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Dietary Carbohydrate restriction as the first approach in diabetes management

The inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines.

•They present major evidence for low-carbohydrate diets as first approach for diabetes.
Such diets reliably reduce high blood glucose, the most salient feature of diabetes.
Benefits do not require weight loss although nothing is better for weight reduction.
Carbohydrate-restricted diets reduce or eliminate medication.
There are no side effects comparable to those seen in intensive treatment with drugs.
Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman
EC, Accurso A, Frasetto L, McFarlane S, Nielsen JV, Krarup T, Gower BA, Saslow L, Roth KS, Vernon MC, Volek JS, Wilshire GB, Dahlqvist A, Sundberg R, Childers A, Morrison K, Manninen AH, Dashti H, Wood RJ, Wortman J, Worm N, Dietary Carbohydrate restriction as the first approach in diabetes
management. Critical review and evidence base, Nutrition  (2014), doi: 10.1016/j.nut.2014.06.011.

You can’t get funding very easily for lifestyle trials because there is no profit to be made. Or is there? Medical Insurance and NHS costs would be reduced dramatically - so there is a cost reduction motive for funding!

Synaptogenesis and Neural Cholesterol

Nowhere is the impact of cholesterol depletion more keenly studied than in the neurologic arena.   

The work of Pfrieger et al. described the functional role of cholesterol in memory through synaptogenesis [24]. Mauch et al. [25] reported evidence that cholesterol is vital to the formation and correct operation of neurons to such an extent that neurons require additional sources of cholesterol to be secreted by glial cells. A recent mini-review by Jang et al. describes the synaptic vesicle secretion in neurons and its dependence upon cholesterol-rich membrane areas of the synaptic membrane [26]. Furthermore, working on rat brain synaptosomes, Waseem [23] demonstrated that a mere 9.3% decrease in the cholesterol level of the synaptosomal plasma membrane could inhibit exocytosis. These data might be particularly worrisome for lovastatin and simvastatin which are known to cross the blood brain barrier [27].

In fact, the proposed use of statins as a therapeutic agent in Alzheimer’s Disease (AD) [28] counters Pfrieger’s evidence [24]. Indeed, a reduction in cholesterol synthesis leads to depletion of cholesterol in the lipid rafts – i.e. the de-novo cholesterol is required in the neurons for synaptic function and also in the neuronal membrane fusion pores [29].

Cognitive problems are the second most frequent type of adverse events, after muscle complaints, to be reported with statin therapy [30] and this has speculatively been attributed to mitochondrial effects. The central nervous sytem (CNS) cholesterol is synthesised in situ and CNS neurons only produce enough cholesterol to survive. The substantial amounts needed for synaptogenesis have to be supplemented by the glia cells. Having previously shown that in rat retinal ganglion cells without glia cells fewer and less efficient synapses could form, Göritz et al. [31] indicate that limiting cholesterol availability from glia directly affects the ability of CNS neurons to create synapses. They note that synthesis, uptake and transport of cholesterol directly impacts the development and plasticity of the synaptic circuitry. We note their very strong implication that local de-novo cholesterol synthesis in situ is essential in the creation and maintenance of memory..  

There should be further consideration of cholesterol depletion on synaptogenesis, behaviours and memory loss for patients undergoing long-term statin therapy. This is particularly important with lipophilic statins which easily cross the blood brain barrier [32].

The effects of statins on cognitive function and the therapeutic potential of statins in Alzheimer´s disease are not clearly understood [28]. Two randomised trials of statins versus placebo in relatively younger healthier samples (lovastatin in one, simvastatin in other) showed significant worsening of cognitive indices relative to placebo [33, 34]. On the other hand, two trials in Alzheimer samples (with atorvastatin and simvastatin respectively) suggested possible trends to cognitive benefit, although these appeared to dissipate at 1 year [35, 36]. A recent Cochrane review concluded that there is good evidence from randomised trials that statins given in late life to individuals at risk of vascular disease have no effect in preventing Alzheimer´s disease or dementia [37]. However, case reports and case series from clinical practice in the real world reported cognitive loss on statins that resolved with discontinuation and recurred with rechallenge [30].

Evidence from observational data and prestatin hypolipidemic randomised trials showed higher hemorrhagic stroke risk with low cholesterol [30]. In fact, in the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial as compared with placebo, the use of high-dose atorvastatin was associated with a 66% increase in the relative risk of hemorrhagic stroke among the patients receiving the statin drug [38]. In addition to treatment with atorvastatin, an exploratory analysis of the SPARCL trial found that having hemorrhagic stroke as an entry event, male sex, and advancing age at baseline accounted for the great majority of the increased risk of hemorrhagic strokes [39]. However, a sensitivity analysis excluding all patients with a hemorrhagic stroke as an entry event in the SPARCL trial found that statin treatment was still associated with an increased risk of hemorrhagic stroke [40]. Furthermore, in a subgroup of patients with a history of cerebrovascular disease enrolled in the Heart Protection Study [41] which did not include patients with hemorrhagic stroke, a similar increased risk of hemorrhagic stroke during follow-up was demonstrated [40].

References:

[24] Pfrieger FW. Role of cholesterol in synapse formation and function Biochim Biophys Acta 2003; 1610: 271-80.

[25] Mauch DH, Nägler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol Science 2001; 294: 1354-7.

[26] Jang D, Park S, Kaang B. The role of lipid binding for the targeting of synaptic proteins into synaptic vesicles BMB Rep 2009; 42: 1-5.

[27] Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors Pharm Res 1994; 11: 305-11.

[28] Kandiah N, Feldman HH. Therapeutic potential of statins in Alzheimer’s disease. J Neurol Sci. 2009 Mar 23. [Epub ahead of print].

[29] Jeremic A, Jin Cho W, Jena BP. Cholesterol is critical to the integrity of neuronal porosome/fusion pore Ultramicroscopy 2006; 106: 674-7.

[30] Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism Am J Cardiovasc Drugs 2008; 8: 373-418.

[31] Göritz C, Mauch DH, Nägler K, Pfrieger FW. Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair J Physiol Paris 2002; 96: 257-63.

[32] Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ. Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord 2006; 22: 392-8.

[33] Muldoon MF, Barger SD, Ryan CM. et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000; 108: 538-46.

[34] Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 2004; 117: 823-9.

[35] Sparks DL, Sabbagh M, Connor D, et al. Statin therapy in Alzheimer’s disease. Acta Neurol Scand Suppl 2006; 185: 78-86.

[36] Simons M, Schwärzler F, Lütjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002; 52: 346-50.

[37] McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev 2009 Apr 15; (2): CD003160.

[38] Amarenco P, Bogousslavsky J, Callahan A 3rd, et al.; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-59.

[39] Goldstein LB, Amarenco P, Szarek M, et al.; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008; 70:2364-70.

[40] Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39:497-502.

[41] Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757–67.

Cholesterol and insulin

Cholesterol and insulin
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 counter-productive over the long-term.

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 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

Cholesterol and Multiple Sclerosis

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.

Beta blockers cost more lives than they save!

glynthincs:

Ever since I read Medical Myths by Joel Kauffman, I have had trouble believing that treating Blood Pressure with one of 5 different chemicals did anything to address the cause of raised blood pressure. Blood pressure is raised by glycation of arterial proteins (Sugar-Damage) how does a pill other than maybe metformin address that?  Lo-Carb Hi-Fat LCHF will address that issue eventually but best not get glycated to start with!

The Independent.ie said today:-

At least 800,000 deaths may have been caused worldwide in the past decade by preventive drugs which are routinely given to patients undergoing surgery to reduce the risk of heart attacks, researchers said yesterday.

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And the source of this story is here

"Even if only 10 per cent of doctors followed the guidelines, and that is a conservative estimate, 100 million patients would have been given beta blockers during surgery in the past decade. On the basis of our findings, that means 800,000 would have died prematurely and 500,000 would have suffered a stroke. If our findings are true, that is death on the scale of a world war." Devereaux P J Associate Professor, Department of Clinical Epidemiology and Biostatistics  Mc Master University

What is it exactly that statins do, apart from causing some serious side-effects?

Cholesterol is known to be vital to health. There is only one kind of cholesterol molecule. Talk about ‘good and bad’ cholesterol indicates a lack of understanding of lipid nutrition.

Understand that statins are defined by their ability to block an enzyme producing mevalonate. Mevalonate is a vital substance which we need to make in our bodies to build terpenes, cholesterol, dolichols, other steroid hormones and CoQ10.

How did the world of medicine get into such a confusion and mess over cholesterol, lipids and fatty nutrients?

This is now looking like a major money making scandal at the expense of our health.

Sugar-Damage in the Lipid Nutrition Cycle

Maybe raised total blood serum cholesterol (TBSC) was trying to tell us something about health, but it was not the message we have been fed for the last 60 years.

Cholesterol has been misrepresented since the 1950s as a cause of heart disease. In reality an excess of dietary sugar that created an unhealthy lipid profiles in our blood stream.  Attempts to fix the problem by a drug called a statin added to our health woes because it targets the wrong issue.

When LDL nutrition is sugar-damaged (Glycated LDL) is raised in the blood. Unrecognised by our fat starved organs it is eventually scavenged by less discriminating visceral fat stores. There is less HDL (erroneously called ‘good’ cholesterol) being returned by the organs.

High Cholesterol (high levels of total blood serum cholesterol TBSC) when caused by damage to the LDL lipid parcels is a sign that lipid circulation is broken. These fats (LDL) will be scavenged to become visceral fats, deposited around the abdomen. This type of damage is associated with poor health.

Preventing the liver from producing new undamaged LDL by using a statin fails to address the problem of getting fatty nutrients to fat starved organs. The action of statins adds to the patients musculo-skeletal and neurological woes by depleting vital supplies of CoQ10 and dolichol.

The problem is fixed by reducing sugar-damage - as measured by an HbA1c test on sugar damage to a blood protein called haemoglobin. Several diabetes clinicians have observed this key connection between sugar damage and poor lipid profiles.

A Healthy Lipid Nutrition Cycle

If the total blood serum cholesterol (TBSC) is high and the organs are getting enough lipids, the blood lipid circulation is healthy.  The large parcels of fatty nutrients (LDL lipids) sent by the liver are consumed by our organs (receptor-mediated endocytosis) and the smaller fatty wrappers and left-over lipids (HDL Lipids) return to the liver. The Fatty Nutrients (LDL) and the recycled lipids (HDL) are in balance. Such a healthy-lipid ‘High-Cholesterol’ person is well nourished and likely to have a long and healthy life.

Sugar-Damage in a Broken Lipid Cycle

If the total blood serum cholesterol is high but the fatty nutrient droplets (LDLs) have sugar-damaged labels, the organs are unable to recognise and feed on them. The supply of fatty nutrients to organs is broken. 

The liver continues to supply fatty nutrients (albeit with damaged LDL labels), but the organs’ receptors are unable to recognise them. The organs thus become starved of their fatty nutrients. Like badly labelled parcels in a postal service, the sugar-damaged lipids build up in the blood (raised LDL) and fewer empty wrappers are returned to the liver (low HDL).

So it really doesn’t matter how high your total blood serum cholesterol (TBSC) is. What really counts is the damaged condition of the blood’s fatty nutrient parcels (LDL lipids). In our research review of metabolic syndromes4 (e.g. diabetes, heart disease, obesity, arthritis and dementia) we explained that the major cause of lipid damage was sugar-related.

Sugar Damage (AGEs)

The abbreviation AGE (Advanced Glycation End-product) is used to describe any sugar-damaged protein.  As we age, excessive amounts of free sugars in the blood5 may eventually cause damage quicker than the body can repair it.  The sugars attach by a chemical reaction and the sugar called fructose is known to be 10 times more reactive, and therefore more dangerous than our normal blood sugar (glucose). Since the 1970s we have been using increasing quantities of refined fructose (from high-fructose corn syrup). Its appealing sweetness, and ability to suppress the ‘no longer hungry’ receptor6 (ghrelin receptor) is driving excessive food intake.  Its ability to damage our fatty nutrients and lipid circulation is also driving waist-line obesity and its associated health problems4,7.

Checking for Damage in our Lipids

There is a ‘simple to administer’ commonly available blood test used to check for sugar-damage.  It is used to check the proteins in the blood of people who are diabetic or at risk of becoming diabetic. It tests for Glycated Haemoglobin (HbA1c) by counting the proportion of damaged molecules (per 1000) of Haemoglobin protein in the blood (mmol/mol). Researchers looking at ways of testing for damage to lipids, have found that sugar-damaged blood protein test (HbA1c), presents a very reasonable approximation of the state of sugar-damage in the blood lipids. Until there is a good general test for sugar-damage in blood lipids, this test (HbA1c) could be a sensible surrogate. This is a better way of assessing health than a simple cholesterol test (TBSC).

Improved sugar-damaged blood protein (HbA1c) scores in diabetic patients is accompanied by improvements in their lipid profiles. This could be very useful to anyone wanting to improve health outcomes by managing lifestyle and nutrition.

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For the full essay with references read follow this ‘bitly link’: http://bit.ly/1fkGYgb

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