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Fasting and it’s Weird Effect on Insulin (Peripheral Insulin Resistance)

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Fasting and it’s Weird Effect on Insulin (Peripheral Insulin Resistance) – Thomas DeLauer

Study – Journal of Clinical Endocrinology and Metabolism

Glucose and glutathione (GHS) metabolism was studied after 12 and 60 hours of fasting on two occasions: with and without aspirin (6 g/d) t

6 healthy lean men participated and, as mentioned, underwent 60 hours of fasting with or without aspirin (approximately 6 g/d)

Fasting decreased insulin-mediated peripheral glucose uptake by 46% after 60 h and Aspirin did not alter this effect of 60 hours of fasting on insulin sensitivity

GSH concentration decreased during fasting, but the fractional synthetic rate of GSH was unaffected either with or without aspirin
Fasting did not affect inflammatory parameters, although aspirin increased soluble TNF receptors I and II

Researchers concluded that prolonged fasting induces profound peripheral IR – in contrast to type 2 diabetes mellitus, high-dose salicylate does not affect fasting-induced peripheral IR


Why Does this Occur

Generally, prolonged fasting (greater than 48 hours) in humans is accompanied by a reduction in insulin sensitivity, elevated plasma FFA levels, elevated intramuscular fat levels, but also an increase in whole-body fat oxidative capacity

Furthermore, prolonged fasting-induced insulin resistance is not accompanied by hyperglycemia or hyperinsulinemia, factors that have been suggested to cause mitochondrial dysfunction in diabetes

It could therefore be anticipated that despite the development of insulin resistance, mitochondrial function is maintained to accommodate increased fat oxidation during prolonged fasting

Conversely, if (lipid-induced) insulin resistance or factors associated with the insulin-resistant state do cause mitochondrial dysfunction, it’s believed a reduction in mitochondrial function with prolonged fasting would occur

Prolonged fasting, however, is a physiologic condition in which insulin resistance develops to spare glucose for utilization by the brain, and increased FFA levels are accompanied by increased fat oxidation

Prolonged fasting-induced lipid accumulation and insulin resistance are considered to be a functional physiologic response

As mentioned, reduced insulin sensitivity saves carbs for the central nervous system, being obligate for glucose and not requiring insulin for its uptake, whereas increased lipid availability at the same time can serve as a direct available energy source for the muscles and is paralleled by an enhanced fat oxidative capacity

FFA & Mitochondria

Elevated plasma free fatty acids induce insulin resistance through activation of Jun NH(2)-terminal kinase and nuclear factor-kappaB inhibitor kappaB kinase, which leads to hyperphosphorylation of the insulin receptor substrate type 1 (IRS1)
Study – Diabetes

In this study, FFA levels were increased approximately ninefold after 60 hours of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity
These findings confirm that the insulin-resistant state has negative effects on mitochondrial function

Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity

The increased exposure of skeletal muscle mitochondria to elevated levels of free fatty acids (FFA), seen in insulin resistance and type 2 diabetes, has been suggested to interfere with proper mitochondrial function

The acute elevation of plasma FFA by lipid infusion is accompanied by downregulation of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and other genes involved in mitochondrial metabolism



1) Van der Crabben SN , et al. (n.d.). Prolonged fasting induces peripheral insulin resistance, which is not ameliorated by high-dose salicylate. – PubMed – NCBI. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18056775
2) Peripheral Insulin Resistance and Impaired Insulin Signaling Contribute to Abnormal Glucose Metabolism in Preterm Baboons. (n.d.). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330304/
3) Intermittent Fasting Increases Peripheral but not Hepatic Insulin Sensitivity | American Diabetes Association. (n.d.). Retrieved from https://professional.diabetes.org/abstract/intermittent-fasting-increases-peripheral-not-hepatic-insulin-sensitivity

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