According to Kohl (Circulation, see enclosed) statins are “ inhibiting the synthesis of isoprenoid and suppressing ubiquinone (CoQ10) biosynthesis and thus delaying formation of ATP by pancreatic β-cells leading to impaired insulin secretion, inhibiting

glucose-induced insulin secretion from pancreatic islets, reducing sensitivity to insulin, altering glycemic control by decreasing various isoprenoids that enhance glucose uptake via glucose transporter (GLUT) 4 in adipocytes, or other mechanisms, including potential

central nervous system actions to impair glucose homeostasis.”

 Another very good explanation of possible mechanism is described below:

Metabolism. 2014 Jun;63(6):735-45. doi: 10.1016/j.metabol.2014.02.014. Epub 2014 Feb 25.

Statin treatment and new-onset diabetes: a review of proposed mechanisms.

Brault M1, Ray J2, Gomez YH3, Mantzoros CS4, Daskalopoulou SS5.

Author information

Abstract

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Also, please find enclosed a very good review from Chung regarding the mechanism of statin induced DM.

Best regards, Michaela

Good question. I intend to follow and learn. You may choose up to 15 topics "up top" to improve circulation & participation.

Stats @ 19:37EST 6/23/14 3 contributors 5 followers

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Stats @ 05:00hrs EST 7/3/14 10 contributors 20 followers 

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I'll share this on the RG & LinkedIn networks, then note the change in stats. I sure will invite my friend from RG Dr. Max Chartrand to share his erudite opinions to help us move forward on this important topic.

Nice and stimulating question. Statins block acetate entry to cholesterol at HMGCoA branching level. The block is two steps ahead of isoprenoids path branching, and thus directly influence Q10 synthesis. We are thinking to investigate the hypothesis that epigenetics and efficiency of respiratory chain may be peculiarly altered in selected sub-populations of patients by excess "poisoning" of HMGCoa reductase they cannot metabolically bear. In turn, this would generate a partial mitochondrial "insufficiency", with excess cytoplasmic NADH/NAD in turn influencing the whole glucose oxydative paths. The number of patients with increased myocyte signs of metabolic impairment after statins suggests it may be a more diffused problem than generally accepted, with organ specificities and possible influence by some food.

Very good question.Statins appear to provoke diabetes through a few different mechanisms. The primary mechanism is by increasing your insulin levels, which can be extremely harmful to your health. Chronically elevated insulin levels cause inflammation in your body, which is the hallmark of most chronic disease. In fact, elevated insulin levels lead to heart disease, which, ironically, is the primary reason for taking a statin drug in the first place!

It can also promote belly fat, high blood pressure, heart attacks, chronic fatigue, thyroid disruption, and diseases like Parkinson's, Alzheimer's, and cancer.

Secondly, statins increase your diabetes risk by raising your blood sugar. When you eat a meal that contains starches and sugar, some of the excess sugar goes to your liver, which then stores it away as cholesterol and triglycerides. Statins work by preventing your liver from making cholesterol. As a result, your liver returns the sugar to your bloodstream, which raises your blood sugar levels.

These drugs also rob your body of certain valuable nutrients, which can also impact your blood sugar levels. Two nutrients in particular, vitamin D and CoQ10, are both needed to maintain ideal blood glucose levels.

statins are known to interfere withhandling of glucose and new on set of Diabetes have been reported by most of the studies with all statin classes , Few statind doit at lesser rate like Pitovastatin

Statins are known to interfere with insulin resistance and most of the studies have shown to increase the new onset of Diabetes . This has been reported with almost all types of statins but few of them show less increase in new onset of Diabetes like Pitovastatin

Interference with CoQ10 synthesis seems like a possible mechanism. We need a study where CoQ10 supplements were taken. Interestingly, CoQ10 is not a vitamin but taking statin drugs may make it an essential nutrient.

Long term treatment with statins is associated with weight gain and changes in dietary patterns according to a recently published cohort study

 High doses of statins have  many debilitating metabolic effects. Do  doctors have a  choice in not  prescribing high doses  to those who are very sick? Statins increase metabolic stress, reduces oxidative capacity and influences generation of reactive oxidative species that leads to accelerated insulin resitance, mitochondrial damage and cytokines which push  an already compromised system towards the diabetic state.  A specific HDL-C profile should be done on all patients taking statin . One has to determine which of the  HDL cholesterol sub-fractions is highest. Whether it is HDL- C3 or HDL-C2 as one is more cardioprotective. Something might also be affecting reverse cholesterol transport(RCT) which is criticial in patients with dyslipidemia on statins.  If  RCT is corrected, one might be able to  take  lower doses of statins.

Statin very moderately affect the secretion, storage and release of insulin from the beta cells of islets of Langerhans. Due to lack of insulin or insulin resistance there is a low to moderate level increase of blood sugar level which subsequently leads to type 2 diabete.

Great discussion!  THANKS!

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Many of the answers here have been shown not to be the case in meta-analysis. The answer is the recent associations with Simvastatin and emergence of Type II diabetes in the epidemiological literature has no molecular explanation yet.

Perhaps more importantly, it is completely incorrect to talk about "statins" as a generic term in terms of side-effects. Each company statin is a distinct small-molecular with known differences in their specificity. Some potentially hit P450 enzymes other receptors related to inflammation. It is naive to refer to them by class name.

Recent studies looking at Simvastin may transpire to be irrelevant as most other statins are now as cheap to prescribe and have potentially better efficacy profiles. These other small molecules may have other side-effects and this may or may not include Type II diabetes risk. 

One thing that is know for sure, is that high inhibition levels of HMGcoR limits cell prenylation - and this post-translational biochemical modification is required for cell signalling. This is common to all statins as its directly related to the cholesterol pathway - but whether drug levels in vivo ever reach the point that this happens is unlikely, except perhaps in the liver/gut. 

Regardless of the mechanism, what really matters is knowing whether this could have long-term clinical implications.

I think one of the problems with this class of drugs is our general ignorance about lipids and health. If we don't understand what we are treating it's hard to pin down an effective drug when it comes to treatment. My friend Jimmy Moore discusses some of these issues in his book "Cholesterol Clarity".

Inflammation appears to drive a lot of our vascular pathology and in my opinion there are more effective ways to counter inflammtion than taking a statin.

http://www.amazon.com/Cholesterol-Clarity-What-Wrong-Numbers/dp/1936608383

According to Kohl (Circulation, see enclosed) statins are “ inhibiting the synthesis of isoprenoid and suppressing ubiquinone (CoQ10) biosynthesis and thus delaying formation of ATP by pancreatic β-cells leading to impaired insulin secretion, inhibiting

glucose-induced insulin secretion from pancreatic islets, reducing sensitivity to insulin, altering glycemic control by decreasing various isoprenoids that enhance glucose uptake via glucose transporter (GLUT) 4 in adipocytes, or other mechanisms, including potential

central nervous system actions to impair glucose homeostasis.”

 Another very good explanation of possible mechanism is described below:

Metabolism. 2014 Jun;63(6):735-45. doi: 10.1016/j.metabol.2014.02.014. Epub 2014 Feb 25.

Statin treatment and new-onset diabetes: a review of proposed mechanisms.

Brault M1, Ray J2, Gomez YH3, Mantzoros CS4, Daskalopoulou SS5.

Author information

Abstract

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Also, please find enclosed a very good review from Chung regarding the mechanism of statin induced DM.

Best regards, Michaela

Time will tell if specific statins increase the risk of T2D, which would arise from changes in insulin action and secretion. It is disappointing that the statin discussion is usually around cost/benefit (good/bad) rather than understanding the biology and simply trying to make this widely used drug class better. It is also surprising that these lipid-lowering drugs do not lower diabetes incidence. I think we have a lot to learn about protein prenylation:

http://www.ncbi.nlm.nih.gov/pubmed/24917577

Dear Temitope

thank you for the intersting paper I just downloaded. Best regards, Michaela

The intake of statins can disrupt the metabolism of liver and muscle and as these two organs have an important role in glucose homeostasis. This could influence the levels of this metabolite in the bloodstream.

Hi Temitope, very good article.

See insulin resistance, its effect on liver metabolism, and be sure about which statin was included in  pharmacotherapeutic trials. Personalized Medicine is very useful to   select each statin for clinical treatment, not only cholesterol but inflammation are key words in this very important question. 

Good day everyone,

I wish to share some thoughts on this very interesting theme. I will try to explain my point of view at start by briefly reviewing particular cell energy formation and intracellular insulin pathway signaling mechanisms.

Well, as known, statin blocks the synthesis of Mevalonic acid and its downstream metabolic pathway products. Besides cholesterol, one of these products, Farensyl pyrophosphate, is ultimately responsible to Ubiquinone (Coenzyme Q10) and Dolichol synthesis, by distinct pathways.

At a cellular level, in the mitochondrial inner membrane, Ubiquinone makes part of the electron transport chain and is responsible for uptaking electrons from protein complexes I (NADH reductase) and II (succucinate dehydrogenase) and transferring them to protein complex III (cytochrome bc1 complex). In a further step, electrons are transferred to Cytochrome oxidase, finally leading to molecular water formation and ATP production coupled to ATP synthase.

Therefore, at a cellular level, Ubiquinone is critically involved in energy production, which metabolically is translated into muscle and glandular activities, for instance.

Depletion of Ubiquinone at skeletal muscle cell level leads to reduction in fiber contraction and strength, clinically expressed as weakness. In fact, long distance runners who have high blood cholesterol levels and are statins users have reported reduction in race performance, making them to withhold the medication during competition periods.

The point is that intracellular ATP reduction in skeletal fibers has been demonstrated to impacts insulin signaling pathway in these cells. In skeletal fiber, protein kinase A is responsible for inactivating iNOS in the presence of high intracellular ATP concentration. Reduction of intracellular ATP concentration leads to intracellular increase in iNOS activity and NO production. NO interacts with S-terminal of cysteine residues causing a reaction named as S-nitrosylation. In its turn, S-nitrosylation of intracellular insulin signaling pathway proteins is related to reduced GLUT4 mobilization to cell membrane and decreased glucose uptake.

At a glandular cell level, reduction in intracellular energy reserve may lead to reduction in intracellular hormone production, mobilization and release. In fact, reduction in pancreatic beta-cells insulin secretion has been associated with statin.

More intense depletion of Ubiquinone blood levels may lead to a more pronounced reduction in energy production in skeletal fiber causing not only weakness but also muscle pain and damage. It has been reported that replenishment of plasma Ubiquinone level is associated with abatement of muscle pain in statins users.

At last, but not least, water soluble statin, Pravastatin has not been associated with significant T2D incidence. On the other hand, a synthetic, more powerful and water soluble statin, Rosuvastatin has also been associated with significant increase in T2D as well as virtually all lipid soluble statins, as far as I am concerned. Thus, there may be a stain-related insulin resistance effect, possibly linked to both physical-chemical properties and clinical potency of the drug.

Peace and blessings.

Dear  Paolo

thank you for this brief and concise mechanism overview!!!

Dear Paulo R Benchimol-Barbosa,

Could you send around the citations for these claims please?

"Pravastatin has not been associated with significant T2D incidence. On the other hand, a synthetic (?), more powerful (?in vitro potency?) and water soluble statin (Less lipophilic?), Rosuvastatin has also been associated with significant increase in T2D as well as virtually all lipid soluble statins"

I've only seen the Simvastatin data so far.

Jamie

Hi James¡ :in your last contribution  I find some of my questions about the differences among lipophlic and water soluble statins. There are interesting pharmacological mechanisms who deserve very important projects to be done in our laboratories, about statins, T2D and atherogenic mechanisms. Some of them are quoted by Research Gate members participating in this interesting discussion

The level of metabolites in blood can influenced by statins intake because it can affect the glucose homeostasis by affecting liver and muscle metabolism, also we have to consider insulin resistance

Some genetic variants puedenn HMGCoA reductase influence the diabetogenic effect of statins. I recommend the recent article by Daniel Swerdlow I "HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomized trials. ".:

The Lancet 09/2014; DOI: 10.1016/S0140-6736(14)61183-1

https://www.researchgate.net/publication/266003731_HMG-coenzyme_A_reductase_inhibition_type_2_diabetes_and_bodyweight_evidence_from_genetic_analysis_and_randomised_trials

Article HMG-coenzyme A reductase inhibition, type 2 diabetes, and bo...

From my point of view, generally statins are drugs that inhibit the synthesis of mevalonate and downstream cholesterol synthesis. It goes beyond that anyway. It also inhibit some other intermediate of this pathways which are responsible for the biosynthesis of some crucial compounds of some other pathways like the Ubiquinone which is been synthesized through Farnesypyrophosphate (Isoprenoid). Statin does this by competitively inhibiting the rate limiting enzyme HMG-CoA Reductase enzyme. This is because they are structural analogues to the substrate of this enzyme and therefore they can serve as a competitive inhibitor of the substrate. 

Ok, looking at the net effect of this downstream inhibition, it will definitely have effect on the availability of Cholesterol transportation by the lipoproteins and this will be of positive relevenace to cardiovascular disease patients because the transportation of this cholesterol had been reported to initiate atherosclerosis which involves the deposition of this lipid content (atherosclerotic plaques) in the arterial intima of the blood vessels thereby causing the constriction of the blood vessels - a condition strictly linked to high blood pressure (hypertension).

Again, looking at how this can be linked with diabetes, I think the inhibition of the Isoprenoid (Farnesyl pyrophosphate) involve in the biosynthesis of Ubiqiinone may be involve in that. If the Ubiquinone synthesis is inhibited, it will definitely inhibit the transportation of electron from any pathway that generate it energy through Oxidative phosphorylation and not substrate level phosphorylation. The Metabolic pathways that produces NADH + H+ and FADH2 will not find their electrons channeled into the ETC for FoF1 ATPase to couple the Gibbs free eneregy produces in the ETC with the phosphorylation of ADP to give ATP. It means they energy production of this pathway will be impaired.

The link between the inhibition of Cholesterol synthesis and diabetes Type II may be due to the transportation of this cholesterol to the cholesterol receptors on the cell surface of the hepatocytes and any other cells. This may cause the insensitivity of the insulin (First messenger) to recorgnize the receptor and thereby inhibit te=he downstream Tyrosine phosphorylation and automatic phosphorylation of some downstream proteins responsible for the intracellular expression of the insulin effects.

Good day folks,

Just a few additional thoughts, if I may. I essentially agree with the very appropriate comments of Paul Ernsberger.

However, data venia, I consider that a few points still need to be checked before Ubiquinone supplementation could be widely recommended to subjects on statins to prevent/ to circumvent muscle pain, or other stain-related collateral effect. In fact, metabolic pathways leading to both Ubiquinone synthesis and cholesterol synthesis share a common substrate, mevalonic acid, which is deprived as a consequence of HMGCoA reductase inhibition.

The question is: Would Ubiquinone supplementation reverse its metabolic pathway leading to mevalonic acid accumulation? Therefore, bypassing HMGCoA reductase inhibition, it would increase de novo cholesterol synthesis all over again. If this is happening, certainly, it would render statins useless for high cholesterol control in the setting of Ubiquinone supplementation.

Thus, at this point, I consider it would be quite appropriate to go back to bench and check whether Ubiquinone supplementation would reverse mevalonic acid deprivation under HMGCoA reductase inhibition. Afterwards, perhaps, if deemed safe, to carry out a large randomized trial, or a systematic analysis of large statin databases, testing clinically the potential effect of Ubiquinone supplementation on outcomes (muscle pain abatement, clinical safety and the impact on reduction of outcomes like MI and revasc, in the same trial) in subjects taking statins.

Who volunteers? Let us compose a task force?

Peace and blessings.

I am not sure how probable this association is, but if it is true, I could speculate that, as statins leach lipids out of tissue, that may have leached lipids out parts of the beta cell membranes, with a consequent loss of normal function.