (12).

Partial pancreatectomy can be performed by the suture-fracture technique, the dissection-ligation technique, or through the use of an electrothermal bipolar vessel-sealing device (4,6,9,13). The bipolar vessel-sealing device (BVSD) denatures collagen and elastin within vessel walls and thus safely seals tissue and vessels while causing less tissue damage than is seen with the higher temperatures used in traditional cautery (13).

Using the BVSD to perform partial pancreatectomy in dogs decreases the incidence of post-operative pancreatitis when compared to dogs undergoing the suture fractionation technique. The BVSD is likely more effective in sealing pancreatic ducts during partial pancreatectomy and minimizes the leakage of pancreatic juices in to the remaining tissue that could cause local or generalized pancreatitis (13).

Whether or not metastatic lesions are visible, biopsy of the liver and mesenteric lymph nodes is recommended for staging (1-4).

Glucose Monitoring During and After Surgery
It is important to monitor the serum glucose concentration throughout and after surgery. Surgical manipulation of insulinoma can enhance the release of insulin from the tumor(s). Anesthesia will mask the signs of neuroglycopenia; thus, the only way of preventing serious hypoglycemia is to monitor the patient carefully and administer dextrose as needed.

While the surgeon is manipulating the pancreas and any metastatic lesions, the serum glucose concentration should be evaluated every 10-20 minutes. After surgery, the glucose concentration should be monitored every 30-60 minutes for the first 4-6 hours, and then every 2-4 hours until the glucose concentration has stabilized and the appropriate concentration of dextrose solution has been selected (1-4). The patient may have hyperglycemia after surgery, and intravenous fluids without dextrose may be appropriate.

Complications of Pancreatectomy
Potential complications include hyperglycemia, persistent hypoglycemia and pancreatitis (1-4,6,9).

• Hyperglycemia and diabetes mellitus— In some animals, the high concentration of circulating insulin secreted by the tumor suppresses the function of normal beta cells, leading to hyperglycemia once the insulin producing tumor is removed. As function of the beta cells returns, postsurgical hyperglycemia is resolved. If treatment with insulin is required after resection of an insulinoma, the clinician and the owner should be aware that endogenous insulin eventually may be produced either by the normal beta cells or by recurrent tumor cells. The owner should monitor glucose in the urine several times per week, and serum glucose should be checked at least monthly to avoid an iatrogenic hypoglycemic crisis.
• Persistent hypoglycemia—Persistent or recurrent hypoglycemia detected any time postoperatively should prompt consideration of symptomatic medical management or the use of chemotherapy. In patients who have had a significant hypoglycemia-free period after surgery, a second operation may result in several months of normoglycemia unless gross metastatic disease is present. In these cases medical management is indicated. This will be discussed in my next post.
• Pancreatitis— In dogs, the most common postoperative complication is pancreatitis. Documented or suspected pancreatitis has been reported in cats and ferrets as well postoperatively.

Relapse of Insulinoma
Although surgery is the most successful treatment we have for controlling hypoglycemia and prolonging survival, surgery will not be able to cure most animals with insulinoma. Almost all will show relapse of hypoglylcemia as the remaining tumor tissue grows and secretes high levels of insulin (1-4).

When a patient that has previously undergone surgery for insulinoma begins to show signs of hypoglycemia, a second surgery may be attempted or medical management instituted (see last post). If all visible tumor can be resected again, animals may remain symptom free for a number of additional months. Alternatively, many of these animals showing relapse can be controlled medically; I'll be discussing long-term medical management in my next post.

References:

1. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
4. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
5. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: A novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32. 
6. Birchard SJ. The pancreas In: Williams M, Niles JD, eds. BSAVA Manual of Canine and Feline Abdominal Surgery. Gloucester: BSAVA Publications, 2005;210–219.
7. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms: Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612.
8. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
9. Matthiesen DT, Mullen HS. Problems and complications associated with endocrine surgery in the dog and cat. Prob Vet Med 1990;2:627-667.
10. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745. 
11. Chen S. Pancreatic endocrinopathies in ferrets. Vet Clin North Am Exot Anim Pract 2008;11:107-123.
12. 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;215:226-230. 
13. Wouters EG, Buishand FO, Kik M, et al. Use of a bipolar vessel-sealing device in resection of canine insulinoma. J Small Anim Pract 2011;52:139-145. 

Emergency Management of Insulinoma and Other Causes of Hypoglycemia

Karo syrup can be used by owners at home to help control hypoglycemia.
Figure from www.gotoaid.com.

Hypoglycemia is a medical emergency that may result in seizures and permanent brain damage (1-5). Mild cases of hypoglycemia can quickly become serious and life threatening if the low blood glucose concentration continues to fall.

Untreated, severe, prolonged hypoglycemia can lead to stupor, coma, and even death in some animals.

Emergency Management of Hypoglycemia

Oral glucose administration
Owners who witness a hypoglycemic seizure can be instructed to rub a sugar solution (e.g., Karo syrup or honey) on their pet’s gums. Most animals will respond rapidly. However, owners should be warned not to place their hands directly into the mouth of an animal that is having a seizure and not to pour a sugar solution into the mouth of an unconscious pet (2,3,6).

If the animal responds to intravenous or oral glucose administration, it then should be fed a small, high-protein meal and kept as quiet as possible. Owners who notice a pet is becoming weak may prevent a hypoglycemic seizure by feeding.

Intravenous glucose administration
All patients with serious neurologic signs referable to hypoglycemia should be treated immediately by intravenous administration of a 50% dextrose solution (1-5 ml is given slowly over 10 minutes).  If the animal responds clinically, continuous intravenous administration of fluids with a 5% dextrose solution should be considered  (2,3,6). Some clinicians prefer to dilute the initial dose in 5% dextrose or sterile water to create a 20-25% solution prior to injection and thereby reduce the osmolality of the infused solution.

Regardless of the glucose concentration chosen to be administered in an emergency, it is important to keep in mind that it is not necessary to completely normalize the serum glucose concentration, but rather, to eliminate the clinical signs related to hypoglycemia.

Intravenous glucagon infusion
When glucose is administered intravenously to a patient with insulinoma, the tumor may be stimulated to release massive amounts of insulin, leading to severe hypoglycemia. This may result in a viscous cycle of the patient receiving larger volumes and more frequent dosing of intravenous dextrose even as clinical signs become more severe (2,3,6,7).

In dogs with insulinoma, intravenous glucagon should be considered if hypoglycemia and associated clinical signs cannot be not stabilized with infusions of dextrose alone. Glucagon stimulates hepatic gluconeogensis and glycogenolysis, thereby raising the circulating glucose concentrations.

One milligram of lyophilized glucagon USP should be reconstituted according to package directions and mixed with 1 liter of 0.9% saline solution. This resulting 1.0 µg/ml solution is given at 5-10 ng/kg/minute (2,6,7). The rate of infusion is adjusted, as needed, to maintain the serum glucose at a concentration of 50-100 mg/dl.

When the dog is able to eat and maintain its own blood sugar, and/or other surgical or medical therapy is used to treat the insulinoma, the glucagon infusion may be slowly tapered over 1-2 days as the serum glucose and clinical signs are monitored (6,7).

Complications of Prolonged Hypoglycemia and Its Treatment

Acquired seizure disorder
Prolonged hypoglycemia can cause focal laminar and pseudolaminar necrosis of the cerebral cortex, which can result in an acquired seizure disorder (2-6). Anticonvulsants may be required long-term for some animals recovering from hypoglycemic seizures.

If seizures persist despite the correction of hypoglycemia, cerebral hypoxia and edema may be responsible. Glucocorticoids, mannitol, or both, should be administered to help treat cerebral edema. Diazepam and phenobarbital may be required to control the seizures. However, we should also consider the possibility that a condition other than hypoglycemia may be the cause of the seizures.

Secondary hypokalemia
Uptake of glucose by cells is accompanied by the transport of potassium from the circulation to the intracellular space. This can result in severe hypokalemia in some cases (2,6). Therefore, the serum potassium concentration should be monitored in patients receiving dextrose infusions and animals supplemented with potassium in most cases (e.g., 16 mEq KCl per liter of intravenous fluids). This is particularly important for animals that are unable or refuse to eat.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. 3rd ed. St Louis: Elsevier Saunders; 2004;616–644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
5. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
6. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013 (in press)
7. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32.

Insulinoma in Dogs, Cat, and Ferrets: Confirming the Diagnosis

Insulinoma, or functional beta-cell tumor, originates from the islet cells of the endocrine portion of the pancreas (1,2). Insulinoma has been described most commonly in dogs and ferrets, and less commonly in cats. Although insulinoma cells produce a variety of polypeptides, most animals with insulinoma are examined because of clinical signs related to hyperinsulinism and resultant hypoglycemia.

Signalment
Insulinoma has been reported in dogs ranging from 3-15 years old but is most common in dogs older than 8 years old (3-8). Insulinoma is very common in domestic ferrets, with an age range from 2-7 years (9-11). No sex predilection has been reported in dogs, but male ferrets seem to be affected more commonly than females. Insulinoma appears to be a rare condition in cats, with only five cats having been reported; these cats ranged in age from 12-17 years (12-15).

Clinical Signs
Clinical signs in animals with insulinoma are caused by hyperinsulinism, which leads to hypoglycemia. In response to a low blood glucose concentration, catecholamines, glucagon, cortisol, ACTH, and growth hormone are released.

When there is a drop in blood glucose in clinically normal animals, these hormones (i.e., catecholamines, glucagon, cortisol, and growth hormone), in conjunction with a decrease in circulating insulin, help prevent progressive and potentially dangerously low blood glucose concentration. In animals with insulinoma, insulin is secreted even in the face of hypoglycemia and the increase in the counterregulatory hormones listed above. In these patients, the blood glucose is not stabilized, but continues to fall.

Dogs with insulinoma may be examined because of clinical signs related to neuroglycopenic symptoms produced by glucose deprivation of the central nervous system (e.g., hypoglycemia). Less commonly, some animals show adrenergic symptoms caused by catecholamines such as epinephrine (e.g., nervousness, tachycardia) (1,2,16).

The most common complaint for dogs with insulinoma is seizures (1-8). Other signs include collapse, lethargy, weakness, ataxia, mental dullness, muscle fasciculation, trembling, and nervousness (Table 1). Similar signs have been reported in cats with insulinoma (1,12-15). Peripheral neuropathy in association with insulinoma and hypoglycemia has been rarely reported in dogs with insulinoma (17,18).

Table 1: Clinical signs associated with insulinoma in dogs, cats, or ferrets (from reference 2).

Ferrets with insulinoma also commonly show signs of weakness and lethargy (9-11). As in dogs, these symptoms may be episodic. However, seizures are relatively uncommon in this species. Ptyalism is a clinical sign associated with insulinoma in ferrets that has not been described in dogs. The cause of this sign is not known, but ptyalism in ferrets may indicate nausea.

Confirming the Diagnosis— Fulfilling Whipple's Triad
A complete history may lead the clinician to suspect that a patient’s presenting clinical signs are related to hypoglycemia, and thus consider insulinoma as a differential diagnosis. A plasma glucose concentration of 40 mg/dl (2 mmol/L) or less supports the conclusion that the signs are caused by hypoglycemia (16).

If administration of glucose relieves the clinical signs of weakness, disorientation, seizures or trembling, we can conclude that these symptoms are caused by hypoglycemia. This full fills Whipple's triad (i.e, signs of hypoglycemia, biochemical confirmation of low blood glucose at time of clinical signs, and relief of clinical signs after glucose administration) (19,20). This positive response may be seen in animals with hypoglycemia for any reason, however, and is not diagnostic of insulinoma.

Other Causes of Hypoglycemia
In addition to insulinoma, there are many other possible causes of hypoglycemia in animals (1,2,16,21) (Table 2).

Table 2: Causes of hypoglycemia in the mature animal

Many of these differential diagnoses can be ruled out quickly during the initial history and physical examination. After consideration of these diseases is eliminated, insulinoma should be seriously considered in a mature patient with clinical signs of hypoglycemia.

Confirming the Diagnosis—Documenting Hyperinsulinemia
Hyperinsulinism is best diagnosed by the interpretation of serum insulin and glucose concentrations obtained from the patient at the same time. If the clinician suspects hyperinsulinism at the time of initial examination of an animal showing signs of hypoglycemia, serum samples for glucose and insulin measurements are best obtained at that time.

If attempts are made to document hyperinsulinism at a later date, blood samples should be obtained after fasting when the glucose is less than 50 mg/dl (<3.0 mmol/L). It is essential that patients suspected of having hyperinsulinism fast under supervision to allow intervention should signs of hypoglycemia occur.

A high insulin concentration in any animal with concurrent hypoglycemia is consistent with hyperinsulinism (1,2,16,22). If a hypoglycemic patient has an insulin concentration that is within the reference range, the animal again should fast, and the test should be repeated when two consecutive serum glucose readings of 50 mg/dl or less are obtained. If the patient is consistently hypoglycemic, an insulin level within the normal range is considered inappropriate and the patient likely has hyperinsulinism.

Identifying the Pancreatic Nodule
Whenever possible, abdominal ultrasound should be performed in dogs and cats with suspected insulinoma. It can be difficult to detect small pancreatic nodules via ultrasound, but it may be helpful in identifying abdominal metastases (2,22,23). In all species, abdominal ultrasonography may help rule out other neoplasms as a cause of hypoglycemia.

Computed tomography (CT) can also be used to accurately identify pancreatic nodules, and this procedure may be helpful in surgical planning (23).

Bottom Line

Although an accurate diagnosis of insulinoma can generally be made by clinical pathologic testing, histologic examination is required for a definitive diagnosis. Exploratory celiotomy is recommended in all patients with insulinoma if the owner wishes to pursue treatment, but long-term medical management can be helpful in many of these animals.

In my next post, I'll be discussing emergency management of hypoglycemia associated with insulinoma.  This is a critical issue—  if we can't control the immediate clinical signs of hypoglycemia, we will never be able to proceed to definitive or long-term treatment of this serious disorder.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Kruth SA, Feldman EC, Kennedy PC. Insulin-secreting islet cell tumors: establishing a diagnosis and the clinical course for 25 dogs. J Am Vet Med Assoc 1982;181:54-58. 
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;188:60-64. 
5. Schrauwen E. Clinical peripheral polyneuropathy associated with canine insulinoma. Vet Rec 1991;128:211-212.
6. Trifonidou MA, Kirpensteijn J, Robben JH. A retrospective evaluation of 51 dogs with insulinoma. Vet Q 1998;20 Suppl 1:S114-115. 
7. Madarame H, Kayanuma H, Shida T, et al. Retrospective study of canine insulinomas: eight cases (2005-2008). J Vet Med Sci 2009;71:905-911. 
8. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
9. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745.
10. Ehrhart N, Withrow SJ, Ehrhart EJ, et al. Pancreatic beta cell tumor in ferrets: 20 cases (1986-1994). J Am Vet Med Assoc 1996;209:1737-1740.
11. Weiss CA, Williams BH, Scott MV. Insulinoma in the ferret: clinical findings and treatment comparison of 66 cases.  J Am Anim Hosp Assoc 1998;34:471-475.
12. McMillan FD, Feldman EC. Functional pancreatic islet cell tumor in a cat. J Am Anim Hosp Assoc 1985;21:741-746.
13. Hawks D, Peterson ME, Hawkins KL, et al. Insulin-secreting pancreatic (islet cell) carcinoma in a cat. J Vet Intern Med 1992;6:193-196.
14. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
15. Greene SN, Bright RM. Insulinoma in a cat. J Small Anim Pract 2008;49:38-40. 
16. Schoeman JP. Investigation of hypoglycaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;259-264.
17. Schrauwen E, Van Ham L, Desmidt M, et al. Peripheral polyneuropathy associated with insulinoma in the dog: Clinical, pathological, and electrodiagnostic features. Prog Vet Neurol 1996;7:16-19.
18. Braund KG, Steiss JE, Amling KA, et al. Insulinoma and subclinical peripheral neuropathy in two dogs. J Vet Intern Med 1987;1:86-90. 
19. Ariamkina OL, Doroshenko GM, Petrenko LV. On diagnostic value of Whipple's triad: a case of insulinoma diagnosis. Klin Med (Mosk) 1997;75:61-63. 
20. Hirshberg B, Livi A, Bartlett DL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endo Metab 2000;85:3222-3226. 
21. Murphy LA, Coleman AE. Xylitol toxicosis in dogs. Vet Clin North Am Small Anim Pract 2012;42:307-312. 
22. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
23. Robben JH, Pollak YW, Kirpensteijn J, et al. Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma. J Vet Intern Med 2005;19:15-22. 

Top Endocrine Publications of 2012: Insulinoma and Other Causes of Hypoglycemia

Insulinoma in a dog, showing up a solidary pancreatic nodule

In my fourth compilation of the canine and feline endocrine publications of 2012, I’m going back to disorders of the pancreas. But now let’s move on to islet cell tumors (e.g., insulinoma) and other causes of hypoglycemia.

Listed below are 13 research papers written in 2012 that review endocrine hypoglycemia in dogs and cats. These include new aspects in pathogenesis of hypoglycemia associated with insulin-secreting tumors of the pancreas (1,3,5), portosystemic shunts (2), or hypoadrenocorticism (4,8).

Other papers review the hypoglycemia and liver toxicosis associated with xylitol toxicosis in dogs (7,10), as well as the hypoglycemia associated with insulin treatment of diabetes mellitus (6,11-13).

2012 Papers on Canine and Feline Islet Cell Tumors of the Pancreas and Other Causes for Hypoglycemia:

1. Buishand FO, van Erp MG, Groenveld HA, et al. Expression of insulin-like growth factor-1 by canine insulinomas and their metastases. Vet J 2012;191:334-340. 
2. Collings AJ, Gow AG, Marques A, et al. A prospective study of basal insulin concentrations in dogs with congenital portosystemic shunts. J Small Anim Pract 2012;53:228-233. 
3. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
4. Gow AG, Gow DJ, Bell R, et al. Insulin concentrations in dogs with hypoadrenocorticism. Res Vet Sci 2012;93:97-99. 
5. Hambrook LE, Kudnig ST. Tumor thrombus formation in two dogs with insulinomas. J Am Vet Med Assoc 2012;241:1065-1069. 
6. Hugler S. Diabetic alert dogs: A good nose for hypoglycemia. Dtsch Med Wochenschr 2012;137:p25. 
7. Imai A, Nishita T, Ichihara N, et al. Binding affinity of anti-xylitol antibodies to canine hepatic vessels. Vet Immunol Immunopathol 2012;149:108-111. 
8. Kasabalis D, Bodina E, Saridomichelakis MN. Severe hypoglycemia in a cat with primary hypoadrenocorticism. J Feline Med Surg 2012;14:755-758. 
9. Mazaki-Tovi M, Segev G, Yas-Natan E, et al. Serum gastrin concentrations in dogs with liver disorders. Vet Rec 2012;171:19. 
10. Murphy LA, Coleman AE. Xylitol toxicosis in dogs. Vet Clin North Am Small Anim Pract 2012;42:307-312. 
11. Niessen SJ. Glucagon: are we missing a (life-saving) trick? J Vet Emerg Crit Care (San Antonio) 2012;22:523-525. 
12. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for dogs with diabetes mellitus. J Vet Intern Med 2012;26:953-961. 
13. Zeugswetter FK, Schornsteiner E, Haimel G, et al. Metabolic and hormonal responses to subcutaneous glucagon in healthy beagles. J Vet Emerg Crit Care (San Antonio) 2012;22:558-563. (See my blog post entitled "Use of a Glucagon Emergency Kit for Insulin-Induced Hypoglycemia" to see my review of this paper.)

Q & A: Hypoglycemia in a Dog with Hepatocellular Carcinoma

My patient is a 10-year-old, male, Husky that presented with hypoglycemic seizures and a large intra-abdominal tumor a year ago. Physical examination at that time showed cachexia and a palpable mass in the cranial aspect of the abdomen. The major laboratory abnormalities included hypoglycemia (32 mg/dl) and high enzyme activities for both alanine aminotransferase (ALT) and alkaline phosphate (AP). Fasting and postprandial serum bile acid concentrations were high. Insulinoma was considered but the serum concentrations of both insulin and insulin-like growth factor I (IGF-1) were found to bee low at that time.

Abdominal radiographs and abdominal ultrasonography confirmed that the intraabdominal mass was of liver origin. At surgery, the liver tumor appeared isolated to the left liver lobe and was removed. Biopsy confirmed hepatocellular carcinoma. Postoperatively, the hypoglycemia resolved and the dog did well.

Recently, the dog has presented again for generalized hypoglycemic seizures; my workup shows that the tumor now has diffusely infiltrated all the remaining liver lobes. The laboratory workup again shows severe hypoglycemia (35 mg/dl) and high ALT and AP activities. The serum concentrations of total bilirubin, total protein, albumin, and urea nitrogen all remain within reference range limits.

My questions are the following:

1. Can I assume that the hypoglycemia is secondary to the hepatic tumor secreting insulin or another insulin-like factor? I originally measured both serum insulin and IGF-1 but both concentrations were normal.
2. Or should I assume that the hypoglycemia is from the liver failing? If that is the case, I thought it odd to not have a concurrent hypoalbuminemia or a high total bilirubin concentration.

I'd appreciate your input on this case.

My Response:

If the etiology of this dog's hypoglycemia was purely from liver failure, then yes, it would be odd to see severe hypoglycemia from liver failure without also seeing a low serum albumin and urea nitrogen. Like you indicated, canine hepatocellular carcinomas can also produce hypoglycemia via paraneoplastic means — these tumors can make an insulin-like substance that causes the blood glucose to fall (1,2). Since it's not insulin being secreted, the serum insulin levels will be low concurrent with the hypoglycemia. The insulin concentrations would never be high, as would be expected with an insulinoma.

Hypoglycemia can be caused by non-insulinoma tumors in the retroperitoneum, thorax, or abdomen. Intra-abdominal tumors that may cause hypoglycemia include hepatocellular carcinoma (the most common primary liver tumor in the dog), hepatoma, leiomyoma, leiomyosarcoma, melanoma, and hemangiosarcoma (1-4). Large mammary gland tumors have also been associated with hypoglycemia in dogs (5).

Large non-islet cell tumors in the abdomen have been previously been associated with hypoglycemia. There may be more than one cause, but the most common is believed to be tumor production of insulin-like growth factors, especially IGF-2 (1,2,4). The tumor may produce excessive IGF-2 or impair IGF-2 binding to serum proteins. Other contributing factors may be rapid glucose utilization by the tumor or deficiency of insulin antagonists. A consistent finding is suppressed serum concentrations of insulin (and IGF-1), like you found in this case.

Sucessful removal of a hepatocellular carcinoma (or other non-non-islet cell tumors) associated with hypoglycemia should correct the hypoglycemia, like it originally did in this dog (1). Due to the widespread tumor infiltration through the liver, this dog's long-term prognosis is guarded at this time. However, use of frequent feedings and treatment with glucocorticoids may help control signs of hypoglycemia, at least temporarily.

References:

1. Sakai M, Asano K, Nakata M, et al. Diabetes mellitus after resection of hepatocellular carcinoma with hypoglycemia in a dog. The Journal of Veterinary Medical Science 2006;68:765-767.
2. Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992-2002). Journal of the American Veterinary Medical Association 2004;225:1225-1230.
3. Zini E, Glaus TM, Minuto F, et al. Paraneoplastic hypoglycemia due to an insulin-like growth factor type-II secreting hepatocellular carcinoma in a dog. Journal of Veterinary Internal Medicine 2007;21:193-195.
4. Leifer CE, Peterson ME, Matus RE, et al: Hypoglycemia associated with nonislet cell tumor in 13 dogs. Journal of the American Veterinary Medical Association 1985; 186:53-5.
5. Rossi G, Errico G, Perez P, et al. Paraneoplastic hypoglycemia in a diabetic dog with an insulin growth factor-2-producing mammary carcinoma. Veterinary Clinical Pathology 2010;39:480-484.

Q & A: Hypoglycemia in a 7-Year-Old Laborador Retreiver

I'm writing about a 7-year-old lab that present today for signs associated with hypoglycemia.He has been progressive lethargic for the last week. The owner noted staggering and weakness and brought him into our clinic for evaluation yesterday.

On examination, the dog was quiet but clinically normal. His blood glucose concentration, however, was low at 26 mg/dl (reference range, 70-125 mg/dl). All other serum chemistry results (including serum sodium and potassium were normal. Radiographs of the chest and abdomen were unremarkable. The owner has been quizzed at length about possible xylitol ingestion, but there is no history of possible ingestion.

We hospitalized the dog for observation and started a 5% dextrose drip overnight. This morning, the blood glucose was still quite low (only 47 mg/dl) after being off dextrose for about an hour. I continued the glucose drip (raised it to a 10% drip), and the blood glucose concentrations ranged from 41 to 70 mg/dl throughout the day. He is eating well and alert on the IV glucose supplementation.

My rule outs are the following intoxications or medical disorders:

• Xylitol ingestion 
• Atypical Addison's (the serum electrolytes and Na:K ratio were normal)
• Insulinoma (insulin-secreting pancreatic islet cell tumor)
• Portosystemic shunt

I have submitted an serum insulin level at the time when the dog's blood glucose was very low (42 mg/dl) and the results are still pending. I've also submitted a baseline cortisol concentration to help rule out Addison's disease. I have not measured his serum bile acids because I did not want to fast him just yet.

Any other thoughts, suggestions for diagnostics? Anything I am missing?

My Response:

You have the correct list of differential diagnoses and are working your way through the list properly. I'd agree with not fasting the dog — I'd just do a random bile acid measurement to first see it that's abnormal.

If this dog has an insulinoma, we have to remember that IV administration of dextrose may stimulate secretion by the pancreatic tumor. Insulin release post-hyperglycemia often results in rebound hypoglycemia, which necessitates additional dextrose administration and leads the clinician into a cyclical hyperglycemia/hypoglycemia "chase" which can be difficult to terminate.

In this cases, it an be really helpful to just use glucagon instead. Glucagon for injection (1 mg vial) is reconstituted according to the manufacturer's instructions with supplied diluent, then added to 1000 ml of 0.9% NaCl. The 1000 ng/ml solution is administered intravenously as a constant rate infusion (CRI) with the use of a syringe infusion pump. The glucagon CRI is initially given as a bolus of 50 ng/kg, then administered at a rate of 10 to 15 ng/kg/min. The dose may need to be increased up to 40 ng/kg/min as needed to maintain euglycemia.

Additional Followup:

I've put the dog on a glucagon constant rate infusion and it's been working great to maintain the blood glucose concentration in the normal range in the hospital!

The dog's resting serum cortisol concentration was normal at 3.2 μg/dl, so Addison's disease appears highly unlikely. My serum insulin and bile acid results still pending.

The owner has been internet investigating and he told me that his dog has eaten a birch limb/stick last week. I read that xylitol is derived from hardwoods such as birch — Is there any way the xylan from the birch could be metabolized to xylitol in the dog?

My Response:

You're right, the normal serum cortisol (>2.0 μg/dl) rules out Addison's disease.

As far as xylitol toxicity is concerned, I did some research myself and found that birch wood itself doesn't contain xylitol so that's unlikely to be the cause of the hypoglycemia. And this would be especially true since it was consumed a week ago, and you wouldn't expect continued hypoglycemia if the problem was due to xylitol toxicity.

Outcome:

Abdominal ultrasound showing
multiple hypoechoic masses in liver

The dog's serum insulin concentration, collected at the time of severe hypoglycemia, was extremely high (402 pmol/L; reference range, 60-230 pmol/L). The bile acids values were normal. An abdominal ultrasound revealed a pancreatic mass with several hypoechoic areas in liver, consistent with pancreatic neoplasia with metastasis to the liver. A trial of diazoxide was performed at home, but hypoglycemia persisted.

Based on the poor prognosis and lack of response to diazoxide, the owners elected euthanasia. Multiple pancreatic and hepatic nodules were identified at necropsy; histopathology confirmed beta cell islet cell neoplasia with metastasis to the liver.

Final Diagnosis: Insulinoma (insulin-secreting carcinoma of pancreas), producing hypoglycemia.

References:

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