Before putting up the main paragraphs in the article, let me make a bit of an evolutionary argument for two elements of the process. They can be found in my book in a compact form.
1. Insulin is the primary storage hormone; it silences at least 7 other hormones that mobilize energy, such as leptin and glucagon. Why? In the evolutionary setting, there was never a situation where it would not make sense to store energy when it was available beyond the immediate need for it. Silencing the hormones that do the opposite is essential to effective storage. The central energy systems of metabolism have a simple rule: no excess energy ever goes un-stored.
2. There is a hierarchy of insulin resistance in tissues. Muscle may be the first tissue to become resistant to insulin and fat the last. Why? In the absence of glucose in the bloodstream, muscle insulin resistance spares glucose for the brain and nervous system. The brain can operate on ketones, the by-product of fat metabolism, and lactate, the by-product of intense muscle contraction, but glucose remains an essential fuel for the brain and nervous system. Fat is the tissue, after the cells of muscle and organs have stored enough fuels, that captures excess energy. It MUST remain sensitive to insulin even after the other tissues become resistant. Otherwise, the excess energy goes to waste.
3. Insulin stores EVERYTHING --- fat, protein, carbohydrate --- and shuts down the mobilization of fats and amino acids as energy sources. When you eat a cookie, a strange thing happens. You switch to storage mode and your fat cells stop releasing free fatty acids and your liver stops producing glucose. Your blood sugar and your free fatty acids decline in your blood. Now the brain is deprived of both. That is why you need another cookie because it contains both glucose and fat. Or, a candy bar. You know the cycle from there; you always hunger for another and another as the insulin storage-hunger cycles oscillate.
4. At a certain stage, all the other tissues lose insulin sensitivity and even fat begins to lose it. Now, you have high insulin, high glucose, and high fatty acids in your blood. The article describes how excess fatty acids reduce insulin receptors and may reduce insulin secretion as well. That may set the stage for outright diabetes. But, this makes sense. At some stage, enough energy is stored and available in the blood stream, so insulin is of little use. Even fat cells will become somewhat insulin resistant. At this stage, I am conjecturing, existing fat cells are storing so much energy that they become stressed and inflamed. New fat cells have to form to store the excess now. This accretion of new fat cells (adipose cells) is protective; the body is making new fat cells to take the stress off existing ones. I think of it as a mass action effect; make enough fat cells, even insulin resistant ones, so they can take up the excesses of fats and glucose in the blood. That is why some studies find adipose tissue to be somewhat protective and a high BMI is not associated with poor health until BMI reaches a morbid level.
5. So, there is no upper limit on adipose tissues. It would surely make no sense in evolutionary times for there to be one and in an excess energy intake world, it becomes the last strategy that can be deployed to protect the body.
Some choices paragraphs from this wonderful article follow:
“Insulin is the primary hormonal signal for energy storage into adipocytes. Insulin hypersecretion by the pancreas plays a role in the pathogenesis of some forms of obesity. For example, infants of diabetic mothers tend to be large for gestational age, and initiation of insulin therapy in diabetes leads to weight gain. The phenomenon of hypothalamic obesity, characterized by vagally mediated insulin hypersecretion provides further evidence for the obesigenic properties of insulin excess. In natural history studies, adults who hypersecreted insulin in response to an intravenous glucose tolerance test gained excess weight over a 15-year follow-up period21; analogously, fasting hyperinsulinemia predicted weight gain over 9 years in a group of Pima Indian children, independent of baseline BMI.
Because insulin resistance and hypersecretion often coexist and are partly interdependent, it can be difficult to tease out the relative contributions of each to the genesis of obesity. Still, insulin resistance appears to contribute to weight gain in adults and children, particularly with regard to the development of abdominal obesity. This may occur because of heterogeneity in insulin resistance between tissues. Adipose tissue tends to retain its sensitivity to insulin in the face of hepatic and skeletal muscle resistance.
In experimental models, adipose tissue-specific and muscle insulin receptor knockout animals remain lean, whereas liver and CNS knockout animals become obese and have type 2 diabetes develop. Chronic insulin administration leads to muscle insulin resistance, whereas adipose insulin sensitivity remains high.
Certain ethnic groups are particularly prone to both insulin resistance and obesity. For instance, Pima Indian and black children have been demonstrated to be insulin resistant in childhood, predating the onset of overweight. South Asian Indians born in India were found to weigh less at birth than their UK-born counterparts, but they have greater adiposity and higher insulin levels.
Prenatal events may also set the stage for insulin resistance in later childhood. Newborns who have experienced intrauterine stress, are small or large for gestational age, or are twins have all been shown to have insulin resistance in later life, a variable predisposition to obesity, and an increased risk of metabolic syndrome.
One postulated explanation for the ability of insulin resistance to cause obesity is the “thrifty phenotype” hypothesis, which holds that to survive periods of scarcity, human metabolism is “programmed” to store nutrients maximally in times of abundance. Humans have arguably never known such energy abundance as our current fast food culture. Despite robust evidence linking insulin hypersecretion and resistance to obesity, the causal mechanism(s) are still being delineated. Insulin hypersecretion may alter glucose transport or downregulate insulin receptor expression. Conversely, insulin resistance in the liver and muscle may trigger compensatory increases in insulin secretion.
It is still not clear whether insulin hypersecretion or resistance occurs first. One study of insulin dynamics among obese schoolchildren suggested that hypersecretion predates development of insulin resistance by several years. In rats, hyperinsulinemia increases expression of a glucose transporter (GLUT4) in adipose tissue while decreasing expression of this same transporter in muscle, demonstrating that excess insulin can simultaneously foster insulin sensitivity in fat while triggering resistance in other tissues. The relative contribution of insulin sensitivity versus resistance in obesity appears to differ among whites as compared with blacks.”