Xia et al. inhibited a late step in the biosynthesis of de-novo cholesterol in murine and human pancreatic β cells [8] and published their findings in 2008. They had previously shown that insulin secretion was sensitive to the acute removal of membrane cholesterol. They now demonstrate that the depletion of membrane cholesterol impairs calcium voltage channels, insulin secretory granule creation, and mobilisation and membrane fusion.
This paper [8] clearly demonstrates that a direct causal link exists between membrane cholesterol depletion and the failure of insulin secretion. Their work is in close accord with data from some statin trials, which also connect cholesterol reduction with increased risk of type 2 diabetes; indeed, statin use has been shown to be associated with a rise of fasting plasma glucose in patients with and without diabetes [9]. The underlying mechanisms of the potential adverse effects of statins on carbohydrate homeostasis are complex [10] and might be related to the lipophilicity of the statin [11]. Indeed, retrospective analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) revealed that 5 years of treatment with pravastatin reduced diabetes incidence by 30% [12]. The authors suggested that although lowering of trigliceride levels could have influenced diabetes incidence, other mechanisms such as anti-inflammatory action might have been involved; however, in the multivariate Cox model, baseline total cholesterol did not predict the development of diabetes [12]. Furthermore, pravastatin did not decrease diabetes incidence in the LIPID trial which included glucose intolerant
patients [13]. On the other hand, in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), which studied apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels [14], the risk of diabetes was increased by a factor of 1.25 [95% confidence interval (CI), 1.05 to 1.51] among individuals receiving rosuvastatin 20 mg daily with respect to placebo. Strikingly, among  persons assigned to rosuvastatin, the median low density lipoprotein (LDL) cholesterol level at 12 months was 55 mg per deciliter [interquartile range, 44 to 72
(1.1 to 1.9)]. It is intriguing that salutary lifestyle measures, which might exert their beneficial action through an anti-inflammatory mechanism without a strong
cholesterol-lowering effect, beyond reducing cardiovascular events and total mortality, reduce also the risk of diabetes and other chronic degenerative diseases. This fact may represent a ‘justification’ not to use a drug in low-risk primary prevention populations: lowering cholesterol at the expense of increasing diabetes might be counterproductive over the long-term.

References for Diabetes

8. Xia F, Xie L, Mihic A, et al. Inhibition of cholesterol
biosynthesis impairs insulin secretion and voltage-gated
calcium channel function in pancreatic beta-cells.
Endocrinology 2008; 149: 5136-45.
9. Sukhija R, Prayaga S, Marashdeh M, et al. Effect of statins
on fasting plasma glucose in diabetic and nondiabetic
patients. J Investig Med 2009; 57: 495-9.
10. Szendroedi J, Anderwald C, Krssak M, et al. Effects of highdose
simvastatin therapy on glucose metabolism and
ectopic lipid deposition in nonobese type 2 diabetic
patients. Diabetes Care 2009; 32: 209-14.
11. Ishikawa M, Okajima F, Inoue N, et al. Distinct effects of
pravastatin, atorvastatin, and simvastatin on insulin
secretion from a beta-cell line, MIN6 cells. J Atheroscler
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12. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the
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13. Keech A, Colquhoun D, Best J, et al.; LIPID Study Group.
Secondary prevention of cardiovascular events with longterm
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14. Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study
Group. Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein. N Engl J Med
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