Insulin and cardiovascular disease
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 hypothesis, and found it to be weaker than its reputation. Instead, I will offer a different hypothesis — the Insulin Hypothesis, represented by the closely-related triad of hyperglycemia (elevated glucose), hyperinsulinemia (elevated insulin) and insulin resistance.
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 end they both drive each other, forced on by glucose.
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 damage is potentially being done. Healthy individuals (with normal fasting blood glucose) may still be somewhere along an insulin resistance spectrum.
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 vascular disease. Damage occurs in major vessels (e.g. atherosclerotic CVD) and in the micro-vasculature (supplying the retina, kidneys and peripheral tissue and resulting in secondary complications therein).
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 partical is LDL by the presence of ApoB. When the LDL has done its job (primarily, carrying cholesterol to tissues that might need it), it returns to the liver where the ApoB is recognised and liver cells take in the LDL particle and its remaining cargo for processing, which may include eliminating surplus cholesterol through the bile duct. It’s like a lock-and-key, a receptor on liver cells is unlocked by the ApoB (which is the key). This clears the LDL and its cargo from the circulation (and possibly from the body), and is how the system evolved to work.
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 take in the LDL and its cargo and break it down. If only a small percentage of LDL is glycated, this process works fine. However, if the percentage is significant, or chronically elevated, macrophage activity can proliferate and set off other processes (e.g inflammation, oxiditive stress etc) that may be the first stages in atherosclerosis, or the proliferating macrophages themselves can become a problem. A build up of cholesterol and other residues in the vascular endothelium may ensue.
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 randomised clinical trials. There are reasons for this: there are no drugs to improve insulin resistance; there is no money to be made through dietary interventions; trials need to be large and are expensive; drug companies are not interested in funding such trials. In comparison, Lipitor (a Pfizer statin drug targeting cholesterol) has been the most profitable drug in the history of medicine.
I see dietery glucose restriction as a sensible (although unproven) strategy for modern disorders beyond CVD and T2D, including obesity, cancer and neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s disease (PD). There is a resurgence of interest in cancer as a metabolic disorder of hyper-glucose utilisation. Some scientists want to see AD renamed ‘type 3 diabetes’. In a study of non-diabetic PD patients, about two-thirds had insulin resistance.
I am not a medical doctor. Nothing herein is, nor should be taken to be, medical advice.