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.