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2: Medications and Diabetes Risk: General Mechanisms
DOI: 10.2337/9781580406192.02
Diabetes has been reported in association with exposure to a wide variety of medications. As summarized in Table 2.1, in many cases, the mechanism relating the particular drug to hyperglycemia is explainable, whereas the mechanism of the association is less clear with regard to several other medications.1 Classically, elevated blood glucose can result from drugs that induce hypoinsulinemia through the destruction of pancreatic β-cells (e.g., pentamidine, Vacor), or drugs that inhibit insulin secretion (e.g., diazoxide). Hypokalemia impairs insulin secretion and also desensitizes the insulin receptor, and it is one mechanism underlying the dysglycemia associated with thiazides, loop diuretics, and hyperaldosteronism.2
Table 2.1—Mechanisms and Examples of Drug-Induced Hyperglycemia
| Mechanisms | Examples |
| A. Interference with insulin secretionPancreatotoxic | Diazoxide, β-blockers Diuretics Pentamidine, Vacor |
| B. Interference with insulin action | Diuretics (via hypokalemia) Glucocorticoids, antiretrovirals β-Agonists, growth hormone |
| C. Impaired insulin secretion and action | Thiazide diuretics Cyclosporin, Tacrolimus |
| D. Increased nutrient flux and gluconeogenesis | Nicotinic acid Total parenteral nutrition α-Interferon |
| E. Alteration of gut flora | Antibiotics? |
| F. Unknown mechanism | Nonsteroidal anti-inflammatory drugs Antipsychotics Antidepressants |
The induction of insulin resistance is a classic mechanism for steroid-induced diabetes, but the underlying processes are complex (with contributions from hyperglucagonemia, glycogenolysis, lipolysis, and gluconeogenesis). Even in the setting of astronomical insulin resistance, a failure of compensatory insulin secretion must be held as a permissive factor for any resultant hyperglycemia. Besides the classical mechanisms of insulin resistance and β-cell dysfunction, other factors, such as alteration of blood flow and intestinal microbial flora, have been proposed in the etiology of drug-associated diabetes.3 As argued, drugs that restrict blood flow impair the normal delivery of substrates to insulin-sensitive tissues (especially, skeletal muscle) and, via that mechanism, could reduce glucose disposal and promote hyperglycemia.4 Theoretically, vasoconstrictors and β-blockers (unopposed α-adrenergic activity) could induce dysglycemia through that mechanism. In many instances, multiple mechanisms, including unknown factors, appear to mediate the effects of drugs on glucose metabolism. It is important to recognize drug-induced diabetes as soon as possible, because withdrawal of the offending drug (if clinically feasible and appropriate) should result in prompt resolution of the diabetes, in the absence of permanent cellular damage to the insulin-secreting β-cells.
Risk Factor versus Causation: The Bradford Hill’s Criteria
Originally