Noakes: Risk Factors and Insulin Resistance. Part 2
Risk factors and insulin resistance – the most prevalent medical condition across the globe.
Perhaps the most abused term in medicine is “risk factors”. For the reason that few truly understand what the term really means.
For when the doctor tells the patient that: “High blood cholesterol is a risk factor for heart disease”, the doctor may or may not really understand what (s)he is saying. But for the patient, the message is abundantly clear. For all she hears is: “High blood cholesterol causes heart disease – your value is too high. You best lower it immediately. Or you will die”.
But this is not what “risk factor”, as currently defined, should convey.
Risk factor is a term that comes from epidemiological studies that attempt to determine which factor(s) present in a population – an experimental cohort –observed for a period from years to decades, is associated with the development of specific illnesses of interest. Epidemiology is a powerful tool for studying diseases for which there is a singular cause – for example an environmental toxin such as asbestos or lead, or a bacterium like those causing typhoid, tuberculosis or cholera. But it is largely ineffective for isolating the precise causative factors in conditions, like nutritional diseases, in which there are likely to be multiple causes.
The point is that these associational studies, performed by observing humans as they go about their daily lives, can only suggest causation – that is, that an identified “risk factor” actually causes the disease of interest – when the relationship between the two is statistically too obvious to ignore. For the proper way to prove causation is to undertake randomized controlled trials (RCTs) in which the suspected causative agent is manipulated in the tested population whilst it remains unchanged in the control group. If the outcome robustly supports the tested hypothesis, then causation may be assumed.
The measure of statistical strength in observational (associational) studies is the Hazard (or Risk) Ratio (HR or RR). Only if the HR is greater than 2 and preferably greater than 5 (indicting that the risk factor is present 2-5 times more frequently in those with the condition than in those without it) can one begin to believe that the associated risk factor is the direct cause of the disease of interest. Classic examples for high HR values in epidemiological studies include an 1875 study showing an HR of 2000 for scrotal cancer in London chimney sweeps, and a 1950 study that found the HR for lung cancer was 10-30 in smokers depending on how heavily they smoked. In 1849 John Snow calculated that the HR for infection with cholera was 14 in those London residents who received their (cholera-infected) water from the Southwark and Vauxhall Company; many argue that his study heralded the beginning of modern epidemiology.
No one would dispute that these extremely high HRs identify a singular causative agent. There is no need to undertake more expensive RCTs to confirm that this relationship is causal. Consider the Parachute RCT Analogy. We do not need to have parachute-less skydivers jump from airplanes to prove that parachutes reduce mortality. Some ideas do not require definitive statistical proof to be accepted as true.
Interestingly the HR for heart attack in cigarette smokers is only 2, which is not high enough, by itself, to prove causation. But intervention RCTs show that stopping smoking immediately reduces heart attack risk, confirming that smoking is one of the factors causing heart attacks.
To return then to where we began – cholesterol as a “risk factor” for heart disease. Observational studies show that the HR for the association between the blood cholesterol concentration and heart disease is at best about 1.3, a figure that is far too low to suggest, by itself, that cholesterol causes heart disease. But a $40 billion/year (statin) drug industry based on the still unproven theory that blood cholesterol is the direct cause of heart attack, insures that this pathetically weak association is never discussed in polite medical circles. To do so invites excommunication, as I and a few others, have discovered. To our surprise and dismay.
By extension of argument, countless associational studies have by now produced a long list of “risk factors” with low to very low HR values that my profession has taught all to fear. This is best described as scare-mongering. For these low HR values simply do not begin to suggest causation. And if a “risk factor” is not a proven causative factor for a particular disease, then how can it be described as a “risk factor”, other than if there is malicious intent to mislead. These are merely elements that are co-incidentally and weakly associated with that disease. Just as umbrellas are always associated with rainy weather. But they are not the cause of atmospheric condensation, any more than the attending fire fighters caused the fire.
This then brings us to the second and more important fact about “risk factors”.
For besides being told (without evidence) that blood cholesterol is a risk factor for heart disease, we are also assured that obesity is a risk factor for high blood pressure, diabetes, heart attack, non-alcoholic fatty liver disease (NAFLD), stroke, arthritis, cancer and dementia. And in the same breath that diabetes is a risk factor for – you guessed it – obesity, high blood pressure, NAFLD, heart attack, stroke, arthritis, cancer and dementia. Or conversely, that high blood pressure is a risk factor for heart attack and stroke.
But this is intellectually absurd – how can everything be a risk factor for everything else? Indeed how do we explain the recent finding that the extent of disease in the (coronary) arteries (supplying the heart muscle) predicts an individual’s risk for developing many other chronic illnesses including cancer and dementia.
The answer can be found in the ignored work of Dr Gerald Reaven MD, now Emeritus Professor of Medicine at Stanford University, California, USA.
Reaven has spent the past 60 years studying the condition that intellectually he now owns, insulin resistance. His interest was peaked early in his career when he read that there are 2 forms of diabetes – the first, insulin-deficient type 1 diabetes mellitus (T1DM) caused by failure of insulin production by the pancreatic beta cells (which are destroyed in an auto-immune process). In the second, insulin-resistant type 2 diabetes (T2DM), insulin must be secreted in abnormally high amounts because the target cells on which the insulin normally acts are resistant to its action; hence the condition of insulin resistance or carbohydrate intolerance. Persons with insulin resistance have blood insulin concentrations that are elevated most of the time, a condition known as hyperinsulinaemia.
Reaven’s great contribution has been to show that this persistent hyperinsulinaemia in insulin resistance, whether or not associated with T2DM, produces a collection of grave secondary consequences, listed in Table 1.
Table 1: Consequences of persistent hyperinsulinaemia present in persons with insulin resistance who eat high (>50g carbs/day) carbohydrate diets.
Increased fat in the abdominal organs (visceral adiposity)
High blood pressure
Abnormal blood fat, glucose and insulin concentrations (atherogenic dyslipidaemia – see later)
Elevated blood uric acid concentrations (gout)
Impaired ability of arteries to dilate (endothelial dysfunction)
Whole body inflammation
Dysfunction of the mitochondria (cellular organs that produce energy)
Progressive increases in insulin resistance (insulin-induced insulin resistance)
Impaired exercise performance
But Reaven’s greatest (and bravest) intellectual contribution is to suggest that insulin resistance and hyperinsulinaemia are the necessary biological precursors definitely for 4 and perhaps for all 6 of the most prevalent chronic medical conditions of our day – the very 6 that will bankrupt our medical services within the next 2 decades. Unless we understand the crucial importance of Reaven’s work and being to act without delay. These conditions are:
2. Arterial disease
Local: Heart attack or stroke
Disseminated: Type 2 diabetes mellitus
3. High blood pressure
4. Non-Alcoholic Fatty Liver Disease (NAFLD)
6. Dementia (Alzheimers’ disease, also known at Type 3 diabetes)
In his honour the term Reaven’s (Metabolic) Syndrome refers to the combination of obesity, diabetes, abnormal blood lipid levels and high blood pressure existing in the same individual. It is this singular combination that best predicts risk of heart attack.
So the key finding from Reaven’s work is that these conditions are not separate – they are different expressions of the same underlying condition. Thus a patient should not be labelled as having high blood pressure or heart disease or diabetes or NAFLD (or perhaps even cancer or dementia). Instead he or she should be diagnosed with the underlying condition – insulin resistance – with the realization that the high blood pressure, the obesity, the diabetes, the NAFLD or the heart attack or the stroke are simply markers, symptoms if you will, of the basic condition.
And that basic condition is insulin resistance which, simply put, is the inability of the body to tolerate more than an absolute minimum amount of carbohydrates eaten each day (without developing hyperinsulinaemia). We now know that for most with more severe insulin resistance, daily carbohydrate intakes of 25-50g are the maximum that can be tolerated. But when Reaven began his work this was not known.
To determine whether nutritional factors contribute to the development of the metabolic syndrome, beginning in the 1980s, Reaven completed a number of RCTs of the effects of low carbohydrate diets in patients with this condition. Without exception his studies showed that removing carbohydrates from the diet uniformly improved all measures of health in those with insulin resistance and metabolic syndrome.
So besides establishing the fundamental role of insulin resistance in these chronic diseases, Reaven also discovered the optimum treatment – carbohydrate restriction. By any measures, Reaven should be a shoe-in for the Nobel Prize in Medicine. But perhaps not. For he failed subsequently to emphasize the curative effects of low carbohydrate diets in insulin resistance.
I suspect that during his daily work at Stanford Medical School, Reaven was in close contact with some of the more important cardiologists in the USA and perhaps in the world. They would not have taken kindly to their colleague’s suggestion that, to prevent heart attacks, cardiologists should be prescribing high fat diets instead of the low fat diet dictated, then as now, by the American Heart Association. Had he chosen that route, Reaven’s colleagues would have excommunicated him, his research funding would have dried up, and his career would have been over, exactly as happened to Dr John Yudkin in England for his (correct) suggestion in the 1970s that sugar, not saturated fat, causes heart disease.
So it seems to me that Reaven kept quiet, choosing rather to continue researching insulin resistance without paying much attention to how a low-carbohydrate high-fat diet might – simply, effectively and at low cost – prevent and reverse all the medical disguises through which insulin resistance reveals itself.
One disease, one cause, many symptoms.
Reaven’s problem is not unlike that faced by Darwin and Galileo whose findings estranged each from religious orthodoxy. For Reaven’s unifying hypothesis of chronic disease must offend not just his colleagues in cardiology. For his hypothesis strikes at the very heart (pun intended) of the pharmacological model that we practice in modern medicine.
For if obesity, diabetes, heart disease, NAFLD and high blood pressure (and perhaps also cancer and dementia) are in fact all symptoms of the same underlying condition, insulin resistance, then our current model of medical management must be wrong, requiring as it does, specific but different pharmacological treatments for each separate condition, overseen by different hierarchies of medical specialists.
But what if the cornerstone for the treatment of all these conditions is a low carbohydrate diet – the very diet that has now been vilified by my profession for the past 50 years?
That must be an extremely frightening thought for very, very many. How does one come to terms with the possibility that, by following medical orthodoxy, one may have harmed very many patients?
It’s the fatty liver disease, stupid.
More support for Reaven’s unifying hypothesis of chronic disease has recently come from an unexpected source – from those doctors, hepatologists, who specialize in the study of diseases of the liver.
It has been known for some time that the added risks associated with obesity depend, in part, on where that extra fat is stored in the body. Thus fat that accumulates under the skin – subcutaneous fat – is far less unhealthy than is fat that accumulates within and between the organs in the abdomen, so-called visceral obesity. The hepatologists have now gone one step further to show that the real killer in visceral obesity is the fat that accumulates within the liver causing NAFLD, a disease that is now also reaching epidemic proportions.
Their work shows that it is NAFLD and not obesity per se that produces the abnormal metabolic state – the atherogenic dyslipidaemia (Tables 1 and 2) – that causes heart disease in those with insulin resistance and the metabolic syndrome.
Table 2: The metabolic features of atherogenic dyslipidaemia present in those with NAFLD and insulin resistance
Elevated blood glycated haemoglobin (HbA1c) levels
Elevated fasting blood insulin levels
Elevated fasting blood glucose levels
Hyperinsulinaemia and hyperglycaemia (elevated blood glucose levels) in response to carbohydrate ingestion
Low blood HDL-cholesterol concentrations
High blood triglyceride concentrations
Elevated numbers of small dense LDL-particles
Elevated blood Apolipoprotein B concentrations
But the absolutely key point is that dietary carbohydrates and not dietary fat cause NAFLD. For when the insulin resistant eat excess carbohydrates including fructose found in sugar and fruits, they must convert into fat any extra carbohydrate they cannot either use as a fuel or store immediately as carbohydrate in liver or muscles. Note that all these options are severely reduced in those with insulin resistance. Instead under the action of insulin – the fat-building hormone – that fat is stored, initially as fat in the liver. But as NAFLD develops, insulin resistance worsens, hyperinsulinaemia increases, atherogenic dyslipidaemia deteriorates and the seeds for the chronic diseases of obesity, diabetes, heart disease, NAFLD and perhaps cancer and dementia are sown.
Thus it is that dietary carbohydrates and not dietary fat that is the direct cause of this group of chronic diseases in those with insulin resistance.
The work of Gerald Reaven MD is as revolutionary to the understanding of medicine as were the works of Newton, Galileo and Darwin to their disciplines.
By producing a unifying theory for perhaps 6 chronic diseases and by presenting the initial evidence that these conditions are initiated by high carbohydrate diets in those with insulin resistance, he has fundamentally changed our understanding of how these conditions develop and how best they should be treated. And also how they might be prevented.
Our challenge is to incorporate this new understanding into our teaching and practice of medicine.
But time is short. We need to act expeditiously if we are to reverse the progressive slide to ill health, with the ultimate bankruptcy of global medical services.
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