HORMONES, SUCH AS insulin, act much like drugs when it comes to resistance.
Both act upon cell surface receptors, and they show the same phenomenon of resistance.
In the case of insulin, prolonged and excessive exposure to this hormone, hyperinsulinemia, causes insulin resistance.
Proving it experimentally is quite simple.
Take a group of healthy volunteers, give them persistent, high doses of insulin, and look for resistance to develop.
Luckily, all the experiments have already been done.
In one study, a forty-hour constant insulin infusion into a group of
healthy young people increased insulin resistance by 15 percent.6 In a similar experiment, a ninety-six-hour constant intravenous infusion of insulin into a group of healthy young people increased insulin resistance by 20 to 40 percent.7 The implications of these results are simply staggering.
Giving normal but persistent amounts of insulin alone to these healthy young people made them insulin resistant.
Insulin causes insulin resistance.
That is, I can make anybody insulin resistant.
All I need to do is give them enough insulin.
In type 2 diabetes, giving large doses of insulin produces increased insulin resistance.
In one study, patients initially not taking insulin were titrated up to a very high dose of 100 units of insulin per day.8 The higher the insulin dose, the more insulin resistance they developed, a direct causal relationship, as inseparable as a shadow is from a body.
Even as blood glucose levels got better, the diabetes was getting worse.
Insulin causes insulin resistance.
However, high hormonal levels by themselves cannot cause resistance or we would all quickly develop crippling levels of resistance.
Our bodies naturally defend against resistance by secreting our hormones in short bursts.
High levels of hormones are released at specific times to produce a specific effect.
Afterwards, the levels quickly drop and stay very low.
This is the body’s daily circadian rhythm.
The prolonged low periods of hormone ensure that resistance does not develop.
For example, the hormone melatonin, produced by the pineal gland to regulate our sleep and wake cycles, is virtually undetectable during the day.
As night falls, it increases to peak in the early morning hours.
Cortisol, produced by the adrenal glands to regulate stress, spikes just before we wake up and then drops down to low levels.
Growth hormone, produced in the pituitary gland to help us regenerate cells, is secreted mostly in deep sleep and then falls to undetectable levels during the day.
Parathyroid hormone, which regulates bone metabolism, peaks in the early morning.
The periodic release of these and other hormones is essential in preventing resistance.
Hormone levels generally stay very low.
Every so often a brief pulse of the specific hormone, often triggered by the circadian rhythm, comes along to create maximum effect.
After it passes, our levels are very low again.
The brief pulse of hormone is over long before resistance has a
chance to develop.
The body does not continuously cry wolf.
When it does on occasion, we experience the full effect.
For resistance to develop, two essential factors are required: high hormonal levels and constant stimulus.
Normally, insulin is released in bursts, preventing insulin resistance from developing.
But when the body is constantly bombarded with insulin, resistance develops.
It should be obvious by now that, since resistance develops in response to high, persistent levels of a stimulus, raising the dose only leads to more resistance.
It’s a vicious, self-reinforcing cycle: exposure creates resistance.
Resistance leads to higher exposure.
Higher exposure increases resistance.
When constant high levels of insulin “yell” for glucose to enter the cell, it has progressively less effect (insulin resistance).
The body’s knee-jerk reaction is to produce even more insulin, to yell even louder.
The louder it yells, the less effect it has.
Hyperinsulinemia drives the vicious cycle.
Hyperinsulinemia leads to insulin resistance, which leads to worsening hyperinsulinemia.
Figure 6.3.
Hormonal obesity III: High insulin → resistance → higher insulin
The cycle keeps going around and around, until the insulin levels in the body are extremely high, which drives weight gain and obesity.
The longer the cycle continues, the worse it becomes, which is why obesity and insulin resistance are so time dependent.
People can be stuck in this vicious cycle for decades, developing significant insulin resistance.
Resistance then leads to high insulin levels, which are independent of diet.
But the story gets worse.
Insulin resistance leads to higher fasting insulin levels.
Fasting insulin levels are normally low.
Now, instead of starting the day with low insulin after the nightly fast, we start with high insulin.
The consequences are dire: the fat get fatter.
As insulin
resistance becomes a larger and larger part of the problem, it can, in fact, become a major driver of high insulin levels.
Obesity drives itself.
The fact that insulin resistance leads to compensatory hyperinsulinemia has been long accepted.
But the novel notion that hyperinsulinemia also causes insulin resistance is slowly gaining acceptance.
Dr.
Barbara Corkey, the 2011 Banting Medal winner from Boston University’s School of Medicine, called her lecture, “Hyperinsulinemia is the root cause of insulin resistance, obesity and diabetes.”9 The Banting Medal is the American Diabetes Association’s highest scientific award, so these are not merely the musings of a fringe group.
The hallmark of type 2 diabetes is elevated insulin resistance.
Both obesity and type 2 diabetes are manifestations of the same underlying problem: hyperinsulinemia.
Their close relationship has given rise to the term “diabesity,” which implicitly acknowledges that they are one and the same disease.
Figure 6.4.
Hyperinsulinemia: The link between obesity and diabetes
HYPERINSULINEMIA AND THE OVERFLOW PHENOMENON
INSULIN RESISTANCE OCCURS when blood glucose remains elevated despite normal or high levels of insulin, since the cells are resisting insulin’s pleas to take up glucose. But how does hyperinsulinemia cause this phenomenon? The currently held lock-and-key paradigm suggests that the key (insulin) opens the lock (cell surface receptor) to allow glucose inside, and that once you remove the key (insulin), blood glucose can no longer
enter the cell.
With insulin resistance, we imagine that the lock and key no longer fit together very well.
The key only partially opens the lock and not very easily, so glucose, which cannot enter normally, instead piles up outside, in the blood.
As less glucose enters the cell, it faces a state of internal starvation and the body produces more insulin.
Since each key works less efficiently, the body compensates by producing more keys.
This hyperinsulinemia ensures that enough glucose gets into the cells to meet its energy requirement.
It’s a nice, neat theory.
Too bad it has no basis in reality.
Is the problem the key (insulin) or the lock (insulin receptor)?
Well, neither.
The molecular structure of both insulin and the insulin receptor is completely normal in type 2 diabetes.
Therefore, something must be gumming up the lock-and-key mechanism.
But what?
Despite decades of intensive research, no plausible culprit has been positively identified.
Recall that insulin goes up when you eat and acts predominantly in the liver to help store incoming food energy.