The trouble with insulin resistance, part III

I was in way over my head starting to ramble on about insulin resistance hoping I would identify a causal link. But I feel I should finish what I’ve started.

The trouble with insulin resistance is that it is so bloody hard to point to the exact cause at a cellular and molecular level. I’ve looked at how insulin resistance could in theory be caused by a lipid overload which through its effect on insulin signaling reduces the effect of insulin. In addition to lipid overload there is the inflammation hypothesis.

It is commonly accepted that chronic inflammation associated with obesity induces hepatic insulin resistance. Not long ago clever scientists discovered that the fat tissue was not simply a waste basket for surplus energy, but also an important endocrine organ. Many of the inflammatory substances thought to induce insulin resistance originate from the fat tissue.

Several inflammatory substances has been looked at with interest, among them are, CRP (C-reactive protein) TNF-α (tumor necrosis factor alfa), IL-1, IL-6 (interleukin 1 and 6) leptin and resistin. These are so called cytokines which are protein signalling molecules much like hormones. Other substances thought to play a part in an inflammatory led insulin resistance include; I-kappa-B-kinase beta (IKK-β), nuclear factor-κB (NF-κB), c-Jun N-terminal kinase (JNK), CC chemokine receptor 2 (CCR2) and macrophage migration inhibitory factor (MIF). And the list goes on. It is long and incomprehensible. But the big picture is clear. Obesity, insulin resistance and inflammation go hand in hand.

Some of the above substances are thought to inhibit insulin signalling in liver cells. This would then be classified as a hepatic insulin resistance. An insulin resistant liver in turn has an impaired suppression of glucose production by insulin. The result is hyperglycaemia.

Then why is the fat tissue so inflamed?

One theory claims that fat cells produce inflammatory cytokines because of endoplasmatic reticulum stress. Stress caused by the expanding of the fat cell as it fills up with excess energy thus promoting adipose tissue production of JNK, which inhibit insulin signalling. The stress also makes macrophages (white blood cells) travel into fat cells to a far larger degree than in lean people.

The source of many of the inflammatory signals originating from the adipose tissue is thought to be macrophages. Obesity-associated adipose tissue inflammation is characterized by an infiltration of macrophages into the adipose tissue. Macrophages also incorporate into artery walls and play an important part in atherosclerosis. According to Taubes quoting Anthony Ferrante, 5% of the adipose tissue in lean individuals is macrophages. In obese, the number comes close to 50%.

Ketogenic or carbohydrate restricted diets have been shown to decrease inflammation in both human and animal models. Although the mechanisms are still unclear the reduced inflammation is in thought to in part be because of reduced levels of reactive oxygen species (ROS). Hyperglycemia, as occurs in insulin resistance and type-2 diabetes, contributes to a breakdown in cellular function that leads to overproduction of reactive oxygen species. It is in fact a rather consistent feature common to all cell types that are damaged by hyperglycemia.

One way that carbohydrate restriction may decrease inflammation is through an altered fatty acid profile. Low-carbohydrate diets may result in profound alterations in PUFA (poly-unsaturated fatty acids), particularly affecting arachidonate, an omega 6 PUFA. When incorporated into membranes arachidonate is commonly assumed to have a deleterious effect on the overall inflammatory balance because of its conversion to proinflammatory eicosanoids (e.g., prostaglandin E2, thromboxane A2, leukotrienes B4).

In contrast, eicosanoids derived from long omega 3 PUFA have less inflammatory effects.

Less oxidative stress should result in better preservation of arachidonate since free radicals play a part in its metabolism. Inflammatory cytokines are known to increase production of free radicals which in turn initiate arachidonic acid release and breakdown.

Most evidence indicates that restricting dietary carbohydrate positively impacts inflammation.

Another part of the inflammation puzzle may lie in AGE (not age, but Advanced Glycation End products). These are proteins which have gotten attached to glucose probably because of hyperglycemia. These modified circulating proteins can then bind to AGE receptors and activate them, thereby causing the production of inflammatory cytokines.

Funny thing here is that mitochondria produce ROS. Researchers claim this is mostly because of an increased FFA flux with accompanying increased FFA oxidation by the mitochondria. The increased oxidation causes mitochondrial overproduction of ROS. Thus, it seems that too much fatty acids in the blood will both cause a lipid overload in tissues and cause a greater production of reactive oxygen species all of which will increase insulin resistance.