**8. Hyperglycemia and diabetes**

GCs are the most common cause of drug-induced hyperglycemia and diabetes. Hyperglycemia and diabetes induced by GCs, is defined as an abnormal increase in blood glucose associated with the use of GCs in a patient with or without a prior history of hyperglycemia or diabetes. GCs cause an exaggerated postprandial hyperglycemia and insensitivity to exogenous insulin. Thus, GCs have a greater effect on postprandial compared to fasting glucose. Postprandial hyperglycemia (defined as blood glucose 200 mg/dL 2 hours after a meal) is a much more sensitive indicator for hyperglycemia and diabetes induced by GCs. The exact prevalence is not known. The incidence of hyperglycemia and diabetes in hospitalized patients treated with GCs without a known history of diabetes is >50%. GCs increases by two- to fourfold the risk of hyperglycemia and diabetes in non-diabetic subjects. Treatment with exogenous GCs disrupts the glycemic balance of known diabetics [84–87].

Development of glucocorticoid-induced diabetes depends on the dose and duration of exposure. A study found that the risk for hyperglycemia increased substantially with increasing daily steroid dose. The risk may change with the type of the GCs, related with biochemical properties (e.g. potency of the anti-inflammatory and metabolic effects and duration of the effects). But, there is little difference between the GCs most frequently used (i.e. prednisone, prednisolone, and methylprednisolone). The effects of GCs on glucose excursions are observed within hours (6–8 hours) of exposure. The predisposing factors for hyperglycemia and diabetes induced by GCs have been suggested to be overweight, old age, non-white ethnicity, previous glucose intolerance, reduced sensitivity to insulin or impaired insulin secretion stimulated by glucose, female sex, Down syndrome, puberty, the severity of the disease itself, a family history of diabetes, type A30, B27, and Bw42 human leukocyte antigens (HLA); and receiving a kidney transplant from a deceased donor. Solid organ transplant patients treated with GCs, 10–20% of them develop diabetes, especially within the first months of exposure. Other immunosuppressive agents can also disrupt glycemic control through other mechanisms. Usually, hyperglycemia and diabetes induced by GCs improves with dose reductions and usually reverses when therapy is discontinued, but patients with high risk may develop persistent diabetes [88–91].

The pathophysiology of glucocorticoid-induced diabetes involves (1) increase in insulin resistance and (2) reduced glucose uptake in muscle and adipose tissue (via insulin-sensitive glucose transporter type 4) as a consequence GCs cause decreasing glucose uptake and glycogen synthesis. On the other hand GCs have profound and reciprocal effects on glyceroneogenesis in liver and adipose tissue. GCs increase the amount of fatty acids released into the blood. Increased fatty acids interfere with glucose utilization and causes insulin resistance, particularly in skeletal muscle. (3) Increased glucose production, increased hepatic gluconeogenesis via peroxisome proliferator-activated receptor α. (4) Direct effects on pancreatic β cells including inhibition of the production and secretion of insulin, a proapoptotic effect on β cells, a reduction in insulin biosynthesis, and β cell failure. (5) GCs may modulate the expression and activity of adipokines, such as adiponectin, leptin, and resistin. By this way GCs may disrupt insulin sensitivity and may also reduce the insulinotropic effects of glucagon-like peptide-1 [92–97].
