Insulin Choices for the Diabetic Cat and Dog: Which is Best?

A multitude of new human insulin preparations are available, and the list changes almost every month as new products are continually being developed while others are withdrawn. Thankfully, the are still two veterinary insulin preparations registered specifically for use in dogs and cats (See Table 1). All products are potentially efficacious for the treatment of diabetes; however, there is only limited veterinary information on most of the recently released human products.

The current trend in human medicine is towards long-acting peakless insulin analogue preparations that aim to provide continuous basal insulin supplementation, and which are typically combined with administration at meal times of a rapid-onset, short-acting insulin preparation. This has resulted in many changes in the market for short- and intermediate-acting insulin products and their pre-mixed combinations. It is these products that are most likely to be useful for management of diabetes in dogs and cats, especially if the veterinary insulin preparations prove ineffective or are not available.

WHICH INSULIN PREPARATIONS HAVE BEEN WITHDRAWN?

Veterinarians must adapt to the withdrawal of several familiar insulin preparations. IDEXX Pharmaceuticals have recently withdrawn PZI-VET, which was a 40 U/ml bovine/porcine preparation of protamine zinc insulin registered in several countries for veterinary use. The loss of this product highlights the practical problems often associated with production of animal-sourced insulins. In the human market, all of the Lente and Ultralente insulin preparations were discontinued a number of years ago. There is a similar trend in the human market to withdrawal many of the older, human recombinant insulin preparations. For example, it appears likely that human recombinant regular insulin will be withdrawn in the near future.

WHICH PREPARATIONS ARE STILL AVAILABLE?

Porcine Lente Zinc Suspension
The only Lente insulin preparation now is Vetsulin (trade name in the USA) or Caninsulin (trade name elsewhere in the world), manufactured by Intervet Schering-Plough. This is a 40 U/ml porcine insulin zinc suspension specifically registered for veterinary use (Table 1).

Availability of Vetsulin in the USA has recently been severely limited by a FDA recall, as a result of their findings that he product may contain varying amounts of crystalline zinc insulin;1 however supply of Caninsulin elsewhere is unaffected and has been reliable for many years.

There is good evidence that this insulin product is effective for the treatment of diabetes mellitus in dogs and cats. (references 2,3,4) Lente insulin has an intermediate duration of action and is a combination of 30% short-acting Semilente insulin and 70% longer-acting Ultralente insulin. It is particularly suited to a twice-daily dosing regimen in diabetic dogs because the meal can be fed at the time of the insulin injection. This more dilute 40 U/ml veterinary preparation is advantageous for small dogs and cats, which might require a total insulin dose of only 1 or 2 U. Dosing is more simple and accurate if specific U-40 syringes are prescribed with this product.

Regular Insulin
Products containing 100% regular crystalline insulin (recombinant human insulin) are still available (100 U/ml) and have long been recommended for the management of diabetic ketoacidosis and ketosis in dogs. These include Humulin R (Eli Lilly) and ActRapid (Novo Nordisk). If these products are withdrawn from the human market, it will be necessary for veterinarians to switch to the newer short-acting insulin analogue preparations, such as insulin lispro or insulin aspart (Table 1).

Isophane (NPH) Insulin
Humulin N (Eli Lilly) and Novolin N (Novo Nordisk) are both recombinant human NPH insulin (100 U/ml) that have an intermediate duration of action (Table 1). The human NPH insulins are effective for the treatment of diabetes in dogs when administered twice-daily.5 These recombinant human NPH insulins do not work well in most cats and are NOT recommended.

Combinations of 70% Isophane (NPH) and 30% Regular Insulins
Humulin 70/30 (Eli Lilly) is still available in most countries. This is a 100 U/ml pre-mixed combinations of 30% short-acting and 70% intermediate-acting insulin (Table 1). Because it has a similar duration/action curve to Lente insulin, this insulin is well suited to a twice-daily dosing regimen in diabetic dogs where meals are fed at the same time as the insulin injections.

WHAT ARE THE NEW INSULIN PREPARATIONS?

Recombinant Human Protamine Zinc Insulin
The release of ProZinc (Boehringer Ingelheim) provides a veterinary product to fill the gap in the market created by the discontinuation of PZI-VET, and efficacy of the new product (references 6,7) for treatment of diabetic cats is comparable to that of the discontinued product (reference 8). ProZinc is an FDA approved insulin and is available as a U-40 insulin concentration.

Protamine zinc insulin is not generally recommended as a first choice therapy for diabetic dogs as it has a less predictable action with a slower onset than Lente insulin or the 70% or 100% NPH preparations.

Short-Acting Lispro Insulin Preparations

Lispro insulin (Humalog, Eli Lilly) has been shown to be a safe and effective alternative to regular insulin for the treatment of diabetic ketoacidosis in dogs. Insulin Aspart (Novolog, manufactured by Novo Nordisk) and glulisine (Apidra, manufactured by Sanofi Aventis) are other short acting insulin analogs that could be used as an alternative to regular insulin (Table 1).

Insulin Glargine
Lantus (Sanofi Aventis) is a long-acting synthetic insulin analogue developed for the human diabetic market to provide continuous basal insulin concentrations that inhibit hepatic glucose production. The therapeutic aim is to mimic the physiological pattern of insulin secretion of healthy subjects, and the basal insulin levels provided by these products are supplemented at meal times by administration of short-acting insulin preparations that act during the postprandial period.

Glargine insulin differs from standard insulins because it has been genetically modified, by replacing an asparagine with glycine and adding 2 arginine amino-acids to the c-terminal end of the molecule. This alters the pH solubility (isoelectric point) of the molecule, so that it is soluble at a pH 4 but insoluble at neutral pH (e.g., in the body). When glargine insulin is injected into the skin, it precipitates because of the pH change and forms insoluble microcrystals, which are slowly absorbed into the circulation. This constant release of small amounts of insulin prevents major peaks and troughs from developing. The formation of micro-precipitates and slow absorption are dependant on the acidity of glargine. Therefore, glargine cannot be mixed or diluted.

Insulin glargine is efficacious for the treatment of diabetes in cats. (references 9,10) Although there is very little information about the use of this product in dogs, it does not appear to work well in this species.

Insulin Detemir

Levemir (Novo Nordisk) is another synthetic insulin analogue with long duration of action that is produced using recombinant DNA technology. The insulin molecule is modified by the addition of an acylated fatty acid chain that enables reversible binding to plasma proteins, from where it is released slowly into plasma.

Detemir results in a similar action profile as glargine, but appears to be more potent and may be longer-acting in some dogs and cats.

Mixtures of Short-Acting and Long-Acting Insulin Analogues
The latest insulin preparations released for the human market are pre-mixed combinations of a short-acting insulin analogue (ie, Lispro or Aspart insulin) with a longer-acting insulin analogue (ie. Lispro or Aspart Protamine Insulin). See Table 1 for more information.

Humalog Mix 75/25 (Eli Lilly) is marketed for human diabetics as an improved product that can be used twice-daily in replacement of Humulin 70/30 (reference 11). Compared with Humulin 70/30, Humalog Mix75/25 in human subjects has a more rapid and predictable onset of glucose-lowering activity, with greater reduction in postprandial glycemia when administered with a meal, and a similar duration of action.

There is currently no published information on the use of these new pre-mixed combinations for the management of diabetes in dogs or cats. At least in diabetic dogs, these insulins might be effective when administered twice-daily at the same times as meals. Based on the human data, it can be predicted that the risk of hypoglycemia might be greatest in the first 2 hours after injection in dogs and so it will likely be crucial that meals are always consumed at the time of injection.

Table 1:

References:

1. 
   FDA CVM alert.
   
   


2. 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;19:675-82.
   
   


3. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237.
   
   


4. 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 10:439-51.
   
   


5. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50-55.
   
   


6. Norsworthy GD, Lynn RC. Clinical study to evaluate a new formulation of protamine zinc for treatment of diabetes mellitus in cats. J Vet Intern Med 22:729-730, 2008.
   
   


7. Nelson RW, Henley K, Cole C. Efficacy of protamine zinc recombinant insulin for treating diabetes mellitus in cats. J Vet Intern Med 22: 730, 2008.
   
   


8. Nelson RW, Lynn RC, Wagner-Mann CC, Michels GM. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38-42.
   
   


9. 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
   
   


10. Rand J. Editorial: glargine, a new long-acting insulin analog for diabetic cats J Vet Intern Med 2006;20: 219-20.
    
    


11. 
    Eli Lilly prescribing information.

Q & A: Best Diet for Dogs with Diabetes Mellitus

I have a 10-year old, male, 4-kg Miniature Pinscher that has been on twice daily NPH insulin injections (0.75 U/kg per injection) for the last 6 months. Because of his diabetes, we have been feeding Hill’s Prescription w/d diet. Overall, the serum glucose curves are quite good, the polyuria and polydipsia have resolved, and the dog seems to feels great. However, despite being well controlled, the dog has been losing weight and has lost over 1.5 kg since diagnosis.

The main problem is that the dog continues to be ravenous and is loosing weight. Despite being well controlled on his blood glucose curved, the dog has lost over 1.5 kg since diagnosis.

Am I feeding the wrong diet? I thought that all diabetic dogs did best when fed a high fiber diet such as Hill’s w/d.

My Response:

First of all, there is not one type of diet that is recommended for all dogs with diabetes. Diabetic dogs can do well when fed a number of diets as long as they are nutritionally complete and balanced, do not contain simple sugars, are fed at consistent times in consistent amounts, and are palatable to ensure a predictable and consistent appetite. As we all know, it’s difficult enough to regulate a diabetic when they are eating consistently well— if they refuse to eat their diet, adequate glucose regulation can become next to impossible.

In many newly diagnosed diabetic dogs, I don’t change their diet at all.  The most important dietary factor in the diabetic is consistency, so that you can match your insulin dose to the degree of post-prandial hyperglycemia. The owner must understand that the key is to feed the same amount of the same diet at the same time every day!

In general, the goals of dietary therapy in canine diabetes mellitus are four-fold:

1. Optimize the dog’s body weight and body condition score (i.e., weight loss versus weight gain, as needed)


2. Minimize post-prandial hyperglycemia


3. Control hyperlipemia and hypertriglyceridemia


4. Modify the diet based any concurrent conditions (e.g., pancreatitis, kidney disease, gastrointestinal disease)

Optimize Body Weight
In diabetic dogs that are obese, I always recommend feeding a reduced calorie diet designed to help the dog lose weight. The high fiber diets are good for this purpose (1-4). No matter what diet is fed, however, it’s also important to limit the amount of fat in the diet when weight loss is the goal. To me, an appropriate weight loss diet should contain restricted amounts of fat — less than 30% on a metabolizable energy (ME) basis, which means <30% of the calories in the diet supplied by fat.
(For more information about how to calculate ME values for fat, protein, and carbohydrates, see Calculating the Metabolizable Energy (ME) Values of a Dog Food, below.)

In underweight dogs with diabetes, the goal of dietary therapy is the complete opposite. In these thin dogs. our priority is to normalize body weight and restore and preserve muscle mass. These dogs may never regain the weight needed if a food with moderate to high amounts of fiber is fed — they may even continue to progressively lose even more weight. Therefore, these thin to emaciated dogs should be fed a high-quality, higher energy diet that can contain a slightly increased fat content to ensure that they regain their lost body weight (3,4).

Minimize Post-prandial Hyperglycemia
Several “older” landmark studies showed that feeding high-fiber diets can improve glycemic control in dogs with diabetes (1,2). The extra dietary fiber slows the digestion and absorption of carbohydrates, and thereby helps to minimize post-prandial hyperglycemia (1-4).

However, there are disadvantages in feeding all diabetic dogs a high-fiber diet. Again, because these diets tend to promote weight loss, they are not suitable for the thin or emaciated dog with diabetes (5). In addition, the high dietary fiber content of the food can result in unwanted side effects, including inappetence, diarrhea, and flatulence in some dogs.

Other more recent studies fail to show a clear-cut clinical benefit of feeding a high-fiber diet over a typical adult maintenance diet with moderate-fiber content to diabetic dogs.  In one study, no significant differences in insulin requirements or glycemic control were found in dogs fed a high-fiber, moderate-carbohydrate, moderate-fat diet versus an adult maintenance diet with moderate fiber, lower carbohydrate, and higher fat (5). As expected, weight loss occurred when the dogs were fed the high-fiber diet, whereas body weights were maintained with the moderate-fiber diet.

For any dog food, the major potential influence on the postprandial glycemic response is the dietary carbohydrate source (6-8). Foods and snacks containing simple sugars which rapidly increased blood glucose should always be avoided, of course. Feeding carbohydrate sources that have a low glycemic index (e.g, sorghum and corn) are preferred for diabetic dogs. Carbohydrates with a higher glycemic index (e.g., rice) are best avoided (6).

Because dogs are omnivores, they can tolerate higher amounts of carbohydrates better than do diabetic cats. Therefore, I recommend a diet that is moderately restricted in carbohydrate content — that is, a diet with <30% metabolizable energy (ME) as carbohydrates— for diabetic dogs to limit their post-prandial glucose load and help control hyperglycemia.

Control Hyperlipemia and Hypertriglyceridemia
A diet containing restricted amounts of fat (again, <30% ME) should be fed to diabetic dogs with concurrent hypertriglyceridemia or hyperlipidemia (4,9).

The presence of hyperlipidemia (i.e., hypertriglyceridemia and, to a lesser degree hypercholesterolemia) has long been associated with pancreatitis in dogs (9). Hyperlipidemia is common in untreated or poorly controlled diabetes mellitus and may contribute to the concurrent pancreatitis that can develop in these diabetic dogs. For my diabetic patients with concurrent pancreatitis, I’ve had good luck with the Royal Canin Veterinary Diet Gastrointestinal Low-Fat LS diet — it contains the lowest amount fat of any of the commercial diets (15% ME for fat), and most dogs find it quite palatable.

However, some dogs with diabetes secondary to chronic pancreatitis also have partial loss of exocrine pancreatic function and can be at risk for excessive weight loss when fed a low fat diet. One approach for the underweight diabetic dog with hypertriglyceridemia is to consider restricting dietary fat intake only after adequate glycemic control has been established. In these dogs, both body weight and serum triglyceride concentrations are followed carefully, and dietary adjustments are made as needed.

High Protein Diets in Canine Diabetes?
The optimal dietary protein for diabetic dogs has not been determined. But it does not appear that the protein requirement for a diabetic dog would be much different than a non-diabetic dog. However, because we frequently aim for either carbohydrate or fat restriction (or both), dietary protein will often provide a substantial source of calories for diabetic dogs (for example, protein >30% ME).

Calculating the Metabolizable Energy (ME) Values of a Dog Food
The most accurate way to evaluate pet foods and their composition is to consider the calories or metabolizable energy (ME) that comes from the protein, fat, and carbohydrate fractions (10). This allows us to compare various diets without worrying about their different fiber, ash, or moisture content.

Remember that the percent carbohydrates, fat, and protein of any diet can be expressed in at least 3 ways — as fed, on a dry matter basis, or on a metabolizable energy (ME) basis. Depending on how the diet composition is expressed, the same food may list a percent carbohydrate value that appears to be very low to rather high (for example, 5% or 25%). As an analogy, if you buy hamburger at the grocery store and the label says it’s 90% lean and 10% fat, you might determine that it is composed mostly of protein and is low in fat. But if you calculate the composition of the hamburger on a caloric or energy basis (ME), the hamburger is actually half fat and only half protein. That’s why the ME basis is the best to really determine what we are actually feeding.

However, unless you are able to obtain the ME values for a diet from the company (always the best way), you may need to estimate the values from the guaranteed analysis (GA) listed for the diet. I like to use the Guaranteed Analysis Converter found on the Balance IT Professional web site to help make this calculation easier (11). The actually calculations are not that difficult but are somewhat cumbersome to perform (10).

The Bottom Line
Dogs should never be fed a high-fiber diet just because they have diabetes. Many dogs do just as well on other maintenance diets containing lower amounts of fiber and carbohydrate and higher amounts of protein. A consistent diet —that is, the type, amount, and time of feeding —is generally much more important in diabetic regulation than any particular fiber content or specific type of diet.

References:

1. Nelson R, Duesberg C, Ford S, et al. Effect of dietary insoluble fiber on control of glycemia in dogs with naturally acquired diabetes mellitus. Journal of the American Veterinary Medical Association 1998;212:380–386. 


2. Graham PA, Maskell E, Rawlings L. Influence of a high fibre diet on glycaemic control and quality of life in dogs with diabetes mellitus. Journal of Small Animal Practice 2002;43:67–73. 


3. Rucinsky R, Cook A, Haley S, et al. American Animal Hospital Association.AAHA diabetes management guidelines. Journal of the American Animal Hospital Association 2010; 46:215-224. 


4. Zicker SC, Nelson RW, Kirk CA, et al. Endocrine Disorders. In: Hand MS, Thatcher CD, Remillard RL, Roudebush R, Novotny, BJ (eds), Small Animal Clinical Nutrition. Mark Morris Institute. 2010; 559-584.


5. Fleeman LM, Rand JS, Markwell PJ. Lack of advantage of high-fibre, moderate-carbohydrate diets in dogs with stabilised diabetes. Journal of Small Animal Practice 2009;50:604-614. 


6. Rand JS, Farrow HA, Fleeman LM, et al. Diet in the prevention of diabetes and obesity in companion animals. Asia Pacific Journal of Clinical Nutrition 2003;12 Suppl:S6.


7. Elliott KF, Rand JS, Fleeman LM, et al. A diet lower in digestible carbohydrate results in lower postprandial glucose concentrations compared with a traditional canine diabetes diet and an adult maintenance diet in healthy dogs. Research in Veterinary Science 2011;96; 288-95. 
   


8. Nguyen P, Dumon H, Biourge V, Pouteau E. Glycemic and insulinemic responses after ingestion of commercial foods in healthy dogs: influence of food composition. Journal of Nutrition (12 Suppl):2654S-2658S. 


9. Xenoulis PG, Steiner JM. Lipid metabolism and hyperlipidemia in dogs. The Veterinary Journal 2010;183:12-21. 


10. Laflamme DP. Determining metabolizable energy content in commercial pet foods. Journal of Animal Physiolology and Animal Nutrition (Berlin). 2001; 85:222-230. 


11. Balance IT Professional Website. Guaranteed Analysis Converter. 

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