of which should ameliorate the deleterious effects of aldosterone on glucoregulation.27
The mineralocorticoid agent, fludrocortisone (Florinef), is prescribed widely for patients with primary adrenal insufficiency and conditions associated with aldosterone deficiency, hyperkalemia, orthostatic hypotension, and type IV renal tubular acidosis. To date, the clinical use of Florinef has not been associated with diabetes risk in published reports. As noted, mineralocorticoid antagonists, spironolactone and eplerenone, have been associated with improved insulin sensitivity and insulin secretion.27
Immunomodulatory Agents
Calcineurin Inhibitors and Post-Transplant Diabetes
Organ transplantation is an expanding area of modern medical practice, and diabetes is being increasingly diagnosed in organ recipients. Post-transplant diabetes (also known as new-onset diabetes after transplantation [NODAT]) refers to the occurrence of diabetes in subjects who previously did not have diabetes following transplantation. The development of NODAT is associated with adverse clinical outcomes, including renal allograft loss, post-transplant infections, cardiovascular disease, and increased mortality.29–31 Variable incidence rates of NODAT have been reported over variable intervals among recipients of different organ transplants. The estimated rates of NODAT at 12 months or longer post-transplant are ~20% for kidney transplants, 9% to 21% for liver transplants, and ~20% for lung transplants.32–34 Most of the data in this field are derived from analysis of renal transplants, because information on other types of transplants is limited. The peak incidence of NODAT appears to occur around 3 months post-transplant, but the risk of diabetes persists for much longer.
The clinical presentation of NODAT is consistent with T2D, and studies have identified insulin resistance and impaired β-cell function as the underlying mechanisms.35 The insulin resistance can be induced in subjects who previously were normoglycemic and can be aggravated in subjects who have prediabetes, following organ transplantation. Medications used for post-transplant immunosuppression have been implicated in the pathogenesis of NODAT. The calcineurin inhibitors (tacrolimus and cyclosporine) and steroids have been the most documented drugs associated with the induction of NODAT. The agents, however, also are the most widely used immunosuppressive agents in the transplant population, and many other risk factors appear to influence the development of NODAT (Table 3.3).32,36
Table 3.3—Risk Factors for Post-Transplant Diabetes Mellitus
| Nonmodifiable | Modifiable |
| Age >45 years Race Ethnicity | • Immunosuppressive regimen - Tacrolimus - Glucocorticoid steroids - Combined tacrolimus and steroid • Acute rejection • Prediabetes (impaired fasting glucose or impaired glucose tolerance) • Body mass (BMI > 25 kg/m2 ) • Cadaveric organ • Hepatitis-C infection |
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