Amber McAlister, DVM Veterinary Medical Specialists (Campbell)
Insulin resistance is a condition in which a normal amount of insulin causes an inadequate decrease in blood glucose levels. This means that the existing pancreatic beta cells, even when they are still functional, cannot produce enough insulin to overcome the inherent insulin resistance of cells, allowing persistent hyperglycemia to occur. In diabetic patients that are receiving exogenous insulin, insulin resistance is diagnosed when greater than 2.2U/kg per dose is necessary to maintain adequate control. An index of suspicion should be raised when marked hyperglycemia persists throughout the day despite administration of greater than 1.5U of insulin/kg per dose. Most diabetic dogs can be maintained with 1U/kg or less of intermediate or long acting insulin once to twice daily.
Confirmation of insulin resistance first requires elimination of problems associated with insulin administration or problems with the insulin itself. Owners should be questioned about their insulin handling (storage, mixing of the insulin, measurement of the dose given), type of syringe they are using (U-40 vs. U-100) and administration technique. The insulin product can be inactivated if it is over shaken, overheated, improperly diluted, or expired. Once technical problems have been evaluated, a blood glucose curve is required to confirm a diagnosis of insulin resistance. The curve is essential to rule out a Somogyi response (post hypoglycemic hyperglycemia) or an excessively short duration of action due to rapid metabolism of insulin. Stress hyperglycemia can result in a blood glucose curve that is similar to that seen with insulin resistance, although the degree of hyperglycemia is often less markedly elevated.
An important issue that often goes unrecognized is reduced subcutaneous insulin absorption (particularly common in dehydrated patients). These patients will not respond well to insulin administered at home, but will respond adequately to administration of intravenous insulin in the hospital setting. Another problem is anti-insulin antibody formation against exogenous insulin. The formation of anti-insulin antibodies can cause insulin resistance or erratic glycemic control in veterinary patients.
Impairment of the immune system and changes in blood supply to tissues are thought to contribute to the increased risk of infection seen in diabetic patients. Diabetic veterinary patients are particularly prone to urinary tract infections, and symptoms may be masked by the ongoing presence of clinical signs attributed to diabetes. In previously controlled diabetics that become unregulated, new diabetic patients, and those receiving high doses of insulin without adequate response, evaluation of a urinalysis with culture and sensitivity is indicated.
Adrenocortical hormone disorders
Hyperadrenocorticism is the most common cause of insulin resistance in dogs. Recognition of concurrent hyperadrenocorticism and diabetes mellitus can be challenging, as the clinical signs of Cushing’s disease (endocrine alopecia, thin skin, and a pot-bellied appearance) may not be readily apparent on initial diagnosis of diabetes mellitus. Early indicators of hyperadrenocorticism can include elevated alkaline phosphatase and adrenomegaly on abdominal ultrasound. Definitively diagnosing hyperadrenocorticism in a patient with concurrent DM can be difficult, as sick diabetics (i.e. DKA patients) can have elevated adrenocortical function tests even in the absence of true Cushing’s disease. Once the diabetes is more stable and the patient is clinically improved, repeat testing may be necessary to confirm a diagnosis of hyperadrenocorticism.
Reproductive hormone disorders
Diestrus should always be considered an inciting cause in any new or poorly controlled diabetic intact female dog. Ovariohysterectomy is recommended at the first signs of emerging diabetes in these dogs as the diabetes mellitus typically becomes a permanent condition by the second estrus cycle.
Growth hormone disorders
Acromegaly in dogs is caused by progesterone stimulation of growth hormone release. The disease is thus restricted to female dogs and treatment involves removal of the progesterone stimulus.
Hypothyroidism is a frequently occurring concurrent disease of dogs, and can contribute to insulin resistance in diabetic patients. The obesity and elevated blood lipid levels that accompany hypothyroidism can also be associated with insulin resistance. Diagnosis of true hypothyroidism (as opposed to euthyroid sick syndrome) can be challenging, but a low TT4, fT4 and elevated TSH level are supportive findings. Treatment of hypothyroidism can lessen insulin resistance, and reduction of insulin requirements by 50-60% may be seen within two months of initiating treatment.
Approximately 35% of dogs with diabetes mellitus have evidence of chronic pancreatitis at necropsy. Fluctuating insulin requirements are common, and management of these patients can be frustrating. Treatment is supportive, and a pancreatic biopsy is required to confirm suspicions of pancreatitis.
Obesity and Hyperlipidemia
Mobilization of fat stores via lipolysis occurs in patients with relative insulin deficiency. Many dogs with hyperlipidemia do not have concurrent DM, but in those dogs that have diabetes and an additional cause of hyperlipidemia (hypothyroidism, hyperadrenocorticism, idiopathic hypertriglyceridemia), insulin resistance can become a problem. A 24 hour fasting triglyceride level is necessary to confirm a diagnosis of hypertriglyceridemia. Treatment involves feeding a low fat diet (<20% of metabolic energy) and supplementation with omega-3 fatty acids. If the triglyceride level remains elevated despite treatment of underlying disorders and diet therapy, drug therapy such as niacin or gemfibrozil can be considered.
Obesity causes carbohydrate intolerance and hyperinsulinemia in dogs. Insulin resistance as a result of obesity is due to down regulation of insulin receptors, reduced receptor binding affinity, and post-receptor defects in intracellular glucose metabolism. Chronic carbohydrate intolerance leads to chronic hyperglycemia which impairs insulin secretion by beta cells, down regulates glucose transport systems, and interferes in post-receptor activity. This beta-cell suppression is called “glucose toxicity”, and is a common finding in cats with diabetes mellitus. The effects of obesity and glucose toxicity are reversible, and insulin sensitivity will improve with treatment.
The most common types of cancers that have been associated with development of insulin resistance in veterinary medicine include lymphoma and mast cell tumors. Other tumor types have also been associated with development of insulin-resistant diabetes mellitus.
Patients with concurrent renal disease and diabetes mellitus are at risk for both prolonged duration of insulin effect and insulin resistance. This puts them at risk of development of both hypo- and hyperglycemia. The polyuria and polydipsia associated with renal failure can be confused with signs of poorly regulated diabetes, making monitoring of disease at home more difficult as well. Management of diabetes in patients with concurrent renal disease can be an exercise in frustration, and owners should be preemptively warned of difficulties associated with treatment of these diseases concurrently.
In conclusion, insulin resistance is a common problem in diabetic veterinary patients. Frequently encountered causes for insulin resistance include infection, obesity and concurrent endocrine disease. However, any illness that increases circulating levels of counter regulatory hormones (cortisol, glucagons, catecholamines, and growth hormone) can contribute to development of insulin resistance. Management of diabetes can be challenging, and often requires a balance of dietary management, insulin therapy, and diagnostic testing for evaluation of both diabetic control and underlying etiologies of insulin resistance.