Richard W. Nelson, DVM, DACVIM
The first step in the evaluation of the poorly controlled diabetic dog or cat is to critically assess the findings on history and physical examination to be certain a problem with diabetic regulation truly exists. Many of the diabetic dogs and cats referred to our hospital for poor diabetic control are actually reasonably well regulated. The basic objective of therapy is to eliminate the clinical signs of diabetes mellitus, while avoiding the common complications associated with the disease. The most important parameters for assessing diabetic control are the owner's subjective opinion of severity of clinical signs and overall health of their pet, findings on physical examination, and stability of body weight. If the owner is happy with results of treatment, the physical examination is supportive of good glycemic control, and the body weight is stable, the diabetic dog or cat is usually adequately controlled. Poor control of glycemia should be suspected if the owner reports clinical signs suggestive of hyperglycemia or hypoglycemia or peripheral neuropathy, the physical examination identifies problems consistent with poor control of glycemia or the dog or cat is losing weight.
If the history, physical examination, change in body weight, and serum fructosamine concentration suggest poor control of the diabetic state, a diagnostic evaluation to identify the cause is warranted. Poor diabetic control is usually caused by problems with biologic activity of the insulin, problems with owner technique in administering insulin, problems with the insulin treatment regimen, or problems causing insulin resistance.
The owner's insulin administration technique and the biologic activity of the insulin preparation should be evaluated by watching the client's insulin administration technique and by administering new, undiluted insulin and evaluating the animal's response to the change. Diet, exercise, and concurrent medications should be reviewed. Caloric intake should be adjusted to correct obesity, if present. Diabetic dogs should be fed diets containing increased fiber content and diabetic cats should be fed diets containing decreased carbohydrate and increased protein content, if possible. Exercise promotes weight loss and lowers the blood glucose concentration. The daily routine for diabetic dogs should include exercise, preferably at the same time each day. Strenuous and sporadic exercise can cause severe hypoglycemia and the Somogyi response and should be avoided. Medications that may promote insulin resistance should be discontinued or modified, if possible.
If problems discussed above are not identified, then a critical evaluation of the insulin treatment regimen, an evaluation for concurrent insulin-resistant disorders, or both is indicated. The most common problems with the insulin treatment regimen in diabetic dogs include inadequate dose of insulin, excessive dose of insulin causing the Somogyi response, short duration of effect of lente or NPH insulin, and once-a-day insulin administration. The most common problems with the insulin treatment regimen in diabetic cats include recurring hypoglycemia and diabetic remission, excessive dose of insulin causing the Somogyi response, incorrect assessment of glycemic control caused by stress-induced hyperglycemia, short duration of effect of NPH, lente and less commonly PZI, glargine and detemir insulin, and prolonged duration of effect of PZI, glargine and detemir insulin causing the Somogyi response.
The serial blood glucose curve is used to assess the current insulin treatment regimen and provide guidance for making rational adjustments in insulin therapy. When generating a blood glucose curve, the insulin and feeding schedule used by the owner should be maintained and blood obtained every 2 to 3 hours throughout the day for glucose determination. Measurement of blood glucose concentrations should continue until the blood glucose nadir is identified and subsequent blood glucose concentrations increase. By measuring the blood glucose concentration frequently throughout the day and until the blood glucose nadir is identified, the clinician will be able to determine if the insulin is effective and to identify the glucose nadir, time of peak insulin effect, and approximate duration of insulin effect.
The ideal goal of insulin therapy is to maintain the blood glucose concentration between 5 and 15 mmol/L throughout the day and night, although many diabetic dogs and cats do well despite blood glucose concentrations consistently between 9 and 18 mmol/L, and to have the average blood glucose concentration less than 14 mmol/L during the time period of the glucose curve. Typically, the highest blood glucose concentrations occur at the time of each insulin injection, but this does not always occur. If the blood glucose nadir is greater than 8.5 mmol/L, the insulin dose may need to be increased. If the blood glucose nadir is less than 4.5 mmol/L, the insulin dose should be decreased. Duration of insulin effect can be assessed if the glucose nadir is greater than 4.5 mmol/L and there has not been a rapid decrease in the blood glucose concentration after insulin administration. Assessment of duration of insulin effect may not be valid when the blood glucose decreases to less than 4.5 mmol/L or decreases rapidly because of the potential induction of the Somogyi response, which can falsely shorten the apparent duration of insulin effect. A rough approximation of the duration of effect of insulin can be gained by examining the time of the glucose nadir.
For most well-controlled diabetic dogs and cats, the initial blood glucose concentration near the time of insulin administration is less than 17 mmol/L, the glucose nadir is greater than 4.5 mmol/L, the glucose nadir occurs approximately 8 hours after injection of insulin, and the average blood glucose concentration throughout the day is less than 14 mmol/L. An initial blood glucose concentration greater than 17 mmol/L combined with a glucose nadir occurring less than 8 hours after insulin administration and subsequent blood glucose concentrations exceeding 14 mmol/L is supportive of short duration of insulin effect. A glucose nadir occurring 12 hours or longer after insulin administration is supportive of prolonged duration of insulin effect. Dogs and cats may develop clinical hypoglycemia or the Somogyi response if the duration of insulin effect is greater than 14 hours and the insulin is being administered every 12 hours.
The Somogyi response is a normal physiologic response to impending hypoglycemia induced by excessive insulin. Hypoglycemia or a rapid decrease in blood glucose stimulates hepatic glycogenolysis and secretion of diabetogenic hormones, most notably epinephrine and glucagon. The physiologic response to hypoglycemia increases the blood glucose concentration, minimizes signs of hypoglycemia, and causes marked hyperglycemia within 12 hours of hypoglycemia. By the next morning, the blood glucose concentration can be greater than 22 mmol/L. Secretion of diabetogenic hormones during the Somogyi phenomenon may induce insulin resistance, which can last 24 to 72 hours after the hypoglycemic episode. Clinical signs of hypoglycemia are typically mild or not recognized by the client; clinical signs caused by hyperglycemia dominate the clinical picture. Unrecognized short and long duration of insulin effect and fluctuating insulin resistance as occurs with inflammatory disease like chronic pancreatitis are common reasons for induction of the Somogyi response. The insulin dose that induces the Somogyi response is variable and unpredictable and can be less than 0.5 U/kg/injection. The diagnosis of the Somogyi response requires demonstration of hypoglycemia (less than 4.5 mmol/L) followed by hyperglycemia (greater than 17 mmol/L) following insulin administration. The Somogyi response should also be suspected when the blood glucose concentration decreases rapidly regardless of the glucose nadir. Treatment involves reducing the insulin dosage and evaluating the dog or cat's clinical response.
Problems with Insulin Resistance
For most diabetic dogs and cats, control of glycemia can usually be attained using 1.0 U or less of an intermediate or long-acting insulin per kilogram of body weight given twice daily. Insulin resistance should be suspected if control of glycemia is poor despite an insulin dosage in excess of 1.5 U/kg, when excessive amounts of insulin are necessary to maintain the blood glucose concentration below 17 mmol/L, and when control of glycemia is erratic and insulin requirements are constantly changing in an attempt to maintain control of glycemia. Failure of the blood glucose concentration to decrease below 17 mmol/L during a serial blood glucose curve is suggestive of, but not definitive for the presence of insulin resistance. An insulin resistance-type blood glucose curve can also result from stress-induced hyperglycemia, the Somogyi response, and other problems with insulin therapy, and a decrease in the blood glucose concentration below 17 mmol/L can occur with disorders causing mild resistance. Serum fructosamine concentrations are typically greater than 500 µmol/L and can exceed 700 µmol/L if resistance is severe.
Many disorders can interfere with insulin action. Obtaining a complete history and performing a thorough physical examination is the most important initial step in identifying these concurrent disorders. If the history and physical examination are unremarkable, a CBC, serum biochemical analysis, serum thyroxine concentration (cat), serum pancreatic lipase immunoreactivity, serum progesterone concentration (intact female dog), abdominal ultrasound, and urinalysis with bacterial culture should be obtained to further screen for concurrent illness. Additional tests will be dependent on results of the initial screening tests.