37. Kitabchi AE, Temprosa M, Knowler WC, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the Diabetes Prevention Program: effects of lifestyle intervention and metformin. Diabetes 2005;54:2404–2414
38. Larson-Meyer DE, Heilbronn LK, Redman LM, et al. Effect of calorie restriction with or without exercise on insulin sensitivity, β-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 2006;29:1337–1344
39. Groop LC, Bonadonna RC, Del Prato S, Ratheiser K, Zyck K, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus: evidence for multiple sites of insulin resistance. J Clin Invest 1989;84:205–213
40. Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, DeFronzo RA. The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1991;72:96-107
41. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996;97:2859–2865
42. Carpentier A, Mittelman SD, Bergman RN, Giacca A, Lewis GF. Prolonged elevation of plasma free fatty acids impairs pancreatic β-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 2000;49:399–408
43. Bray GA, Glennon JA, Salans LB, Horton ES, Danforth E Jr, Sims EA. Spontaneous and experimental human obesity: effects of diet and adipose cell size on lipolysis and lipogenesis. Metabolism 1977;26:739–747
44. Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, Cooper GJ, Holman RR, Turner RC. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988;9:151–159
45. Haataja L, Gurlo T, Huang CJ, Butler PC. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev 2008;29:303–316
46. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110
47. Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 1970;49:837–848
48. Meier JJ, Kjems LL, Veldhuis JD, et al. Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. Diabetes 2006;55:1051–1056
49. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003;14:2873–2882
50. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427–3434
51. Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272–1277
52. Cincotta AH, Meier AH. Bromocriptine inhibits in vivo free fatty acid oxidation and hepatic glucose output in seasonally obese hamsters (Mesocricetus auratus). Metabolism 1995;44:1349–1355
53. Barnard ND, Noble EP, Ritchie T, et al. D2 dopamine receptor Taq1A polymorphism, body weight, and dietary intake in type 2 diabetes. Nutrition 2009;25:58–65
54. Cincotta AH, Tozzo E, Scislowski PW. Bromocriptine/SKF38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice. Life Sci 1997;61:951–956
55. Pijl H, Ohashi S, Matsuda M, Miyazaki Y, Mahankali A, Kumar V, Pipek R, Iozzo P, Lancaster JL, Cincotta AH, DeFronzo RA. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 2000;23:1154–1161
56. Gaziano JM, Cincotta AH, Vinik A, Blonde L, Bohannon N, Scranton R. Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major adverse cardiovascular events in type 2 diabetes subjects. J Am Heart Assoc 2012;1(5):e002279. doi: 10.1161/JAHA.112.002279. Epub 2012 Oct 25
57. Garber AJ, Blonde L, Bloomgarden JT, Dagogo-Jack S. Bromocriptine-QR for type 2 diabetes: AACE Expert Panel review of its potential place in therapy. Endocr Pract 2013;19:100–106
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