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.)

What's the Best Insulin for Diabetic Cats and Dogs?

With the reintroduction of Vetsulin (porcine insulin zinc suspension) to the U.S. market (1-3), I've received a number of questions concerning the use of this insulin in dogs and cats. Here are the major questions I've received:

• Is this the initial insulin of choice for dogs? 
• How about for cats? Should this be an insulin that we turn to for our newly diagnosed feline diabetics?  
• If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
• How will this insulin compare to NPH, glargine (Lantus), detemir (Levemir), or PZI (ProZinc) in cats or dogs?  How does the cost compare to these other insulin preparations?

Is this the initial insulin of choice for dogs?
In my opinion, the answer to that is yes, this is the initial insulin of choice for most dogs. Because it's composed of both short and long-acting insulin components, Vetsulin helps control postprandial hyperglycemia and has a longer duration of action than NPH in most dogs (4-7). The cost is approximately the same as NPH, but less than the insulin analogues (e.g., detemir and glargine). See more below, where I do my cost-comparisons for the various insulin preparations.

Is this the initial insulin of choice for cats?
A number of studies have proven that Vetsulin will certainly control hyperglycemia in cats, especially if combined with a low carbohydrate diet (<10% of calories) (8-11). However, the duration of action may be too short in some diabetic cats, and most feel that the longer acting insulin preparations (glargine, detemir or ProZinc) work better to maintain better control of hyperglycemia in cats (11-13).

Of course, maintaining glycemic control throughout the day is more important if diabetic remission is the goal (13,15,16)— if not, Vetsulin might be less expensive and certainly would be more than adequate in most cats (8-10).

If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
For diabetic dogs not regulated on NPH, the answer is a definite "yes." For cats that are on NPH, Vetsulin would certainly be a better choice, but switching to one of the  longer-acting insulin preparations (insulin glargine, detemir, or PZI) would be a better choice.

How will this insulin compare to NPH, detemir, glargine, or PZI in cats or dogs?  
In dogs, I generally use 3 insulin preparations: Vetsulin, NPH, and insulin detemir. Again, the main problem with NPH insulin in dogs is that the duration of action is too short, and many of these dogs will respond better to Vetsulin. Insulin detemir is the most potent insulin we have for use in dogs, with a longer duration of action (14), but it's much more expensive than either NPH or Vetsulin.

In cats, I never use NPH because of it's short duration, but I will sometimes use Vetsulin as an intermediate-acting insulin.  Most authorities would rank insulin glargine as the first choice of insulin in cats, then insulin detemir or PZI (not the compounded product (17), but FDA-approved ProZinc), then Vetsulin, then finally NPH as a very last choice.

How does the cost of Vetsulin compare to these other insulin preparations?
NPH insulin, insulin glargine, and insulin detemir are all available as 10-mL vials at a U-100 insulin concentration. The retail prices of an individual vial of NPH insulin, insulin glargine, and insulin detemir vary, depending on the pharmacy and its location. I checked out the prices today at my local Walmart, CVS, and Rite Aid pharmacies, and here are the range of prices I was quoted:

• NPH —$24.88 (Walmart's ReliOn brand) to $100.39 (CVS) and $107.99 (Rite Aid)!
• Glargine — $152.84 (Walmart) to $169.99 (CVS) and $188.99 (Rite Aid)
• Detemir — $160.32 (Walmart) to $190.99 (CVS)

Vetsulin (porcine insulin zinc suspension) is available as a 10-mL vial of insulin in a U-40 insulin concentration. The wholesale cost of the updated Vetsulin product is inexpensive ($23.97 per vial), similar to the original product. In most veterinary practices, the retail price of a vial of Vetsulin will be approximately $50.

Therefore, the cost of a bottle of Vetsulin is similar or even less than the price of NPH insulin and costs much less (about 25-30%) than that of insulin glargine or detemir.  But remember, the total amount of insulin in a vial of NPH, glargine, and detemir (all U-100 insulins) is 1000 units, where a vial of Vetsulin (a U-40 insulin) contains 400 units, only 40% as much. So in the end, the cost per unit of most of these insulins preparations woud generally turn out to be similar.

Therefore, the cost of all of these insulin preparations would be similar in most diabetic cats and smaller dogs receiving a typical daily dose of insulin (0.5-0.7 U/kg). Because the concentration of Vetsulin is 40 U/mL, owners of larger diabetic dogs, owner will often go through a bottle within a few days. In these dogs, if insulin resistance is present, it's sometimes cheaper to use a U-100 insulin, such as detemir.

However, the bottom line is clear: it doesn't matter how much money we are saving if the insulin isn't working. Instead, for most pet owners, it's more important use an insulin preparation that best controls the diabetic state. And for most diabetic dogs, that insulin would be Vetsulin, followed by insulin detemir.

References:

1. Peterson ME. Vetsulin Insulin Updated and Approved for Release in USA. Insights into Veterinary Endocrinology. April 17, 2013.
2. Vetsulin website. www.vetsulin.com
3. Vetsulin website: Veterinary Product Updates. www.vetsulin.com/vet/Product_Update.aspx
4. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682. 
5. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237. 
6. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
7. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
8. Martin GJ, Rand JS. Pharmacology of a 40 IU/ml porcine lente insulin preparation in diabetic cats: findings during the first week and after 5 or 9 weeks of therapy. J Feline Med Surg 2001;3:23-30. 
9. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94. 
10. Michiels L, Reusch CE, Boari A, et al. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008;10:439-451. 
11. Rand JS. Feline diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;133-147.
12. Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther 2008;31:205-212.
13. Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg 2009;11:683-691. 
14. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2011;90:396-403.
15. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
16. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
17. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605. 
18. Drugstore.com. www.drugstore.com. (accessed 2006 Oct 3).
19. http://www.relion.com/diabetes/insulin