There are many potential mechanisms surrounding the pathogenesis of atherosclerotic cardiovascular disease (CVD), spanning metabolism, environment (including lifestyle), genetic disposition and a host of associated risk-factors from various causes. Amid all of this, one hypothesis stands out in public and health perception – cholesterol. More specifically, the cholesterol carried by low-density lipoprotein (LDL) particles. I have previously surveyed the evidence for this
The elegance of the Insulin Hypothesis is that it can offer an explanation for why the rates of CVD and other metabolic disorders (type 2 diabetes, cancer, obesity, neurodegeneration etc) have increased so alarmingly in recent decades – we have adopted a glucose-rich diet that our evolutionary biology did not prepare us for.
1. An increase in the availability and desirability of refined carbohydrates (made up of readily digestible glucose) and sugars (glucose), together with dietary guidelines (circa 1960-80) which discourage fat and recommend grains and cereals instead, chronically or regularly increases blood glucose concentration.
2. The pancreas responds by releasing more insulin to drive this excess glucose out of the blood and into cells for energy, or storage as fat. Insulin has many roles, but this is a primary one.
3. Over time, cells increasingly oppose the action of insulin and insulin resistance develops. This phenomenon may be a form of habituation (such as stimulatory drugs requiring more dose over time), or a more active process in which cells say no to glucose they don’t need or that is damaging them. Even the excess energy that comes from burning unneeded glucose can be damaging to cells (e.g. increased free-radical byproducts). Thus, insulin resistance may not be a malfunction of glucose metabolism, rather a defence against it.
4. The problem is that such a scenario is circular so long as sources of glucose continue to be regularly consumed. The chronic need for insulin to dispose of glucose, and the corresponding resistance to that insulin, creates a need for more insulin that drives greater resistance to it. Insulin drives insulin resistance, but in the
Our evolutionary biology has not prepared us for this outcome – plentiful refined starchy carbohydrates and sugars are recent human-made foods of commerce.
The Insulin Hypothesis is that this sets up a chronic pathological state conducive to the development of CVD (among a host of other conditions).
The type 2 diabetes (T2D) connection
Steps 1-4 may be going on ‘silently’ and for decades. Standard blood-screening tests do not usually measure insulin or insulin resistance, although insulin resistance might be inferred indirectly from an oral glucose tolerance test (even then, only the glucose response and not insulin response is measured). Fasting blood glucose can be normal until the system reaches a tipping point. No one notices that anything is amiss, but
The tipping point arises from worsening insulin resistance and a corresponding decline in pancreatic insulin secretion (perhaps due to the development of fatty pancreas, it’s not necessarily that the pancreas ‘fails’). The inability to dispose of glucose shows up as an increase in blood glucose measures. A diagnosis of pre-diabetes or diabetes may be made. However, even a diagnosis of pre-diabetes indicates that disease progression is advanced. Testing for insulin or insulin resistance could have provided a more timely warning. There are ways to estimate these in a clinical setting.
Disturbingly, if insulin drives insulin resistance and the need for more insulin in a reinforcing fashion, then the medical treatment of T2D with insulin injection is likely to add to insulin resistance, and so exacerbate disease progression. The rational approach, that doesn’t need drugs, is to eat less glucose in the first place.
It should be no surprise that the same T2D triad of insulin, its resistance, and high blood glucose are implicated in CVD. Vascular disease is the cardinal complication of T2D, and some claim that T2D is
The Insulin Hypothesis explains this connection – both CVD and T2D arise from the same metabolic state.
Mechanisms: Insulin and insulin resistance
While insulin is a critically important hormone regulating multiple aspects of our biology, chronic high concentrations can be unfavourable. One mechanism is insulin-mediated release of nitric oxide (NO) in the vascular walls (vascular endothelium). NO is an important vascular dilator, and insulin resistance inhibits its production, constricting blood vessels and raising blood pressure. Notice that this is a direct way in which insulin and its resistance can increase blood pressure. Insulin can also have other direct effects on the autonomic nervous system that regulates cardiovascular functions such as heart rate. Insulin can modify kidney sodium regulation, thereby increasing sodium retention (in turn increasing blood pressure). Finally, insulin is both directly and indirectly a growth-promoting agent, and high insulin is associated with overgrowth of smooth muscle cells in vessel walls, a characteristic of advanced atherosclerosis.
The primary indirect effect of insulin and insulin resistance in cardiovascular health is likely the accompanying chronically elevated levels of blood glucose.
In a process called glycation, glucose can randomly stick itself to proteins and disable their function. As an example, the percentage of haemoglobin (a protein) that has been glycated, is often used as a measure of average blood glucose concentration. The more glucose, the more glycation.
A protein of interest for this narrative is apolipoprotein B (abbreviated ApoB). This is the largest protein molecule in our body. It courses around and within LDL particles, and the liver identifies that a
However, if the exposed parts of ApoB become glycated, it no longer fits the lock. The LDL is left to circulate with nowhere to go. Ultimately, these modified LDL particles are recognised by scavenger receptors on immune system cells (macrophages) in the vascular endothelium, that
An additional consideration is that endothelial cells are not in direct contact with circulating blood, they are protected by a thin gel-like barrier (less than a micron thick) of hair-like cells called the glycocalyx. This hasn’t been studied in depth until fairly recently, because it is difficult to measure and easily damaged. Glucose readily breaks down the glyocalyx and exposes endothelial cells to secondary damage. Furthermore, the glycocalyx is thinnest where blood vessels branch (fork) and where blood flow is turbulent, which is also where atherosclerotic plaques are more likely to form.
There will be many other mechanisms, all of which will interact in complex ways.
Insulin and its resistance in response to chronic glucose overload represents a relatively new (in evolutionary terms) form of metabolic dysfunction that could lead to serious and life-threatening diseases such as CVD and T2D. However, it is encouraging that this might be reversible by reducing or minimising dietary sources of glucose and allowing time for everything else, including insulin resistance, to take care of itself. If caught early enough, there should be no drugs required.
The Insulin Hypothesis for CVD has not been tested rigorously in
I am not a medical doctor. Nothing herein is, nor should be taken to
Common sources of dietary glucose: Grains (e.g. wheat, rice, corn). Products made from them (e.g cereals, pasta, bread). Sugar (e.g. table sugar, high-fructose corn syrup, honey, nectars). Fruit (except for some berries and vegetable-fruits such as avocado, tomato, cucumber). Starchy root vegetables (potato, sweet potato).
My (rather laborious) Keto page.
The evolutionary significance of cholesterol ►
How cholesterol and other lipids are trafficked in the circulation ►
Does cholesterol even cause heart disease? ►
A case study of an RCT: the marketing science of Lipitor ►
An overview of statin RCTs ►
Heart disease risk calculators ►
Cholesterol clinical guidelines ►
Statin adverse effects ►