Causes of Insulin Resistance

There are several levels of insulin resistence causation including diet, cellular, molecular, genetic, and disease.

Diet

Grounds exist for linking insulin resistance to a high-carbohydrate diet. An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance.

Insulin resistance has also been linked to PCOS (polycystic ovary syndrome) as either causing it or being caused by it. Further studies are in progress. Other studies have also linked to the increased amounts of fructose (e.g., in HFCS — high fructose corn syrup, currently the least expensive nutritive sweetener available in industrial quantities); in humans, fructose causes changes in blood lipid profiles, among other things, mostly due to its effects on liver function. The high amounts of ordinary sucrose (i.e., table sugar) in the typical developed-world diet is also suspected of having some causative effect on the development of insulin resistance (sucrose is 1/2 fructose, which may account for the effect, if any). Insulin resistance has certainly risen in step with the increase in sugar consumption and the substantial commercial usage of HFCS since its introduction to the food trades; the effect may also be due to other parallel diet changes however. Further research may distinguish between candidate causes. .

Cellular

At the cellular level, excessive circulating insulin appears to be a contributor to insulin resistance via down-regulation of insulin receptors. This occurs due to prolonged and repeated elevations of circulating insulin. Since the usual instances of Type 2 insulin resistance are distinct from pathological over production of insulin, this does not seem to be the typical cause of the insulin resistance leading to Type 2 diabetes mellitus, the largest clinical issue connected with insulin resistance. The presence of insulin resistance typically precedes the diagnosis of Types 2 diabetes mellitus, however, and as elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is a likely contributor. Additionally, some Type 2 cases require so much external insulin that this down-regulation contributes to total insulin resistance.

Inflammation also seems to be implicated in causing insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it.

Vitamin D deficiency is also associated with insulin resistance.

Some research has shed light on a complex interaction between elevated free fatty acids and inflammatory cytokines seen in obesity activating Protein Kinase C isoform theta. PKC Theta inhibits Insulin Receptor Substrate (IRS) activation and hence prevents glucose up-take in response to insulin.

Molecular

Insulin resistance has been proposed at a molecular level to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as a antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It is also based on the finding that insulin resistance can be rapidly reversed by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.

Genetic

Individual variability is a cause with an inherited component, as sharply increased rates of insulin resistance and Type 2 diabetes are found in those with close relatives who have developed Type 2 diabetes.

Disease

Sub-clinical Cushing's syndrome and hypogonadism (low testosterone levels) seem to be the major insulin resistance causes .

Recent research and experimentation has uncovered a non-obesity related connection to insulin resistance and Type 2 diabetes. It has long been observed that patients who have had some kinds of bariatric surgery have increased insulin sensitivity and even remission of Type 2 diabetes. It was discovered that diabetic / insulin resistant non obese rats whose proximal small intestine and duodenum has been surgically removed also experienced increased insulin sensitivity and remission of Type 2 diabetes. This suggested similar surgery in humans, and early reports in prominent medical journals (January 8) are that the same effect is seen in humans, at least the small number who have participated in the experimental surgical program. The speculation is that some substance is produced in that portion of the small intestine which signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity. No such substance has been found as yet, so its existence remains speculation.