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Cholesterol & Insulin

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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 counter-

productive over the long-term.

References
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 high-
dose 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
Thromb 2006; 13: 329-35.
12. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the
development of diabetes mellitus: evidence for
a protective treatment effect in the West of Scotland
Coronary Prevention Study. Circulation 2001; 103: 357-62.
13. K
eech A, Colquhoun D, Best J, et al.; LIPID Study Group.
Secondary prevention of cardiovascular events with long-
term pravastatin in patients with diabetes or impaired
fasting glucose: results from the LIPID trial. Diabetes Care
2003; 26: 2713-21.
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
2008; 359: 2195-207.

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It is incredible that medications that lower cholesterol have been proposed for the treatment of Multiple Sclerosis.  Myelin is 50% cholesterol and maintaining it requires huge amounts. No wonder statins  devastate the neural systems!

Here is a quote from our published paper on what you are not told cholesterol lowering treatments: (click text for full paper)

The process in which axons are protected by the myelin secretions of the oligodendrocyte requires a specialised cholesterol-rich membrane [42]. Klopfleisch et al. [43] describe experimental in vivo evidence that new myelin (re-myelination) secretion by oligodendrocytes is impaired by statins.  

Whilst they attribute much of this failure to signalling interference, they also prevented detrimental outcomes in vitro by re-incubating oligodendrocytes with cholesterol. How long are oligodendrocytes able to repair and maintain myelin in an environment where cholesterol is depleted?  

It has been argued that statins can prevent de-myelination [44] through a pleiotropic anti-inflammatory effect and this has led to research on its use as a multiple sclerosis therapy.  

This would appear to contradict Klopfleisch’s findings [43], until you consider that initially there may be multiple conflicting effects over different time scales: Possibly the initial inhibiting of an auto-immune action associated with a de-myelination and  subsequent inhibition of oligodendrocyte repairs by cholesterol depletion.

Research is needed to establish whether the apparent initial slowing of de-myelination in statin therapy would be followed by a catastrophic failure of the re-myelination work of oligodendrocyte exocytosis [45] as cholesterol synthesis fails. Furthermore, consideration should be given to the structural state of membranes involved in any auto-immune process where a complex interplay of essential membrane lipids, mediated by cholesterol, affects the immune response [46].

[42] Fitzner D, Schneider A, Kippert A, et al. Myelin basic protein-dependent plasma membrane reorganization in the formation of myelin EMBO J 2006; 25: 5037-48.

[43] Klopfleisch S, Merkler D, Schmitz M, et al. Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo J Neurosci 2008; 28: 13609-14.

[44] Paintlia AS, Paintlia MK, Singh AK, Singh I. Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis Mol Pharmacol 2008; 73: 1381-93.

[45] Trajkovic K, Dhaunchak AS, Goncalves JT, et al. Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites J Cell Biol 2006; 172: 937-48.

[46] Harbige LS. Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 2003; 38: 323-41.

Cholesterol and Multiple Sclerosis