Managing Dogs with Insulin-Sensitive, Brittle Diabetes

My problem patient is a 13-year-old, female-spayed Yorkie with brittle diabetes mellitus. In contrast to many diabetic dogs that I see, this dog is very insulin sensitive, with frequent bouts of hypoglycemia. Fortunately, these hypoglycemic episodes do not appear to be causing clinical problems (i.e., no weakness or seizures have been observed), and she seems to be doing great at home. We have the owner feeding her several times a day to prevent hypoglycemia.

To complicate diabetic control in this dog, the owner's elderly father cares for the dog during the day. On the weekends, the owner works quite late so she "pre-fills" the insulin syringe in the morning so her father can give the insulin shot later that day. I've told the owner that the NPH insulin particles will likely be out of suspension by the evening (unless her father remembers to roll the syringe to remix the insulin suspension), but the owner says she doesn't have much choice.  I'm not sure how this is affecting the diabetic control, but it cannot be helping. We try to do her glucose curves toward the end of the week after the owner (rather than the father) has been injecting the insulin herself.

Below are two recent blood glucose curves, the first done about a month ago and the second one just done this week:

Glucose Curve 1

• 0800 hr—372 mg/dl (Fed; Gave 1 unit of NPH, SC)
• 1000 hr—109 mg/dl
• 1130 hr—Fed small meal
• 1200 hr—98 mg/dl
• 1400 hr—75 mg/dl
• 1530 hr—Fed small meal
• 1600 hr—67 mg/dl
• 1800 hr—214 mg/dl

I thought this curve indicated pretty good glycemic control. However, I found her latest glucose curve to be especially concerning.

Glucose Curve 2

• 0800 hr—310 mg/dl (Fed; Gave 1 unit of NPH, SC)
• 1000 hr—65 mg/dl
• 1015 hr—Fed small meal
• 1100 hr—101 mg/dl
• 1300 hr—24 mg/dl (Sample sent to lab confirmed hypoglycemia: 45 mg/dl)
• 1310 hr—Fed small meal (ate well)
• 1400 hr—98 mg/dl
• 1600 hr—240 mg/dl
• 1800 hr—270 mg/dl

Even with the very low blood glucose value at 1300 hr, this dog was acting fine and was not exhibiting any signs of hypoglycemia.

So I'm at a loss. I told the owner to decrease to 0.5 unit of the NPH twice daily and to feed more at each meal. However, I'm worried that it's going to be very difficult to give such a tiny dose of insulin. Can the NPH be diluted?

I'm also wondering if part of the problem here is a too short of a duration for NPH or a Somogyi effect (hypoglycemia-induced hyperglycemia). Should we try a different insulin?

My Response:

Obviously, this dog has a higher insulin sensitivity than is the typical dog with diabetes mellitus. Such an insulin-sensitive diabetic will require smaller amounts of insulin to lower blood glucose levels than the average canine diabetic with "normal" sensitivity or insulin resistance.

The glucose-lowering effect of insulin varies from diabetic dog to dog, depending on a number of factors including age, degree of insulin deficiency, and concurrent disease (1).  Generally speaking, having a higher sensitivity to insulin makes it easier to regulate the diabetic patient.  However, there are times when this increased sensitivity can be problematic. As in this dog, having high insulin sensitivity will increase the risk of hypoglycemia and can even make it difficult to accurately draw up a small enough dose.

Minimizing hypoglycemia in dogs with increased insulin sensitivity
So what can we do to minimize iatrogenic hypoglycemia in the insulin-sensitive diabetic?  Factors to consider include the following (1-4):

• Insulin dose
• Type of insulin (short, intermediate, or long-acting)
• Timing of food ingestion to insulin injection
• Exercise
• Decreased clearance of insulin

Lowering the insulin dose— You certainly could dilute the NPH insulin and lower the insulin dose to 0.5 U twice a day. Both Eli Lilly and Novo Nordisk make diluents for their brand of NPH insulin, but these diluents can be difficult to obtain (5).  Insulin can also be diluted with sterile water or saline solution, but these insulin solutions are not as stable.

A better option is to use a U-100 insulin syringe with 0.5 unit markings. Again, these syringes may be difficult to find, but are generally available at WalMart  (ask for ReliOn U-100 3/10 cc insulin syringes marked in 1/2 unit dosing).

Using a less potent type of insulin — In general, short-acting insulins (e.g., regular insulin, NPH, lente) have a more potent hypoglycemic effect than do the long-acting insulin preparations (protamine zinc insulin, glargine).  The reason for this is mainly because short-acting insulins are absorbed faster and result in higher levels of circulating insulin concentrations (1,6-8). Long-acting preparations, such as glargine (Lantus) or protamine zinc insulin (PZI, ProZinc) are absorbed much slower and result in much lower peak circulating insulin concentrations (1,6-10). The big exception to this rule is the long-acting insulin preparation detemir (Levemir), which turns out to be a very potent insulin in dogs (11).

Adjusting the timing of food ingestion and insulin injection—In general, I like to have owners inject insulin about 30 minutes before the dog eats in order to prevent severe post-prandial hyperglycemia and help regulate the dog's diabetic state (12).  In most dogs, I strongly discourage the feeding of extra meals or snack throughout the day, since it commonly leads to poor glycemic control when using twice daily insulin injections.

In dogs with severe insulin sensitivity, however, I would try the opposite approach. In these dogs, I feed the dog about 30 to 60 minutes before injecting the insulin to encourage a rise in blood sugar to help prevent the hypoglycemia that commonly occurs in these dogs shortly after the insulin injection.

Accounting for the effect of exercise—Although it does not appear to be a contributory factor in this dog, physical activity is well known to have insulin sensitizing effects, and this can also present a higher risk of hypoglycemia for patients on insulin (13). The insulin sensitizing effects of exercise can sometimes last for hours so it is important to be aware of the increased risk of hypoglycemia in these dogs.

Exclude disorders that result in a decreased clearance of insulin—The liver is responsible for about half of the total insulin degradation with the kidney responsible for the rest (14,15). Therefore, the development of severe liver disease or chronic kidney disease can contribute to the increased insulin sensitivity seen in a dog with diabetes. Again, this does not appear to be a contributory factor in your dog.

My Bottom Line

You certainly could lower the NPH insulin dose, but I don't think that's the best solution for this dog.  I would recommend switching to a longer-acting insulin preparation, such as ProZinc or Lantus.  Although not generally considered as first-choice insulin preparations, both of these long-acting insulin preparations have been reported to be effective in dogs (9,10). Because they are slowly absorbed, both of these insulins have a less potent hypoglycemic effect as compared with NPH insulin.

However, we can't forget about the "premixing" of the insulin dose that the owner does on the weekends, can we! When we throw that into the equation, my choice becomes more obvious. Let's change to Lantus, which is a solution so the insulin won't precipitate out of suspension like the premixed NPH insulin would likely do.

References:

1. Nelson RW. Canine diabetes mellitus. In: Ettinger SJ, Feldman EC (eds). Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition. Saunders Elsevier, St Louis. 2010;1782-1796.
2. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003;26:1902-1912. 
3. Cryer PE. Hypoglycemia risk reduction in type 1 diabetes. Exp Clin Endocrinol Diabetes 2001;109 Suppl 2:S412-423. 
4. Boyle PJ, Zrebiec J. Management of diabetes-related hypoglycemia. South Med J 2007;100:183-194. 
5. Insulin administration. Diabetes Care 2001;24:1984-1987. 
6. Goeders LA, Esposito LA, Peterson ME. Absorption kinetics of regular and isophane (NPH) insulin in the normal dog. Domest Anim Endocrinol 1987;4:43-50. 
7. Wallace MS, Peterson ME, Nichols CE. Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats. Domest Anim Endocrinol 1990;7:509-515. 
8. Clark M, Thomaseth K, Heit M, et al. Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs. J Vet Pharmacol Ther 2012;35:342-350. 
9. 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. 
10. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
11. 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.
12. 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. 
13. Zisser H, Gong P, Kelley CM, et al. Exercise and diabetes. Int J Clin Pract Suppl 2011:71-75. 
14. Duckworth WC, Hamel FG, Peavy DE. Hepatic metabolism of insulin. Am J Med 1988;85:71-76. 
15. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia 1984;27:351-357. 
16. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Vet Clin North America Small Anim Prac 2010;40:297-307.