A 12-year-old female cat was presented for polyphagia. Diagnostic work-up revealed a diagnosis of diabetes mellitus. The cats was poorly responsive to insulin therapy. The diagnostic investigation and treatment of insulin resistance in this cat will be discussed in an interactive format.
Causes of Insulin Resistance
- Elevations in hormones other than insulin can cause insulin resistance. For example, hypoglycemia, stress, and other factors can induce counter-regulatory hormones that act to raise blood glucose. Glucagon and catecholamines are examples of these hormones.
- Anti-insulin antibodies can render insulin administered to a diabetic patient less effective or ineffective. Because cats receive insulin preparations based on the amino acid sequences for insulin of other species, some probably develop antibodies to insulin.
- Infection is associated with hyperglucagonemia in human patients, leading to insulin resistance. Although this mechanism of insulin resistance has not been studied in dogs and cats, it may still be present. For this reason, control infection may help decrease insulin resistance. Dental disease is extremely common in cats, and may contribute to insulin resistance in diabetics. Occult urinary tract infections are fairly common in cats with diabetes, so urinalysis and culture should always be part of the work-up for insulin resistance. In addition to infection indirectly causing hyperglycemia, it is thought that hyperglycemia can cause infections in a variety of organ systems. This phenomenon is well-described but not well understood. It is thought that diabetic patients have altered host defenses making them more prone to infections.
- Glucocorticosteroid hormones can cause insulin resistance. Glucocorticoids cause increased gluconeogensis in the liver, and thus raise blood glucose concentrations. These hormones also inhibit glucose transport, increase glucagons secretion, interfere with insulin receptor binding, and cause abnormalities in insulin secretion from beta cells. Dogs with naturally-occurring hyperadrenocorticism can have diabetes secondary to their hypercortisolemia. This problem is even more striking in cats. All of the cats with hyperadrenocorticism reported in the veterinary literature have been severe insulin-resistant diabetics.
- Hyperthyroidism is associated with glucose intolerance in people. Thyroid hormone excess augments hepatic glucose production. My clinical impression is that cats with both hyperthyroidism and diabetes mellitus have lower insulin requirements when their hyperthyroidism is controlled. Diagnosis of diabetes mellitus in hyperthyroid cats, however, is sometimes challenging. The stress associated with hyperthyroidism often causes hyperglycemia. In some cats, stress-induced hyperglycemia can even result in glycosuria. Normally, stress-induced hyperglycemia can be differentiated from diabetes by measuring serum frustosamine, which reflects persistent hyperglycemia over a 2 – 3 week period. In cats with hyperthyroidism, however, protein catabolism is increased and fructosamine concentrations can be falsely lowered. A normal fructosamine concentration in a hyperglycemic cat with hyperthyroidism does not necessarily exclude a diagnosis of diabetes mellitus.
- Growth hormone is an insulin antagonist. Cats with acromegaly are commonly insulin-resistance diabetics.
Diagnostic Work-up of Insulin Resistance
The first step in evaluation of insulin resistance in a dog or cat is careful review of insulin administration procedures. Feeding history, diet, insulin storage, injection techniques, and insulin handling must be evaluated to rule out "apparent" insulin resistance. To rule out other disorders underlying insulin resistance, animals receiving inappropriately high doses of insulin in the face of poor glycemic control should have a CBC, urinalysis, urine culture, serum chemistry profile, and, in the case of cats, a serum T4 determination performed. Because many animals with diabetes, hyperthyroidism, or hyperadrenocorticism are hypertensive, blood pressure should be measured. Pituitary-adrenal axis function testing should be performed if there are sufficient clinical data to make a diagnosis likely. It should be remembered that false positive ACTH stimulation or dexamethasone suppression test results are common in animals with diabetes. For this reason, astute clinical skills are required to diagnose hyperadrenocorticism in diabetics. Diagnostic imaging for insulin resistance may include CT or MRI of the pituitary gland. In one recent study (Elliott et al, JAVMA 2000;216:1765-8) 16 of 16 cats with insulin resistance diabetes mellitus had pituitary masses. Disorders like acromegaly and hyperadrenocorcticism may be more common in cats than we think.