Abstract
Over the past 10 years it has become clear that intact vascular function, especially at the level of the endothelium {cells lining the blood vessels}, is paramount in the prevention or delay of cardiovascular disease. It has also become clear that insulin itself, in addition to its metabolic actions, directly effects vascular endothelium and smooth muscle. Insulin, at normal physiologic concentrations, causes changes in skeletal muscle blood flow in healthy, insulin-sensitive subjects. Insulin’s effect on the endothelium is mediated through its own receptor and insulin signalling pathways, resulting in the increased release of nitric oxide. Insulin’s vascular actions are impaired in insulin-resistant conditions such as obesity, Type II (non-insulin-dependent) diabetes mellitus and hypertension, which could contribute to the excessive rates of cardiovascular disease in these groups. Insulin-resistant states of obesity and Type II diabetes show a multitude of metabolic abnormalities that could cause vascular dysfunction. Non-esterified fatty acid levels increase long before hyperglycaemia becomes present. Raised non-esterified fatty acids impair insulin’s effect on glucose uptake in skeletal muscle and the vascular endothelium and thus could have detrimental effects on the vasculature, leading to premature cardiovascular disease.
If it is true that NEFA levels rise before blood glucose becomes elevated, then perhaps a screening for pre-pre-diabetes should involve measurement of this blood biomarker?
What causes elevated NEFA? It's largely not dietary fats as these are mostly transported as chylomicrons, although there's some indication that in an obese person more FFA's escape re-esterification in the fat cells. However NEFA levels are largely regulated by their release from adipose tissue in the ever-present FFA/Triglyceride cycling. The release of NEFA is policed by the inhibitory action of insulin, and this role of insulin has been described as protective.
So if elevated NEFA is the first symptom in the cascade, and an indication of impaired insulin inhibitory action on fat stores, then is the progression of IR proposed by Taubes totally wrong? Taubes contends that peripheral tissues develop IR first followed by organs and finally adipose tissue. This statement in this article would indicate that it's the other way around. Elevated NEFA would indicate some degree of insulin resistance of the fat cells. Insulin is not largely involved in storing fat, it is involved in its release. But what causes this? Hmmmm.... over-stuffed fat cells perhaps? As circulating NEFA's rise these induce insulin resistance skeletal muscle and perhaps the liver as well so that it pumps out too much glucose.
It seems more and more apparent to me that carbohydrate consumption per se has relatively little to do with the development of IR. It naturally occurs in certain phases of life (puberty, aging) but most of us are able to compensate for mild IR by increasing insulin production. To be fair, it's not dietary fat that necessarily causes it either, although there's still the question of higher IMCL just from eating a higher fat diet and the potential for IMCL derived diacylglycerol and/or ceramides to induce IR in skeletal muscle cells. Using our insulin does not appear to cause us to become resistant to it. Indeed the opposite seems to be closer to the truth as low carbers are advised to "carb up" for several days prior to taking an oral glucose tolerance test so as to restore their insulin responses to as normal as possible.
I propose that the fat accumulation leads to elevated NEFA leads to peripheral IR and other deleterious effects on the liver and pancreas. Only chronic carbohydrate overfeeding seems to contribute to increases in fat mass, but net fat accumulation will still largely be contributed by dietary fat. IOW fat accumulation leads to IR leads to hyperinsulinemia. Fat accumulation is, in the end, dictated by energy balance.
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