Glucocorticoid-Induced Diabetes Mellitus

The mechanism of glucocorticoid-induced diabetes mellitus is multifactorial. Glucocorticoids induce hepatic and extrahepatic insulin resistance, says Pankaj Shah, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic.

Glucocorticoid treatment impairs both glucose transport in fat and muscle cells and the ability of glucose to stimulate its own utilization (glucose effectiveness), as well as reducing glucose clearance. These agents have direct harmful effects on insulin-secreting beta cells of the pancreatic islets by inducing apoptosis. In addition, hyperglycemia induced by glucocorticoids is associated with reduced GLUT-2 expression and a decrease in glucose transport into the beta cells. Also, glucocorticoids can increase appetite and weight.

Glucocorticoid use is associated with increased concentrations of fasting and post-meal insulin and glucagon.

Dr. Shah notes, "As long as compensatory insulin release is adequate for the prevailing glucose concentration, hyperglycemia does not occur because the higher insulin level adequately suppresses glucose production and stimulates glucose utilization." The risk of glucocorticoid-induced diabetes increases with the glucocorticoid dosage, duration of therapy, advanced patient age, family history of diabetes mellitus, obesity, certain ethnicity/race, and high blood glucose concentrations before glucocorticoid therapy. The glycemic effect of glucocorticoid use also depends on the route of administration and the type of glucocorticoid.

Therapeutic Considerations

Management strategies for glucocorticoid-induced diabetes or for the glucocorticoid-induced worsening of diabetes mellitus have not been systematically studied in prospective trials. Dr. Shah says that physicians at Mayo Clinic advise patients:

• To avoid both overeating and consuming concentrated sweets such as fruit juices and other drinks with simple carbohydrates, cakes, cookies, pies, or donuts. Restricting fatty foods is also helpful in restricting calories.
• That sugar-free does not always mean carbohydrate-free, fat-free does not necessarily suggest that a food is low in sugar or low in calories, and a diabetic label does not always mean that a food is low in calories. Low-calorie sweeteners often help improve the taste of sodas, baked goods, and candies.
• To increase consumption of fiber to approximately 25 grams to 30 grams per day. The importance of physical activity is always stressed.

"The most important goal of therapy for hyperglycemia induced by glucocorticoids is to prevent acute hyperglycemic complications, as well as serious adverse effects from therapy. It is generally believed that a glucose concentration less than 180 mg/dL for most of the day will prevent infections associated with hyperglycemia," says Dr. Shaw.

General Approach to Treatment of Patients with Glucocorticoid-Induced Hyperglycemia at Mayo Clinic

All patients

• Diet: Avoid overeating and consuming concentrated simple carbohydrates
• Exercise: Regular as tolerated and the maximum possible for up to 150 min per week
• Self-monitoring of blood glucose concentrations: Frequency depends on type and stability of the treatment regimen

Patients with mild hyperglycemia (all blood glucose concentrations <200 mg/dL)

• First-line treatment: metformin^a (at the maximum tolerated dose, up to 2 g/day)
• Second-line treatment: sulfonylureas,^a,b meglitinides,^a,b or thiazolidenediones^a,c
• Third-line treatment: single-dose neutral protamine Hagedorn (NPH) insulin

Patients with fasting glucose concentration in goal but other glucose concentrations e200 mg/dL^d,e

• NPH insulin or premixed (with rapid-acting insulin) insulin once a day; start at a generous dose (e.g., 0.2-0.4 units/kg per day)
• May need another dose of rapid-acting insulin with evening meal if bedtime blood glucose concentrations are high

Patients with fasting and daytime blood glucose concentrations e200 mg/dL^e

• Treat like any patient who newly requires insulin but at a much higher starting dosage (eg, 0.6-0.8 units/kg per day)
• Patients often require a much larger proportion of their insulin as prandial doses
  • May be contraindicated in patients with other comorbidities
  • Hypoglycemia is a real danger with this treatment, especially for sick patients whose food intake and physical activity are erratic
  • Weight gain and fluid retention may be problematic; long-term use of these agents may have an impact on bone health
  • These patients should take no NPH insulin at bedtime if fasting blood glucose concentrations are under control.
  • Avoid sliding-scale-only protocols with these agents; patients should not take rapid-acting insulin at bedtime unless blood glucose concentrations are very high (eg, >350 mg/dL)