Insulin Resistance

Chapter 47

Insulin Resistance

Insulin resistance is defined as a condition in which a normal amount of insulin produces a subnormal biologic response. Insulin resistance may result from problems occurring before the interaction of insulin with its receptor (e.g., circulating insulin-binding antibodies), at the receptor (e.g., altered insulin receptor binding affinity or concentration), or at steps distal to the interaction of insulin and its receptor (e.g., block in insulin signal transduction). Postreceptor problems are difficult to differentiate clinically from receptor problems, and both often coexist. In dogs and cats, receptor and postreceptor abnormalities are usually attributable to obesity, inflammation such as pancreatitis or gingivitis, or a disorder causing excessive or deficient secretion of one or more insulin-antagonistic hormones, specifically glucagon, catecholamines, cortisol, and growth hormone. Clinically relevant problems caused by insulin resistance include development of diabetes mellitus, stimulation of ketogenesis and development of diabetic ketoacidosis (DKA), and interference with the effectiveness of exogenous insulin injections for treating diabetes mellitus.

Role in the Pathogenesis of Feline Diabetes and Diabetic Remission

Amylin is a polypeptide produced by pancreatic β cells in cats. It is stored in secretory granules that contain insulin and is cosecreted with insulin. Stimulants of insulin secretion stimulate the secretion of amylin. Chronic increased secretion of insulin and amylin, as occurs with obesity and other insulin-resistant states, results in aggregation and deposition of amylin in the pancreatic islets as amyloid. Amyloid fibrils cause apoptotic islet cell death. Deposition of islet amyloid and subsequent loss of β cells is progressive with persistent insulin-resistant states and ultimately results in diabetes mellitus. The severity of islet amyloidosis and loss of β cells determines, in part, a cat’s need for insulin treatment to control hyperglycemia and the potential for diabetic remission once treatment is initiated. Total destruction of the islets results in insulin-dependent diabetes mellitus and the need for insulin treatment for the rest of a cat’s life. Partial destruction of the islets may or may not result in clinically evident diabetes, insulin treatment may or may not be required to control hyperglycemia, and diabetic remission may or may not occur when treatment is initiated.

The presence, severity, and reversibility of insulin resistance is an important variable that influences the severity and progression of islet amyloidosis, treatment options at the time diabetes is diagnosed, and likelihood of diabetic remission in cats. Any chronic insulin-resistant disorder can have a deleterious impact on the population and function of β cells and play a role in the development of diabetes. Identification and correction of concurrent problems that cause insulin resistance is critical to the successful treatment of diabetes in cats (Box 47-1). Correction and subsequent avoidance of insulin resistance may result in diabetic remission in cats with partial loss of pancreatic β cells, and recurrence of insulin resistance may result in recurrence of symptomatic diabetes.

Role in Diabetic Ketoacidosis

Insulin is a powerful inhibitor of lipolysis and ketone production. A deficiency of insulin or the presence of insulin resistance, or both, promotes lipolysis, ketogenesis, and development of DKA. Virtually all dogs and cats with DKA have a relative or absolute deficiency of insulin and insulin resistance at the time DKA is diagnosed. Some diabetic dogs and cats develop ketoacidosis despite receiving daily injections of insulin, and circulating insulin concentrations may be increased. In these dogs and cats, insulin deficiency results from insulin resistance caused by an increase in insulin-antagonistic hormones, most notably glucagon, and the presence of concurrent disorders such as pancreatitis. Insulin dosages that were effective in controlling hyperglycemia become inadequate with development of insulin resistance and predispose a diabetic dog or cat to developing DKA. Almost all dogs and cats with DKA have some coexisting disorder, such as pancreatitis, infection, or hormonal excess or deficiency. Recognition and treatment of disorders that coexist with DKA are critical for successful management (see Box 47-1).

Role in Control of Hyperglycemia

Insulin resistance interferes with the actions of exogenously administered insulin, resulting in persistent hyperglycemia; glycosuria; clinical signs (polyuria, polydipsia, and weight loss); and development of complications of chronic diabetes, such as cataracts in dogs and peripheral neuropathy in cats. Persistent problems with diabetic regulation should raise suspicion for insulin resistance. However, other issues with the insulin treatment regimen should also be considered, such as an inadequate or excessive dosage of insulin and a short or prolonged duration of effect of the insulin preparation.

There is no insulin dosage that clearly defines insulin resistance. For most diabetic dogs and cats, control of hyperglycemia can usually be attained using a dosage of 1.0 U or less of an intermediate-acting or long-acting insulin preparation per kilogram of body weight given twice daily. Insulin resistance should be suspected if control of hyperglycemia is poor despite an insulin dosage greater than 1.5 U/kg, when excessive amounts of insulin (i.e., insulin dosage >1.5 U/kg) are necessary to maintain the blood glucose concentration less than 300 mg/dl, and when control of hyperglycemia is erratic and insulin requirements are constantly changing in an attempt to maintain control. Failure of the blood glucose concentration to decrease below 300 mg/dl is suggestive of, but not definitive for, the presence of insulin resistance. Failure of blood glucose concentration to decrease after insulin administration can also result from stress-induced hyperglycemia, induction of the Somogyi response, and other problems with insulin therapy. Similarly, a decrease in the blood glucose concentration to less than 300 mg/dl does not rule out insulin resistance because responsiveness to insulin may be present with disorders causing mild insulin resistance (e.g., obesity, chronic pancreatitis). Serum fructosamine concentrations are typically greater than 500 µmol/L in dogs and cats with insulin resistance and can exceed 700 µmol/L if resistance is severe. However, serum fructosamine concentrations can also be greater than 500 µmol/L with other problems involving the insulin treatment regimen.

The severity of insulin resistance depends in part on the underlying etiology. Insulin resistance may be mild and easily overcome by increasing the dosage of insulin or may be severe, causing persistent severe hyperglycemia regardless of the type and dosage of insulin administered. Some causes of insulin resistance are readily apparent at the time diabetes is diagnosed, such as obesity and the administration of insulin-antagonistic drugs (e.g., glucocorticoids). Other causes of insulin resistance are not readily apparent and require an extensive diagnostic evaluation to be identified. Generally, any concurrent inflammatory, infectious, hormonal, neoplastic, or organ system disorder can interfere with the effectiveness of insulin. The most common concurrent disorders interfering with insulin effectiveness in diabetic cats include diabetogenic drugs (e.g., glucocorticoids), severe obesity, chronic pancreatitis, kidney failure, hyperthyroidism, oral infections, acromegaly, and hyperadrenocorticism. The most common concurrent disorders interfering with insulin effectiveness in diabetic dogs include diabetogenic drugs (i.e., glucocorticoids), severe obesity, hyperadrenocorticism, diestrus, chronic pancreatitis, kidney failure, oral and urinary tract infections, hyperlipidemia, and insulin antibodies in dogs treated with beef insulin. Obtaining a complete history and performing a thorough physical examination is the most important step in identifying these concurrent disorders. If the history and physical examination fail to identify the underlying problem, a complete blood count, serum biochemical analysis, serum thyroxine concentration (cat), serum pancreatic lipase immunoreactivity (IDEXX Spec cPL), serum progesterone concentration (intact female dog), abdominal ultrasound, and urinalysis with bacterial culture should be considered to screen further for concurrent illness. Additional tests depend on the results of the initial screening tests.

Treatment and reversibility of insulin resistance depend on the etiology. Insulin resistance is reversible with treatable disorders (e.g., sodium levothyroxine treatment in a diabetic dog with concurrent hypothyroidism or ovariohysterectomy in an intact female diabetic dog in diestrus. In contrast, insulin resistance often persists with disorders that are difficult to treat, such as chronic recurring pancreatitis in diabetic dogs and cats or acromegaly in diabetic cats. In some situations, measures can be taken to prevent insulin resistance, such as avoidance of glucocorticoids in diabetic dogs and cats or performing an ovariohysterectomy at the time diabetes mellitus is diagnosed in an intact female dog.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Insulin Resistance

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