Blood Glucose Curves and the Fractious Diabetic Cat

My problem patient is a 12-year old, DSH, female spayed cat with a 2-year history of insulin-dependent diabetes mellitus. She has been treated with glargine insulin at a variable dose, but typically between 1-3 units, BID. This cat will not eat canned food so we are feeding higher protein, lower carb dry foods (Hill's MD and Purina DM).

Six months ago, the cat was diagnosed with immune-mediated hemolytic anemia (IMHA) and was treated successfully with prednisolone and cyclosporine (Atopica). This led to development of insulin resistance and loss of diabetic control, but the cat did relatively well after raising the insulin dose to 6 units while on prednisolone. After a long and slow taper, the cat is now off all glucocorticoids for the last month, and the insulin dose is back down to 2 U, twice daily. The cat remains on Atopica, probably for life.

We have periodically done in-house blood glucose curves to adjust her insulin dose, but she becomes extremely fractious when hospitalized, and we can't really handle her (she bites, scratches, cries, and screams louder than any other cat I've ever had!). The owner does not care to check blood glucose at home, and given the cat's nature, I doubt if they could even do it. Since weaning her off the prednisolone, we have seen a couple of hypoglycemic readings on spot blood glucose checks so we are now worried that the current insulin dose may be too high.

Therefore a week ago, we performed a serial glucose curve on 2 units glargine, BID. The results were as follows:

• 6 am = Insulin given
• 8 am = 317 mg/dl
• 10 am = 376 mg/dl
• 12 noon = 352 mg/dl
• 2 pm = 299 mg/dl
• 4 pm = 229 mg/dl

We were a bit surprised by the high glucose concentrations during the day on this curve, but we increased glargine from 2 to 3 units BID based on the severe and persistent hyperglycemia. However, when I checked a spot afternoon blood glucose value yesterday, it was low-normal at 69 mg/dl. I rechecked another blood glucose reading 30 minutes later, and it was even lower at 57 mg/dl. Right or wrong, I put her back down to 2 units glargine BID and pm spot check in 1 week.

My main question is this: could this cat's in-hospital curve be leading us astray because she is so fractious? I am aware that spot checks aren't ideal. However, this cat is relatively easy to handle during a quick exam and single spot check, but she become so angry when hospitalized throughout the day.

What would you do? How do I adjust the insulin dosage in this cat? We've been trying to get the cat into remission but it's not looking good!

My Response:

Well, first the bad news: I can almost guarantee that this cat's diabetes will not go into remission, given the fact that she has been diabetic for 2 years. A number of studies have reported that diabetic remission, when it does occur, will generally happen within the first 6 months of diagnosis (1,2). In addition, the fact that she has concurrent disease and has been treated with glucocorticoids certainly hasn't increased her chances for remission.

The good news is that once we decide that diabetic remission is no longer our goal, then we can be more lax with our glucose regulation. Our goal for diabetic cats should then be 3-fold:

1. Control clinical signs of diabetes (e.g., weight loss, polyuria, polydispsia)
2. Prevent diabetic ketoacidosis
3. Avoid hypoglycemia

To do this, it's not really necessary to do the tight glucose regulation and frequent blood glucose monitoring that we would ideally do if we are trying to increase the odds for diabetic remission (3-5).

In fractious diabetic cats, I would never recommend doing serial blood glucoses to determine the best insulin dose. The release of catecholamines during this excitable state can absolutely increase the glucose readings during the curve (commonly referred to as stress hyperglycemia) (6). Overall, this means that all of the serial blood glucose curves you have done in this cat are most likely next to meaningless and that such testing should be stopped.

Spot glucose checks can't hurt, but as you say, they can be hard to interpret and may be misleading. If the blood glucose reading is low, you might want to decrease the insulin dose, but if the blood glucose is in the ideal range or high, you could still be overdosing the insulin.

In cats like this, I'd recommend that you adjust the insulin dose based on the presence or absence of clinical signs, including body weight and water intake (7).  If the owners can measure water intake at home, that can be a very sensitive way to help determine if more insulin is needed. If there are no clinical signs of diabetes and the weight is stable, the cat is probably adequately controlled. Monitoring an occasional serum fructosamine level can also help (8,9), as well as home measurement of urine glucose, if the owner can do it (7,19,11). A weekly check for urinary ketones can also be used to monitor for pending ketoacidosis, and become extremely important if anorexia, vomiting, or any other signs of illness develop.

Bottom Line:
In fractious cats, I would not recommend in-hospital blood glucose curves for monitoring. Stress hyperglycemia will give you results that are meaningless, and one could easily be misled into giving higher doses of insulin than are actually needed. This is especially true in cats with long-term diabetes that are unlikely to ever develop remission.

In cats like this case, I use a combination of clinical signs and blood/urine values, looking at the overall trend in results rather than the specific or individual values. For example, I don't use serum fructosamine concentration as the sole means of judging control, but I still think it is helpful as one piece of the puzzle. If it is high, that suggests that the insulin dosage may have to be increased; if the fructosamine value is low to low-normal, this may indicate overdosage and hypoglycemia.

Believe me, both your hospital staff and the fractious diabetic cat will all be better off with this approach!

References:

1. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clinics North America 2013: 43: 245-249
2. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321.
3. 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.
4. 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.
5. Nack R, DeClue AE. In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Vet Q 2014; 34:132-136.
6. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002;16:123-132. 
7. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
8. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 1996;10:360-364. 
9. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64-68. 
10. Bennett N. Monitoring techniques for diabetes mellitus in the dog and the cat. Clin Tech Small Anim Pract 2002;17:65-69. 
11. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 

Top Endocrine Publications of 2013: Feline Diabetes Mellitus

In my ninth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline endocrine pancreas. I covered the canine diabetic publications in a blog post last spring. Click this link to review my list of 2013 research papers that pertain to diabetes in dogs.

Listed below are 29 papers published in 2013 that deal with a variety of diabetic topics of clinical importance for diabetic cats.

These topics range from a study of survival time and prognostic factors in cats with newly diagnosed diabetes (2) to studies involving pathogenesis or risk factors for development of diabetes (6,15,20,21,24); from the relationship between diabetes and kidney disease and pancreatits (1,3) to a review of what we know about diabetic remission (10); and, from reviews of insulin treatment of diabetic cats (4,16,26) to the use of oral hypoglycemia agent or incretin hormonal therapy in cats (22,25).

Other studies range from investigations of diet management of obese and diabetic cats (5,7,17,29) to studies of insulin antibodies in cats (28); from reviews of secondary diabetes, including acromegaly and hyperadrenocorticism (18,19) to ketoacidosis (16,23); and finally, from the use of routine home glucose monitoring (9) to continuous glucose monitoring in cats (11,27).

References:

1. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
2. Callegari C, Mercuriali E, Hafner M, et al. Survival time and prognostic factors in cats with newly diagnosed diabetes mellitus: 114 cases (2000-2009). J Am Vet Med Assoc 2013;243:91-95. 
3. Caney SM. Pancreatitis and diabetes in cats. Vet Clin North Am Small Anim Pract 2013;43:303-317. 
4. Caney SM. Management of cats on Lente insulin: tips and traps. Vet Clin North Am Small Anim Pract 2013;43:267-282. 
5. Coradini M, Rand JS, Morton JM, et al. Fat mass, and not diet, has a large effect on postprandial leptin but not on adiponectin concentrations in cats. Domest Anim Endocrinol 2013;45:79-88. 
6. Dirtu AC, Niessen SJ, Jorens PG, et al. Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: A clue for endocrine disruption in humans? Environ Int 2013;57-58:60-67. 
7. Farrow HA, Rand JS, Morton JM, et al. Effect of dietary carbohydrate, fat, and protein on postprandial glycemia and energy intake in cats. J Vet Intern Med 2013;27:1121-1135. 
8. Fleischhacker SN, Bauersachs S, Wehner A, et al. Differential expression of circulating microRNAs in diabetic and healthy lean cats. Vet J 2013;197:688-693. 
9. Ford SL, Lynch H. Practical use of home blood glucose monitoring in feline diabetics. Vet Clin North Am Small Anim Pract 2013;43:283-301. 
10. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249. 
11. Hafner M, Lutz TA, Reusch CE, et al. Evaluation of sensor sites for continuous glucose monitoring in cats with diabetes mellitus. J Feline Med Surg 2013;5:117-123. 
12. Hoenig M, Pach N, Thomaseth K, et al. Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity. Obesity (Silver Spring) 2013;21:E407-414. 
13. Hoenig M, Traas AM, Schaeffer DJ. Evaluation of routine hematology profile results and fructosamine, thyroxine, insulin, and proinsulin concentrations in lean, overweight, obese, and diabetic cats. J Am Vet Med Assoc 2013;243:1302-1309. 
14. Leal RO, Gil S, Brito MT, et al. The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome. Ir Vet J 2013;66:19. 
15. Link KR, Allio I, Rand JS, et al. The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). Gen Comp Endocrinol 2013;188:269-281. 
16. Marshall RD, Rand JS, Gunew MN, et al. Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis. J Vet Emerg Crit Care (San Antonio) 2013;23:286-290.
17. Mimura K, Mori A, Lee P, et al. Impact of commercially available diabetic prescription diets on short-term postprandial serum glucose, insulin, triglyceride and free fatty acid concentrations of obese cats. J Vet Med Sci 2013;75:929-937. 
18. Niessen SJ. Update on feline acromegaly. In Practice 2013;35:2-6. 
19. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 
20. O'Leary CA, Duffy DL, Gething MA, et al. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. N Z Vet J 2013;61:354-358. 
21. Osto M, Zini E, Reusch CE, et al. Diabetes from humans to cats. Gen Comp Endocrinol 2013;182:48-53. 
22. Palm CA, Feldman EC. Oral hypoglycemics in cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:407-415. 
23. Rand JS. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in cats. Vet Clin North Am Small Anim Pract 2013;43:367-379. 
24. Rand JS. Pathogenesis of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:221-231. 
25. Reusch CE, Padrutt I. New incretin hormonal therapies in humans relevant to diabetic cats. Vet Clin North Am Small Anim Pract 2013;43:417-433. 
26. Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin North Am Small Anim Pract 2013;43:251-266. 
27. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 
28. Takashima S, Nishii N, Hachisu T, et al. Natural anti-insulin autoantibodies in cats: enzyme-linked immunosorbent assay for the determination of plasma anti-insulin IgG and its concentrations in domestic cats. Res Vet Sci 2013;95:886-890. 
29. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:233-243. 

Managing Diabetic Dogs with Exocrine Pancreatic Insufficiency

My problem patient is a 9-year old, female spayed Yorkie with concurrent exocrine pancreatic insufficiency (EPI) and diabetes mellitus. The stools, which had been very large and odoriferous, are smaller and not as smelly now that we have started the pancreatic enzyme replacement therapy.  However, the stools are still not completely normal. The dog remains very thin, but she has gained a pound over the past month.

The diabetic control has been more problematic. Six weeks ago, the dog was on 3 units of Novolin N every 12 hours and had serial blood glucose values running in the range of 400-600 mg/dl throughout the day.  After starting on the enzyme powder, the insulin dosage has fallen to only 0.5 unit twice daily. The current glucose curves start with a morning reading of 400 mg/dl, but the blood glucose then drops down during the day to values in the 100's or, at times, to as low as 45 mg/dl. The owner is trying to be as consistent as possible in feeding (the dog has a very good appetite) and giving the insulin. The dog has shown signs of clinical hypoglycemia, despite the low blood glucose values.  

What do you suggest? Is there a better insulin for this dog?  Would a special diet help?

My Response:

The vast majority of dogs with EPI have a concurrent B12 (cobalamin) deficiency; therefore, cobalamin should be part of this dog's treatment regimen (1). If this Yorkie weighs less than 7 kg, I would suggest administering 250 µg SC every 7 days for 8 weeks, then 250 µg every 14 days for 2 months, then 250 µg once monthly for a couple more months. The treatment may need to be repeated based on serum cobalamin levels.

In addition, some dogs with EPI have dysbiosis (the new term for bacterial overgrowth/gut microbial imbalance), so metronidazole or tylosin power given for a couple weeks plus a probiotic may be helpful. Lastly, if the stools don't get better with the above treatments then the dog may have inflammatory bowl disease (IBD) in addition to the EPI (2). This breed appears predisposed to developing IBD or lymphangietasia (2). As far as what to feed this dog, I'd recommend a diet low in fat because of the concurrent diabetes and GI issues (1).

As far as the insulin type, it looks like the duration of NPH activity is too short for this dog. Use of an insulin with a longer duration of action, such as Vetsulin or glargine, may be a better choice for this case. Based on the fact that the insulin dose is so small and the dog is so very sensitive to the insulin, I'd go with glargine, starting with 1 U,  twice daily. This insulin is much less potent than either NPH or Vetsulin in dogs, making hypoglycemia less unlikely (3).

References:

1. Wieberg, M. Exocrine pancreatic insufficiency in dogs. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;558-560.
2. Simmerson SM, Armstrong PJ, Wünschmann A, J., et al. Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. J Vet Intern Med. 2014;28:331-7. 
3. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. doi: 10.1136/vr.100070.

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 3

Following last week’s post, this is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review another of these "top 12" abstracts (finishing up with the diabetes abstracts). Next week, we will turn to the top clinical abstracts dealing with the adrenal gland, and then finish with disorders of the thyroid over the next 2 weeks. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Bertalan AV, Drobatz KJ. Hess RS. NPH and Lispro Insulin for Treatment of Dogs with Diabetes Mellitus. J Vet Intern Med 2014;28:1026.

Some dogs, treated with twice-daily NPH insulin and Hill's W/D diet, have postprandial hyperglycemia despite having clinically well-regulated diabetes mellitus (DM). The goal of this study was to determine whether postprandial hyperglycemia and fructosamine concentration can be decreased by adding lispro insulin to the treatment protocol.
      Six dogs were enrolled into this ongoing prospective study. Dogs were enrolled if they had clinically well-regulated DM while treated with NPH insulin and W/D q12 hours and if they had postprandial hyperglycemia defined as an increase in blood glucose concentration (BG) within two hours of NPH insulin administration and feeding. Fructosamine was quantified and BG was measured just before feeding and NPH insulin administration (T0), every 30 minutes for the first 2
hours (T30, T60, T90, T120), and every two hours thereafter for eight additional hours. Dogs were then treated at home with the same NPH insulin dose and W/D, but a separate lispro insulin injection of 0.1 Unit/kg SC was added to the NPH insulin and W/D protocol. Serial BG and fructosamine were measured two weeks later and compared to the original values using the Wilcoxon Signed Rank Test. Median [range] fructosamine (400 μmol/L [289–624 μmol/L]), and BG at T60 (313 mg/dl [187–376 mg/dl]) and T90 (239 mg/dl [166–332 mg/dl]) were significantly higher before lispro insulin was introduced compared to two weeks later (390 μmol/L [253–486 μmol/L]), p = 0.046, 117 mg/dl [42–307 mg/dl]), p = 0.028, and 94 mg/dl [48–197 mg/dl]), p = 0.028, respectively). 
      It is concluded that addition of lispro insulin to an NPH and W/D treatment protocol may significantly decrease fructosamine and postprandial hyperglycemia.

Comments— In this study, addition of a rapid-acting insulin analog (insulin lispro; Humalog, Lilly) to a standard twice-daily NPH insulin regimen appeared to improve glycemic control in dogs with clinically controlled diabetes. This finding is not unexpected, since it is well known that the administration of a short-acting insulin at time of meals will help lessen post-prandial hyperglycemia and lead to improved overall glycemic control in diabetic patients (1-4).

Rapid-acting insulin analogs— Although human recombinant regular insulin is still used as a short-acting insulin by most veterinarians, this insulin has been replaced for the most part with one of the more rapid-acting insulin analogs in human medicine (5-7). One of these newer rapid-acting insulin analogs is insulin lispro, which was the first commercially available insulin analog produced (6,7). Compared with regular human insulin, this insulin analog offers the advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action. Although not used frequently in dogs, insulin lispro has been reported by this same group of investigators to be as effective as regular insulin in the treatment of ketoacidosis (8).

Long-acting insulin analogs and analog mixtures—Like human regular insulin, use of human NPH insulin is gradually being phased out and replaced with a mixture of rapid- and long-acting insulin analogs (5-7, 9-11). For example, newly diagnosed insulin-dependent human patients may be treated with a combination of once to twice daily injections of glargine (Lantus) or detemir (Levemir), together with a rapid-acting analog (e.g., insulin lispro or aspart) given at time of meals (11-14). Pre-mixed combinations of a short-acting synthetic insulin analog (i.e., lispro or aspart insulin) with a longer-acting insulin analog (i.e., lispro or aspart protamine insulin) are also commercially available as Humalog Mix 75/25 (Eli Lilly) or NovoLog Mix 70/30 (Novo Nordisk) (5,10). Both of these insulin analog mixtures are given twice daily with meals.

Time interval between insulin injection and meal intake— When a short-acting insulin (either human recombinant regular insulin or lispro) is added to the overall insulin regimen, it is standard protocol that the rapid-acting insulin be given shortly prior to ingestion of the meal (2-4,15,16). This allows enough time for the injected insulin to be absorbed into the circulation and blunt the post-prandial rise in blood glucose concentration. If the insulin injection is delayed until after the meal, severe post-prandial hyperglycemia may develop, which can lead to a clinical state resembling insulin resistance in some patients.

Most veterinarians fail to consider the importance of the time interval between insulin injection and meal intake when evaluating glycemic control in their diabetic dogs on standard insulin protocols. Whenever possible, I like to have my owners inject insulin (NPH, Vetsulin, or NPH/regular combinations) about 20-30 minutes before the dog eats, which allows enough time for insulin to to be partially absorbed and prevent severe post-prandial hyperglycemia (17).  With a more rapidly absorbed insulin, such as lispro, the timing between insulin injection and feeding can likely be shortened to less than 20 minutes. Of course, administering insulin injections prior to feeding is not always possible or even advisable, especially if the dog's appetite is poor or variable.

It is unclear what the time interval was between insulin injection and meal intake in this study by Bertalan et al., since it was not stated. If not given prior to feeding, however, the results might have been improved by using such a protocol.

The Bottom Line— In dogs with problem diabetes, addition of a short-acting insulin to the overall insulin regime may be helpful, especially in those dogs that experience severe post-prandial hyperglycemia.  The interval between insulin injection and meal intake must be taken into consideration when employing this protocol, and the addition of a short-acting insulin would likely be less effective when injected after eating. In any case, further research needs to be done on the effect on the timing of insulin injections and meals in dogs with diabetes mellitus.

Although insulin lispro works well in dogs, a major disadvantage of using any insulin analog, including lispro, is the high cost. All of the insulin analogs are approximately 3 to 5 times more costly than conventional human recombinant NPH, regular, or mixtures of NPH 70/30 insulins.

On a practical basis, there is little reason to use insulin lispro over human regular insulin in dogs, especially when you consider the great difference in cost. Premixed NPH/regular insulin is commercially available as Humulin 70/30 (Eli Lilly) or Novolin 70/30. Both of these commercial preparations contain a 100 U/ml pre-mixed combination of 30% short-acting (regular insulin) and 70% intermediate-acting insulin (NPH). In the USA, the cheapest place to purchase human regular, NPH, and 70/30 combinations is at Walmart, which sells these insulins as the ReliOn Novolin brand for around $25 per vial (19).

Another option, of course, is porcine lente insulin (Caninsulin or Vetsulin), which is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente, respectively) (20,21). Although more expensive than the ReliOn Novolin 70/30 insulin, Vetsulin is certainly much more cost effective than any of the insulin analogues. With either insulin preparation, I like to give the injection about 20-30 minutes prior to feeding to ensure that adequate insulin concentrations will be present in the circulation when the meal is absorbed to blunt the rise in blood glucose concentration and help better control the diabetic state (17).

References:

1. Brownlee M. Insulin treatment of diabetes. Hosp Pract 1979;14:85-94. 
2. Phillips M, Simpson RW, Holman RR, et al. A simple and rational twice daily insulin regime. Distinction between basal and meal insulin requirements. Q J Med 1979;48:493-506. 
3. Holman RR, Turner RC. A practical guide to basal and prandial insulin therapy. Diabet Med 1985;2:45-53. 
4. Zinman B. Insulin regimens and strategies for IDDM. Diabetes Care 1993;16 Suppl 3:24-28. 
5. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183. 
6. Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother 1996;30:1263-1271. 
7. Noble SL, Johnston E, Walton B. Insulin lispro: a fast-acting insulin analog. Am Fam Physician 1998;57:279-286, 289-292. 
8. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care (San Antonio) 2012; 22:211-218.
9. Kalra S. Newer basal insulin analogues: degludec, detemir, glargine. J Pak Med Assoc 2013;63:1442-1444. 
10. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006;66:31-49. 
11. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 2004;47:622-629. 
12. Ashwell SG, Gebbie J, Home PD. Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times. Diabet Med 2006;23:46-52. 
13. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med 2006;23:285-292. 
14. Lucchesi MB, Komatsu WR, Gabbay MA, et al. A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes. Pediatr Diabetes 2012;13:519-524. 
15. MacGillivray MH, Mills BJ, Voorhess ML. Meal intolerance in type 1 diabetes mellitus: influence of time interval between insulin therapy and meal intake. J Med 1984;15:417-435. 
16. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 
17. Peterson ME. New development in the use of insulin mixtures and analogs for the problem diabetic. Proceedings of the 2013 American College of Veterinary Internal Medicine (ACVIM) Forum 2013;534-537.
18. Sawicki PT. Commentary: Does additional benefit justify additional costs of insulin analogues? BMJ 2011;343:d5858. 
19. ReliOn Insulins. http://relion.com/diabetes/insulin
20. Horn B, Mitten RW. Evaluation of an insulin zinc suspension for control of naturally occurring diabetes mellitus in dogs. Aust Vet J 2000;78:831-834. 
21. 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.

Escalating Costs of Insulin Glargine (Lantus): Can We Switch to Another Insulin?

My patient is a 14-year-old male Toy Poodle (weighing only 5 kg) that has been maintained on insulin glargine (Lantus; Sanofi-Aventis) for several years. Currently, the dog is receiving an insulin dose of 6 units twice daily and is doing well (i.e., no obvious polyuria, normal appetite with stable body weight). However, over the last few months, the price of Lantus has skyrocketed to over $250 for a 10-ml vial. The owner would like to switch to a more affordable insulin, if possible. At 12 units a day, she is going through a 10-ml vial of Lantus every 2.5 months or so.

My question is this: would another long-acting insulin —such as detemir (Levemir) or PZI (ProZinc)— be more cost-effective in this dog? Or would you suggest that I start over with an intermediate-acting insulin, such as NPH (Humulin N or Novolin N) or Vetsulin?

I did not start this dog on Lantus, but the owner claims that they had great difficulty in regulating him after his initial diagnosis. Therefore, I'm a bit hesitant to "rock the boat" when the Lantus seems to be doing the job. Do you have any ideas why the price has gone up so much over the last year or so?

My Response:

Long-acting insulins, such as glargine, are not commonly used in dogs with diabetes, although they can work fine to control clinical signs in some dogs (1-3). However, because these insulins have a less potent glucose-lowering effect than do more commonly used intermediate-acting insulins (NPH, Vetsulin), larger doses of the long-acting insulin preparation are often needed (1,2). Therefore, use of glargine or PZI (ProZinc) are generally cost-effective only in smaller dogs.

For example, notice that the daily glargine dose in this Toy Poodle is over 1 U/kg twice a day, which is in the expected dose range for a long-acting insulin in dogs (1-3). If this dog weighed 50 kg rather than only 5 kg, this would equate to a dose of 60 U twice a day, which means that we would go through a 10-ml vial of Lantus every two weeks or so! In contrast, most diabetic dogs on an intermediate-acting insulin can be well-regulated using doses of 0.5-0.7 U/kg per injection (4,5).

What's leading to the steady increase in the price for insulin glargine(Lantus)?
The drug maker Sanofi-Aventis has steadily raised its price of Lantus (insulin glargine) during the past 12 months, prompting angst among many pet owners and veterinarians alike. These concerns, of course, are inconsequential to Sanofi, since Lantus is FDA-approved for human diabetic patients (a huge market), and the insulin is not marketed for use in either dogs or cats.

Since I don't work for Sanofi-Aventis, I do not know what’s driving the escalating price increases that we have seen over the past few months. However, we do know that Sanofi's patent for Lantus expires in 2015, opening the market to competitors who can then release generic glargine insulins. Therefore, it is likely that Sanofi is trying to generate as much income as the company can from this branded insulin preparation before the patent expires and generic glargine preparations hit the market.

In support of that, it's known that Eli Lilly also has a generic equivalent in the works (6). Sanofi recently responded by suing Eli Lilly for alleged patent infringement (7). The lawsuit triggered a stay of approval by the FDA, delaying the release of Eli Lilly’s generic to mid-­2016.

However, Merck & Co. also recently announced that it's version of generic glargine is in the late stages of clinical trials (8). It's likely that Sanofi will also sue Merck in order to delay their release of a generic product too, but again, I don't know.

Do you understand why I sometimes hate using these human insulin analogs? We, as veterinarians, have absolutely no say or control in anything that is going to happen to price or availability, and it's certainly no use to complain. These companies don't market their products to us and really do not even want to know we use them in our patients.

Are other long-acting insulins less expensive than Lantus?
Unfortunately, when we look at the cost of other long-acting insulin preparations, the cost is not much cheaper than the current cost of Lantus, at least when we look at the cost per unit of insulin. The dose of ProZinc would likely be approximately the same as the glargine in this dog— at about $100 per 10-ml vial, the cost of ProZinc seems significantly less, at least at first glance. However, we must remember that each vial of ProZinc (a U-40 insulin) contains only 400 units of insulin, so this dog (on 6 units, twice a day) would need about one new vial per month. Since each 10-vial of Lantus contains 1,000 units, the cost per unit of insulin is about the same when these two insulin preparations are compared.

Insulin detemir (Levemir, Novo Nordisk) is another story. Although the cost of this U-100 insulin is equivalent to Lantus (about $250 per vial), this insulin is a very potent insulin when used in dogs (this is not true in cats). The average determir dose that most diabetic dogs require ranges from only 0.1-0.2 U/kg per injection — 5 to 10 times less that the average glargine dose needed for diabetic dogs (9,10).

That all said, I would hesitate to use detemir in this toy breed dog because of it's high potency. The calculated starting dose for a 5 kg dog would only be 0.5 U, and it's unlikely that more than 1 U per injection would ever be needed. As we all know, it's very difficult to measure 0.5 units of insulin accurately and overdosage might be expected. Because of its potent glucose-lowering effects, hypoglycemia is more common with detemir than the other longer-acting insulins.

Should a switch to an intermediate-acting insulin be considered?
Most diabetic dogs that we treat are not started on a long-acting insulin. In fact, use of an intermediate acting insulin, such as NPH or Vetsulin, are generally considered to be the insulins of choice when starting treatment for dogs with diabetes mellitus (4,5).

NPH is a much less expensive human U-100 insulin that is available at Walmart as their ReliOn brand of Novolin-N for only about $25 (11). Personally, I find that Vetsulin (Merke Animal Health) is a better choice than NPH in most dogs since it's a bit longer acting, and this insulin is also made by a veterinary company (Merck Animal Health) and licensed for use in dogs. As you know, the veterinarian cost for Vetsulin is around $30 per 10-vial, but, again, each insulin vial contains only 400 units rather than the 1000 units in each vial of NPH. Therefore, the cost is indeed a bit more for Vetsulin than NPH, at least when we look at the price of the Walmart ReliOn brand.

No matter what insulin we change to (ProZinc, Levemir, NPH, or Vetsulin), the dog will have to again be regulated. This may go very smoothly—but then again, this is a diabetic, it's always difficult to predict what is going to happen with certainty. I'd give the owner the pro's and con's of continuing the Lantus vs switching, but in the long-run, it may be best to stick with the Lantus and hope that the generic versions hit the market sooner than Sanofi would like!

References:

1. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
2. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. 
3. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
4. 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. 
5. 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. 
6. Eli Lilly Press Release, Dec. 20, 2013. Eli Lilly and Company and Boehringer Ingelheim announce new drug application filing in the U.S. for new insulin glargine product. 
7. Reuters,  Jan 30, 2014. Sanofi sues Eli Lilly over patents for top-selling insulin drug.
8. Merck Newsroom.com, February 10, 2014. Merck and Samsung Bioepis Enter Collaboration Agreement to Develop and Commercialize Insulin Glargine Candidate for Diabetes.
9. Mori A, Sako T, Lee P, et al. Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Vet Res Commun 2008;32:563-573. 
10. 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. 
11. ReliOn Insulins. http://relion.com/diabetes/insulin

Humulin Versus Novolin NPH Insulin: Are They Bioequivalent?

Two available brands of NPH insulin, manufactured by Eli Lilly (Humulin N) and Novo Nordisk (Novolin N)

Recently, several of my diabetic dog owners have asked if they can switch their NPH brand to Walmart's Relion/Novolin insulin to replace the Humulin N insulin that they are now using. It turns out that the Walmart ReliOn brand of NPH is much cheaper (only $25 per vial).

Though the two insulins both seem to be NPH insulin, I have some concerns about this change. Any concerns with the ReliOn brand or in switching from Humulin N to Novolin N insulin?

My Response:

In theory, you'd think that Humulin N (Eli Lilly) and Novolin N (Novo Nordisk) would be bioequivalent (and therefore interchangeable), as they're just different brands of NPH insulin. However, that is not always the case.

Humulin N and Novolin N are made using different ingredients and manufacturing techniques, so they are not identical (1,2). Like you noted, Walmart sells NPH insulin as the Novolin/ReliOn brand for much less than most other pharmacies do, at only about $25 per vial (3).

A number of dogs have now been reported where they were stable and doing well on Humulin N. However, when switched to the same dose of Novolin N, their diabetic state was no longer regulated and the dogs developed signs of either hypo- or hyperglycemia, requiring significant dose adjustments (4).

Bottom Line:

Most dogs will respond well to the Novolin/ReliOn brand of insulin, which is indeed much less expensive than most other brands of NPH insulin. However, we cannot just assume that the two insulin preparations would be equivalent. I would not recommend switching from one insulin to the other without close monitoring (including blood glucose curves) so that the dose can be adjusted as needed.

References:

1. Humulin.com website. 
2. Humulin N Prescribing Information. 
3. Novolin N Prescribing Information.  
4. ReliOn Insulins. http://relion.com/diabetes/insulin
5. VIN News Service. Changing insulin brands may disrupt diabetics. February 5, 2013. 

Can Twice-Daily Insulin Be Injected at Any Time of the Day?

I have questions regarding treatment of a 8-year old, male labrador retriever with poorly-regulated diabetes. He has been treated with once daily insulin (Vetsulin), administered once a day in the morning at 11 pm for the last 3 months. Despite insulin treatment, the dog remains hyperglycemic and glycosuric and if very thin.

The owner has a very odd work schedule, and he is not generally home in the early morning when the AM dose of insulin is generally given, so that's why the insulin shot is given in the late morning. I would like to put him on twice daily insulin; however, I was hesitant because the dog would have to get the two doses of insulin at 11 am and 11 pm if we are going to give the insulin at 12-hour intervals.

I have always assumed there was some sort of diurnal influence on blood glucose concentrations that mandated that we give the insulin first thing in the morning (6-8 am at time of breakfast) and then again in the early evening at dinner time. But when I actually dug out my physiology textbook and did not some on-line research, I didn't find any mention of this.

So my questions— is there any reason to not give him insulin injections at different times during the day? Why do we routinely start injections in the earlier morning— is just because that's when animals (and people) typically get fed?

My Response:

The problem of nocturnal hypoglycemia in human diabetics
In human patients treated with insulin (type 1 diabetes), nocturnal hypoglycemia is a well-recognized complication that can lead to major problems in regulation (1-7). Almost half of all episodes of severe hypoglycemia that develops in human patients occur at night during sleep. Such episodes of nocturnal hypoglycemia can be prolonged and can lead to seizures or coma in rare cases (7). In addition, this nocturnal hypoglycemia can lead to rebound hyperglycemia (Somogyi phenomenon) (1,8).

The problems of overnight hypoglycemia in human type I diabetes are further complicated by the dawn phenomenon (1,9,10). The dawn phenomenon is the combination of an initial decrease in insulin requirements between ~2400 and ~0300, followed by an increase in the insulin needs (and therefore, a tendency to develop hyperglycemia) between ~0500 and ~0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients (1,9,10).

Overall, this brings up the questions: does nocturnal hypoglycemia or the dawn phenomenon occur in dogs with diabetes?

Studies of canine diabetics
In a recent study, Mori and colleagues (11) monitored 5 diabetic dogs (treated with either NPH or insulin detemir) with a continuous glucose monitoring system (CGMS) over a 2-week period. They evaluated the daily glycemic profiles obtained with CGMS and compared glucose fluctuations between day- and night-time in these diabetic dogs. For data analyses, day-time was defined as 9:00 am-9:00 pm and night-time as 9:00 pm-9:00 am.

Using these glucose profiles, the investigators evaluated the following parameters: 1) the mean blood glucose concentrations (1- and 12-hr intervals); 2) the time spent in the hyperglycemic range (greater than 200 mg/dl); and 3) the time spent in the hypoglycemic range (less than 60 mg/dl). None of these parameters differed significantly between day-time and night-time in these insulin-treated dogs. 

Overall, this study confirmed that there are no differences in glucose fluctuations between day- and night-time, in diabetic dogs on a similar feeding regimen and insulin administration when monitoring carefully using CGMS. These studies also indicate that diabetic dogs do not frequently develop nocturnal hypoglycemia, unlike the situation in human patients with diabetes. Finally, dogs do not appear to develop the dawn phenomenon, as manifested by a morning surge in hyperglycemia, which again occurs in nearly all human diabetic patients.

Bottom line:

Based on these studies, there does not appear to be any physiologic reason why we must administer insulin injections first thing in the morning (with breakfast) and then again later at dinnertime. The reason we tend to give in the morning and evening is that most folks go to work during the day, not at night.

It doesn't matter when we give the insulin injections, but dogs almost always need twice-daily insulin injections, so we would want to give the injections about 12 hours apart. In this dog, I see no reason not to give insulin injections at 11 am and 11 pm if that schedule works best for the owner.

References:

1. Bolli GB, Perriello G, Fanelli CG, et al. Nocturnal blood glucose control in type I diabetes mellitus. Diabetes Care 1993;16 Suppl 3:71-89. 
2. Matyka KA. Sweet dreams?--nocturnal hypoglycemia in children with type 1 diabetes. Pediatr Diabetes 2002;3:74-81.
3. Yale JF. Nocturnal hypoglycemia in patients with insulin-treated diabetes. Diabetes Res Clin Pract 2004;65 Suppl 1:S41-46. 
4. Raju B, Arbelaez AM, Breckenridge SM, et al. Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab 2006;91:2087-2092. 
5. Greenhill C. Diabetes: Nocturnal hypoglycemia is frequent in patients with type 1 diabetes mellitus. Nat Rev Endocrinol 2010;6:299. 
6. Ahmet A, Dagenais S, Barrowman NJ, et al. Prevalence of nocturnal hypoglycemia in pediatric type 1 diabetes: a pilot study using continuous glucose monitoring. J Pediatr 2011;159:297-302. 
7. Bay C, Kristensen PL, Pedersen-Bjergaard U, et al. Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia. Diabetes Technol Ther 2013;15:371 377. 
8. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med 1988;318:1537-1538.
9. Campbell PJ, Bolli GB, Cryer PE, et al. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 1985;312:1473-1479. 
10. Carroll MF, Schade DS. The dawn phenomenon revisited: implications for diabetes therapy. Endocr Pract 2005;11:55-64. 
11. 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. 

Top Endocrine Publications of 2013: Canine Diabetes Mellitus

In my second compilation of the canine and feline endocrine publications of 2013, I’m moving on to the theme of canine diabetes mellitus.

Listed below are 27 research papers written in 2013 that deal with a variety of topics and issues related primarily to the pathophysiology, diagnosis, monitoring, and treatment of diabetes mellitus in dogs.

These range from studies of the possible gene defects that may be involved in the pathogenesis of diabetes mellitus and obesity (1,5) to a review of diabetic nephropathy in animals (2); from a study of the impaired immune response of dogs with hyperglycemia (3) to a novel treatment of diabetic dogs with insulin and glucokinase gene therapy (4); from studies of the influence of diet on glucose metabolism in the dog (6,7,14,18) to investigations of glucagon-like peptide (GLP) receptor agonists and antagonists as antidiabetic agents (9,11,15,17); from studies of the use of insulin glargine (Lantus) in dogs with diabetes (12) to the effect of chronic diabetes on the loss of optic nerve axons and development of retinopathy in dogs (13).

Other studies included a review of the use continuous glucose monitoring systems in dogs (22) to the use of a continuous glucose monitoring system to investigate if nocturnal hypoglycemia occurs in diabetic dogs, as it does in man (16); from a study of diabetic remission in dogs after ovariohysterectomy and resolution of progesterone excess (19) to an investigation of the mechanism of insulin production in canine bone marrow-derived stem cells (23); and from a large study detailing the clinical features associated with the acquired proximal renal tubulopathy in dogs fed dried chicken treats (24) to the evaluation of a large series of dogs with the hyperosmolar hyperglycemia syndrome (25).

Finally, I've included 3 studies that involve human rather than canine diabetic patients, in which dogs are trained as "glycemia alert" animals to detect pending hypoglycemia in these human diabetic patients (8,10,21).

2013 Papers on Canine Diabetes Mellitus:

1. Batchelor DJ, German AJ, Shirazi-Beechey SP. Relevance of sodium/glucose cotransporter-1 (SGLT1) to diabetes mellitus and obesity in dogs. Domest Anim Endocrinol 2013;44:139-144. 
2. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
3. Bosco AM, de Almeida BF, Pereira PP, et al. High concentrations of glucose reduce the oxidative metabolism of dog neutrophils in vitro. BMC Vet Res 2013;9:24. 
4. Callejas D, Mann CJ, Ayuso E, et al. Treatment of diabetes and long-term survival following insulin and glucokinase gene therapy. Diabetes 2013;62:1718-1729. 
5. Catchpole B, Adams JP, Holder AL, et al. Genetics of canine diabetes mellitus: Are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs? Vet J 2013;195:139-147. 
6. Coate KC, Kraft G, Irimia JM, et al. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Diabetes 2013;62:392-400. 
7. Coate KC, Smith MS, Shiota M, et al. Hepatic glucose metabolism in late pregnancy: normal versus high-fat and fructose diet. Diabetes 2013;62:753-761. 
8. Dehlinger K, Tarnowski K, House JL, et al. Can trained dogs detect a hypoglycemic scent in patients with type 1 diabetes? Diabetes Care 2013;36:e98-99. 
9. Edgerton DS, An Z, Johnson KM, et al. Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2013;305:E132-139. 
10. Gonder-Frederick L, Rice P, Warren D, et al. Diabetic alert dogs: a preliminary survey of current users. Diabetes Care 2013;36:e47. 
11. Guzman-Perez A, Pfefferkorn JA, Lee EC, et al. The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus. Bioorg Med Chem Lett 2013;23:3051-3058. 
12. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
13. Howell SJ, Mekhail MN, Azem R, et al. Degeneration of retinal ganglion cells in diabetic dogs and mice: relationship to glycemic control and retinal capillary degeneration. Mol Vis 2013;19:1413-1421. 
14. Kimura T. The regulatory effects of resistant starch on glycaemic response in obese dogs. Arch Anim Nutr 2013;67:503-509. 
15. Moore MC, Werner U, Smith MS, et al. Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2013;305:E1473-1482. 
16. 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. 
17. Oda H, Mori A, Lee P, et al. Characterization of the use of liraglutide for glycemic control in healthy and Type 1 diabetes mellitus suffering dogs. Res Vet Sci 2013;95:381-388. 
18. Ogbu SO, Agwu KK, Asuzu IU. Gongronema latifolium delays gastric emptying of semi-solid meals in diabetic dogs. Afr J Tradit Complement Altern Med 2013;10:325-331. 
19. Poppl AG, Mottin TS, Gonzalez FH. Diabetes mellitus remission after resolution of inflammatory and progesterone-related conditions in bitches. Res Vet Sci 2013;94:471-473. 
20. Ramnanan CJ, Kraft G, Smith MS, et al. Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog. Diabetes 2013;62:74-84. 
21. Rooney NJ, Morant S, Guest C. Investigation into the value of trained glycaemia alert dogs to clients with type I diabetes. PLoS One 2013;8:e69921. 
22. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 
23. Takemitsu H, Zhao D, Ishikawa S, et al. Mechanism of insulin production in canine bone marrow derived mesenchymal stem cells. Gen Comp Endocrinol 2013;189:1-6. 
24. Thompson MF, Fleeman LM, Kessell AE, et al. Acquired proximal renal tubulopathy in dogs exposed to a common dried chicken treat: retrospective study of 108 cases (2007-2009). Aust Vet J 2013;91:368-373. 
25. Trotman TK, Drobatz KJ, Hess RS. Retrospective evaluation of hyperosmolar hyperglycemia in 66 dogs (1993-2008). J Vet Emerg Crit Care (San Antonio) 2013;23:557-564.  
26. Winnick JJ, An Z, Kraft G, et al. Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. Diabetes 2013;62:96-101. 
27. Winnick JJ, Ramnanan CJ, Saraswathi V, et al. Effects of 11beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Am J Physiol Endocrinol Metab 2013;304:E747-756. 

How to Feed Cats with Diabetes: Part 2— Protein

Evolutionary events shaped the cat’s core metabolism such that their systems are uniquely set up to metabolize a diet which is high in moisture, high in protein, and very low in carbohydrates. Because this is the diet cats have relied upon for tens of thousands of years, they depend more on protein intake than omnivores (e.g., dogs and man) (1-3).

As I discussed in my last blog post (How to Feed Cats with Diabetes), cats do not have the ability to process carbohydrates very efficiently and show relative carbohydrate intolerance. This becomes extremely important when selecting a diet for cats with diabetes, and what is fed can play a key role in the successful management of the diabetic cat.

Weight Loss, Obesity, Muscle Wasting, and Sarcopenia— Common Features of Diabetes
At time of diagnosis of diabetes, weight loss is reported in about 70% of cats. However, cats are more often overweight or obese (40%) than of normal weight or underweight. In addition, muscle wasting and poor muscle condition scores are reported in about half of cats with diabetes.

One contributing factor for the muscle wasting seen in the diabetic cats is their age. The typical diabetic cat is a senior, with about 70% older than 10 years of age at time of diagnosis (4,5). Therefore, since most of these cats are older, they are also prone to develop sarcopenia (from the Greek meaning "poverty of flesh") which is commonly associated with aging. 

In human patients, Type 2 diabetes is associated with an increased risk of concurrent sarcopenia (8). In addition, because skeletal muscle is a primary site for insulin-mediated glucose uptake and deposition, sarcopenia (and especially sarcopenic obesity) (9) may promote insulin resistance, predisposing patients to development of type 2 diabetes and making existing diabetes more difficult to control (10,11).

We do not know if the loss of muscle mass alone (sarcopenia) or combined with weight gain (i.e., sarcopenic obesity) also contributes to the insulin resistance and hyperglycemia associated with the feline disorder. However, given that both obesity and some degree of muscle wasting are common in diabetic cats, it seems reasonable to assume that sarcopenia and sarcopenic obesity may indeed contribute to worsening of feline diabetes, as it does in man (8-11).

Management Goals of Feline Diabetes
In cats with diabetes, a primary goal of therapy is to feed a diet that will lessen postprandial hyperglycemia, reduce marked fluctuations of blood glucose concentrations, minimize the demand on beta cells to produce insulin, and improve insulin sensitivity (6,7,12). By doing this, we decrease the effect of “glucose toxicity” and hopefully allow the pancreatic islet cell to partially recover. In about half of newly diagnosed diabetic cats, this will lead to remission of the diabetic state (13-15). As I discussed last week, we can do this in our diabetic cats by feeding a diet low in carbohydrates.

A secondary goal of therapy is to provide a diet that will help normalize body weight and maintain and/or restore lost muscle mass (16,17), as discussed below.

Recommendations for Diabetic Cats: Higher Dietary Protein:
Because diabetes is a catabolic state, loss of muscle mass is common in cats with diabetes, even if their body condition score indicates overweight or obesity. In these cats, high-protein diets are essential to ensure replacement of any lost muscle mass. In addition, higher protein diets will help prevent the hepatic lipidosis from developing during induction of weight loss (needed in many diabetic cats), and are essential to increasing metabolism to help promote fat burning and normal insulin function (16-19).

Protein is the primary macronutrient responsible for maintenance of muscle mass (20,21). Restoring and preserving any remaining muscle tissue in diabetic cats, an obligate carnivore, depends upon the cat consuming a diet with sufficient amounts of high-quality protein (greater than 40% ME; greater than 10 g/100kcal). This higher than average protein level also helps restore and maintain lost muscle mass, since many diabetic cats will develop “sarcopenia” as they age.

Although it is important to implement a low-carbohydrate/high protein diet in the management of cats with diabetes as soon as possible, there are circumstances where this should be delayed or may be inappropriate (18). For example, in cats with advanced (IRIS stage 3-4) chronic kidney disease (CKD) requiring phosphorus restriction and a reduction in dietary protein, high-protein/low-carbohydrate diabetic diets may not be appropriate (19,22,23).

In cats with earlier stages of CKD, phosphorus should be restricted using other methods than changing to a protein-restricted/higher carb diet (if possible), because feeding higher amounts of carbohydrates would reduce the probability of remission. It is important to remember that over-the-counter low carbohydrate cat foods often contain predominantly fish or meat and tend to have substantially higher phosphate levels than some of the veterinary prescription diets designed for diabetes.

References:

1. MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984;4:521-562. 
2. Zoran DL. The carnivore connection to nutrition in cats. J Am Vet Med Assoc 2002;221:1559-1567. 
3. Eisert R. Hypercarnivory and the brain: protein requirements of cats reconsidered. J Comp Physiol B 2011;181:1-17. 
4. Farrow H, Rand JS, Morton JM, et al. Postprandial glycemia in cats fed a moderate carbohydrate meal persists for a median of 12 hours -- female cats have higher peak glucose concentrations. J Feline Med Surg 2012;14:706-715. 
5. Farrow HA, Rand JS, Morton JM, et al. Effect of dietary carbohydrate, fat, and protein on postprandial glycemia and energy intake in cats. J Vet Intern Med 2013;27:1121-1135. 
6. 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.
7. Baral RM, Little SE. Endocrine pancreatic disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;547-571.
8. Kim TN, Park MS, Yang SJ, et al. Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS). Diabetes Care 2010;33:1497-1499. 
9. Stenholm S, Harris TB, Rantanen T, et al. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care 2008;11:693-700. 
10. Srikanthan P, Hevener AL, Karlamangla AS. Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III. PLoS One 2010;5:e10805. 
11. Moon SS. Low skeletal muscle mass is associated with insulin resistance, diabetes, and metabolic syndrome in the Korean population: The Korea National Health and Nutrition Examination Survey (KNHANES) 2009-2010. Endocr J 2013. 
12. Zini E, Osto M, Franchini M, et al. Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat. Diabetologia 2009;52:336-346. 
13. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321. 
14. Reusch CE, Hafner M, Tschuor F, et al. Diabetes remission in cats: a review. Schweiz Arch Tierheilkd 2011;153:495-500. 
15. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249. 
16. Nguyen P, Leray V, Dumon H, et al. High protein intake affects lean body mass but not energy expenditure in nonobese neutered cats. J Nutr 2004;134:2084S-2086S. 
17. Keller U. Dietary proteins in obesity and in diabetes. Int J Vitam Nutr Res 2011;81:125-133. 
18. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:233-243. 
19. Frank G, Anderson W, Pazak H, et al. Use of a high-protein diet in the management of feline diabetes mellitus. Vet Ther 2001;2:238-246. 
20. Paddon-Jones D, Short KR, Campbell WW, et al. Role of dietary protein in the sarcopenia of aging. Am J Clin Nutr 2008;87:1562S-1566S. 
21. Wakshlag JJ. Dietary protein consumption in the healthy aging companion animal. Proceedings of the Nestlé Purina Companion Animal Nutrition Summit: Focus on Gerontology 2010;32-39.
22. Kidder AC, Chew D. Treatment options for hyperphosphatemia in feline CKD: what's out there? J Feline Med Surg 2009;11:913-924. 
23. Ross SJ, Osborne CA, Kirk CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. J Am Vet Med Assoc 2006;229:949-957. 

How to Feed Cats with Diabetes

Diet plays a key role in the successful management of the diabetic cat. Because cats are obligate carnivores (1-3), diabetic cats are relatively carbohydrate intolerant and respond best to a low carbohydrate diet. This differs from dogs, which are omnivores and are quite tolerant of a moderate to high carbohydrate meal, even when diabetic (4,5).

Evolutionary events shaped the cat’s core metabolism such that their systems are uniquely set up to metabolize a diet which is high in moisture, high in protein, and very low in carbohydrates. Because this is the diet they have relied upon for tens of thousands of years, they do not have the ability to process carbohydrates very efficiently and show relative carbohydrate intolerance (1-3). This becomes extremely important when selecting a diet for cats with diabetes.

Postprandial Glycemia in Man, Dogs, and Cats
As a result of these differences, plasma glucose clearance rates are longer in cats compared to dogs or humans after feeding a moderate to high carbohydrate meal — in other words, even normal cats have much more prolonged postprandial period of hyperglycemia than might be expected. In healthy humans and dogs, postprandial hyperglycemia normally persists for 2 to 6 hours (4,6).

In contrast, recent studies of healthy cats found that both serum glucose and insulin concentrations remained significantly increased for a median time of 12 hours following ingestion of a moderate carbohydrate meal (25% of calories), and that both glucose and insulin concentrations remained above baseline values for 24 hours in approximately 20% of the cats (7,8). Most feline diets contain even higher amounts of carbohydrate (greater than 25%) and, therefore, would be expected to result in more severe postprandial hyperglycemia and a longer time to return to baseline.

Management Goals of Feline Diabetes
In cats with diabetes, a primary goal of therapy is to feed a diet that will lessen postprandial hyperglycemia, reduce marked fluctuations of blood glucose concentrations, minimize the demand on beta cells to produce insulin, and improve insulin sensitivity (9-11). By doing this, we decrease the effect of “glucose toxicity” and hopefully allow the pancreatic islet cell to partially recover. In about half of newly diagnosed diabetic cats, this will lead to remission of the diabetic state (12-14).

A secondary goal of therapy is to provide a diet that will help normalize body weight and maintain and/or restore lost muscle mass (15,16). I'll be covering the reason why higher protein diets are also important for diabetes in my post next week.

Recommendations for Diabetic Cats: Low Dietary Carbohydrates:
It is well accepted dogma, at least by most practicing veterinarians who specialize in feline medicine, that feeding a low-carbohydrate diet is the mainstay in the treatment of diabetes mellitus, especially if remission of the diabetic state is the goal. In accord with that, there is strong clinical and research evidence that a diet containing very low concentrations of carbohydrate (e.g., carbohydrates less than 12% of calories) is the most effective means for achieving our nutritional goals for cats with diabetes (5,9,17-19).

Feeding a low carbohydrate diet will improve insulin sensitivity, help stabilize glucose metabolism, and can reduce or eliminate the need for exogenous insulin in these cats (5,20,13,14).  The likely mechanism for these observations is relatively simple —decreasing dietary carbohydrate load reduces the postprandial blood glucose elevation, which in cats is prolonged, sometimes lasting for over 12 hours (7,8).

In some diabetic cats, decreasing carbohydrate content to a level significantly less than 12% of the daily calories may help increase their rate of remission. In accord with that, the highest remission rates (greater than 80%) have been reported feeding diets with approximately 6% of energy from carbohydrate (21).

If a change in feeding to a low-carbohydrate diet is made in a diabetic cat already stabilized on insulin, it is extremely important to realize that this will result in a lowered daily insulin dosage — often significantly (9.20). If not closely monitored—ideally with home glucose testing— severe hypoglycemia can develop in these cats because they become more sensitive to insulin after the diet composition is changed.

Therefore, when changing from a higher-carbohydrate to a low-carbohydrate diet, we recommend initially reducing the insulin dose by 30% to 50% to help avoid hypoglycemia. If the diabetic cat goes into remission (no more insulin needed to maintain euglycemia), we recommend maintaining the low-carbohydrate diet for life to help prevent relapse of the diabetic state.

References:

1. MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984;4:521-562. 
2. Zoran DL. The carnivore connection to nutrition in cats. J Am Vet Med Assoc 2002;221:1559-1567. 
3. Eisert R. Hypercarnivory and the brain: protein requirements of cats reconsidered. J Comp Physiol B 2011;181:1-17. 
4. 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. Res Vet Sci 2011;93. 
5. Rucinsky R, Cook A, Haley S, et al. AAHA diabetes management guidelines. J Am Anim Hosp Assoc 2010;46:215-224. 
6. American Diabetes Association. Postprandial blood glucose. Diabetes Care 2001;24:775-778. 
7. Farrow H, Rand JS, Morton JM, et al. Postprandial glycemia in cats fed a moderate carbohydrate meal persists for a median of 12 hours -- female cats have higher peak glucose concentrations. J Feline Med Surg 2012;14:706-715. 
8. Farrow HA, Rand JS, Morton JM, et al. Effect of dietary carbohydrate, fat, and protein on postprandial glycemia and energy intake in cats. J Vet Intern Med 2013;27:1121-1135. 
9. 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.
10. Rand JS. Pathogenesis of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:221-231. 
11. Zini E, Osto M, Franchini M, et al. Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat. Diabetologia 2009;52:336-346. 
12.  Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321. 
13. Reusch CE, Hafner M, Tschuor F, et al. Diabetes remission in cats: a review. Schweiz Arch Tierheilkd 2011;153:495-500. 
14. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249. 
15. Nguyen P, Leray V, Dumon H, et al. High protein intake affects lean body mass but not energy expenditure in nonobese neutered cats. J Nutr 2004;134:2084S-2086S. 
16. Keller U. Dietary proteins in obesity and in diabetes. Int J Vitam Nutr Res 2011;81:125-133. 
17. Baral RM, Little SE. Endocrine pancreatic disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;547-571.
18. Bennett N, Greco DS, Peterson ME, et al. Comparison of a low carbohydrate-low fiber diet and a moderate carbohydrate-high fiber diet in the management of feline diabetes mellitus. J Feline Med Surg 2006;8:73-84. 
19. Boari A, Aste G, Rocconi F, et al. Glargine insulin and high-protein-low-carbohydrate diet in cats with diabetes mellitus. Vet Res Commun 2008;32 Suppl 1:S243-245. 
20. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:233-243. 
21. 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. 

Purina Discontinues ''Glucotest'' Feline Urinary Glucose Detection System

For the last few years, I've routinely used the Purina Glucotest urine glucose indicator packets to provide owners of diabetic cats with an easy means of monitoring their cat at home. This detection system added to the cat's litter provided a nice gauge of the degree of glucosuria at home in a non-invasive way. 

I have especially found the Glucotest granules helpful in telling me if there is any glucose in the urine after I've lowered or discontinued the insulin dose in a cat that I think is going into diabetic remission.  

The bad news is that I just found out from the company that they have discontinued the product and will no long make it. Can you recommend an alternate product that has a similar function?

My Response:

Purina Glucotest brand Feline Urinary Glucose Detection System gave cat owners a way to help monitor their diabetic cats at home. The indicator particles were mixed in with the litter and checked within a 12-hour period for a color change to indicate the level of glucose in your cat's urine (1).

Unfortunately, I don't know of an alternate product to replace the Glucotest. Obviously, we can still check urine glucose concentrations using a reagent strip (e.g., Diastix or KetoDiastix) (1-3).

However, the problem for many owners is how to collect the urine to test from their diabetic cats. I have had some luck with owners collecting urine using non-absorbable litter, such as No-Sorb or Kit4Cat hydrophobic litter and then using glucose reagent strips to test the litter.  Of these two non-absorbable litters, most cats prefer the Kit4Cat product since it looks and feels like regular sand; its hydrophobic sand keeps the cat’s urine on top, making sample collection easy (see box on right).  

Obviously, these non-aborbable litter products are also useful for collection of urine for any other purpose, including running a complete urinalysis.

That said, I do not recommend monitoring urine glucose concentrations to change the insulin dose in cats.  Monitoring of urine glucose is only a very indirect way to assess blood glucose concentrations, and results can be very misleading, especially when used as the sole monitoring method (1,2,4).  Remember that the results of a urine glucose concentration reflects the average blood glucose concentration over many hours, as urine is produced and high blood glucose concentrations exceed the renal threshold and is excreted into the urine.  Therefore, transient hypoglycemia or the Somogyi effect (prolonged rebound hyperglycemia following a profound decrease in circulating glucose concentrations) will be missed by urine glucose monitoring (2,4).

Over the last few years, it has become more common for owners to directly measure blood glucose at home, which has many advantages over urine glucose monitoring (4-7). In fact, many veterinarians now routinely recommend home glucose monitoring for their diabetic cats, which is particularly helpful if tight glucose regulation and diabetic remission is the goal. If this is not possible, use of a combination of clinical signs, determination of serum fructosamine concentrations, and periodic in-hospital glucose curves can be used for diabetic regulation (2,4).

This trend away from the use of urine glucose monitoring is probably one reason Purina Veterinary Diagnostics decided to stop making this Urinary Glucose Detection System.

References:

1. Fletcher JM, Behrend EN, Welles EG, et al. Glucose detection and concentration estimation in feline urine samples with the Bayer Multistix and Purina Glucotest. J Feline Med Surg 2011;13:705-711. 
2. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
3. Schaer M. A justification for urine glucose monitoring in the diabetic dog and cat. J Am Anim Hosp Assoc 2001;37:311-312. 
4. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 
5. Reusch CE, Kley S, Casella M. Home monitoring of the diabetic cat. J Feline Med Surg 2006;8:119-127. 
6. Zeugswetter FK, Rebuzzi L, Karlovits S. Alternative sampling site for blood glucose testing in cats: giving the ears a rest. J Feline Med Surg 2010;12:710-713. 
7. Ford SL, Lynch H. Practical use of home blood glucose monitoring in feline diabetics. Vet Clin North Am Small Anim Pract 2013;43:283-301.