INSULIN RESISTANCE AND INFECTION
Q. What's the mechanism behind chronic infections causing insulin resistance?
A. This issue is complicated but is due, in part, to increased endogenous cortisol released by any physiologic stress, along with insulin antagonism due to inflammatory mediators such as the cytokines. Studies in people have shown that numerous chemicals released in response to infection or inflammation, such as tumor necrosis factor, C-reactive protein, and interleukin-6, impact the peripheral response to insulin.
TIMING OF BACKGROUND INSULIN
Q. If a background insulin is considered (glargine or detemir) once a day, does it matter when it's administered during the day (i.e. close to or separated from the Lente injection)?
A. The Lente insulin should be given with meals, but it probably doesn't make much difference when the background insulin is administered. For client convenience, it is probably best to give both insulins at the same time—that is the plan I have used in the past. As with any diabetic treatment plan, consistency is essential, so give the long-acting insulin on a routine schedule and not randomly. As always with a challenging diabetic patient, it is essential to monitor glucose curves to know what effect the insulin plan is having and to identify hypoglycemia.
ITIME FOR A SWITCH?
Q. I have a canine patient with newly diagnosed diabetes that is receiving Vetsulin (Intervet/Schering-Plough Animal Health) and coming in for repeated glucose curves. Regulation is not good at this point, but it's getting there. It seems like the duration of action of Vetsulin in this dog is only four to six hours. Since you mentioned that Vetsulin and NPH can have similar durations of action, is it worth trying a complete switch to NPH at some point, or does this indicate that NPH alone will not solve the problem?
A. Lente and NPH are generally similar in action and duration. However, if this patient is experiencing a very short duration of effect while receiving the Lente, you cannot predict the effect of the NPH. It may last longer, so I would probably try the NPH before I added a long-acting/background insulin to this patient's protocol. In general, I only resort to combinations of insulin when I have exhausted every easy option, as these plans are more costly and less well understood at this time. We don't have sound guidelines on dosage combinations, and close monitoring is needed in the early stages of these plans.
A TOUGH CASE
Q. Buster is an 11-year-old 75.5-lb neutered male Shar-Pei mix with a sweet disposition. He is receiving carprofen, tramadol, and glucosamine for chronic arthritis. In March, we saw him for a wellness exam, vaccines, and a senior comprehensive profile. At that time, he had elevated alkaline phosphatase (208), amylase (1,242), and lipase (1,313) activities; an elevated cholesterol concentration (431), normal T4 and free T4 (by equilibrium dialysis) concentrations; normal complete blood count results; and normal urinalysis results (specific gravity = 1.050, pH = 7, inactive sediment).
We measured the lipase activity again about two weeks later, and it had increased to 5,898. We then recommended an ultrasonographic examination, which identified a small hepatic mass and nodule in the same lobe and left adrenal gland enlargement. The pancreas looked normal, as did the kidneys. The ultrasonographer suspected the increased lipase activity was due to gastrointestinal disease.
Buster was not experiencing polyuria or polydypsia at that time, so we measured his urine cortisol-creatinine ratio to screen for hyperadrenocorticism; the results were normal (7; normal < 13.5). The owners opted not to pursue any surgical intervention for the hepatic masses but to watch for any clinical signs.
About 10 days later, the owners reported a huge and sudden increase in Buster's water intake and urination. A urinalysis revealed glucose (4+), no ketones, a urine specific gravity of 1.042, and pH = 6. His blood glucose concentration that day was 532. We started therapy with Humilin N (Eli Lilly) insulin at 9 U twice a day. The owners bought a home glucose monitoring system, which has seemed to work well.
The problem is that we have continued to increase Buster's insulin dose, and his blood glucose concentration has not budged below 400 at any time during the curve. Most of the time, the owner is getting glucose readings of 400 to 500, and Buster is still experiencing polyuria and polydypsia. He now receives 25 U twice a day.
We have done another urinalysis, which showed no sign of inflammation. But it was a free-catch sample, so a culture has not been done yet. His mouth is in pretty good condition. He eats a holistic diet with brown rice and chicken, which the owners do not want to change because he is sensitive to dietary changes. I am worried about his adrenal gland enlargement and wonder if hyperadrenocorticism could still be possible.
Is it time to consider another insulin, or should I just increase the dose until we reach 1.5 U/kg? Buster has lost 6 lb since his diabetes was diagnosed. Any advice you could give would be appreciated.
A. Some cases are certainly more challenging than others, and this seems to be one of those. First, I would perform a urine bacterial culture since this is the most common cause of insulin resistance. Based on what you have said, I think that Cushing's is unlikely, so I would not explore that further at this point, particularly if the hair shaved from the ultrasonographic scan is growing back. If he has no hair growth, I might think differently because that is a good (and cheap!) marker for an endocrinopathy.
Do you see any response to the insulin? If you see some response but not enough, then I'd keep on increasing the insulin dose. If you don't see any response, I'd make sure that the injection technique was appropriate and that the insulin isn't getting injected into the hair or right through the skin. If there is absolutely no response, you could try giving Buster a dose of regular insulin in the clinic (10 U subcutaneously) and see if his glucose concentration decreases. You'll need to check the blood glucose concentration every 90 minutes for about six hours so that you can see a response. If the concentration does decrease, this would tell me that he is able to respond to insulin, but the NPH is just not doing what we would expect. Therefore, I'd try Vetsulin, starting at 0.25 U/kg twice daily.
The other point I'd like to stress is that the glucose curves must truly involve a reading every two hours. The pattern you are seeing is quite common in patients getting blood glucose checks rather than full curves. In these patients, a rapid drop in the blood glucose concentration is missed and the only value documented is a high blood glucose concentration in response to a low nadir (the Somogyi effect). These patients often receive progressive increases in their insulin dose because of apparent poor response.
If you don't make any progress with these suggestions, I'd perform thoracic radiography to check for occult disease before considering referral to a specialist for a fresh look. An internist may not do any better, but sometimes a new look at a tough case makes a difference. Good luck!
Audrey Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA
Department of Small Animal Clinical Sciences
College of Veterinary Medicine & Biomedical Sciences
Texas A&M University
College Station, TX 77843