Intermittent Fasting and Insulin Sensitivity

In

Lean Healthy Male Subjects.

An important adaptation during fasting is a change in fuel utilization. In skeletal muscle, fatty acids and ketone bodies will be used for ATP production and glucose uptake and subsequent glucose oxidation will be minimized. The supply of fatty acids is derived from lipolysis and partly by oxidation of stored intramyocellular triglycerides and diacylglycerol.



Our early ancestors (50.000 – 10.000 B.C.) had no unlimited access to food as most people in Western countries have these days. Furthermore they had to hunt/gather to obtain food and periods of fasting and exercise were followed by periods of feeding and rest with implications for metabolism (“cycles of feast and famine”). In the last few hundred years, but most notably very recently, a tremendous change has occurred in feeding and exercise behaviour leading to the troublesome obesity and diabetic epidemic. Some postulate that 10.000 years ago our genome was made, build for the cycles of feast and famine, but not made for the continuous oversupply of food and lack of exercise in our modern era. This hypothesis is outlined underneath.



A recent study found that intermittent fasting (IF) for two weeks, mimicking cycles of feast and famine, improves insulin sensitivity. In this study total IMCL and the expression of glucose transporter GLUT 4 did not change. This could indicate that IMCL composition and lipid turnover may be responsible for the difference found in insulin sensitivity. In the same study, during the hyperinsulinemic euglycemic clamp, IMCL decreased very rapidly, indicating that even under hyperinsulinemic conditions, fatty acid oxidation is the main energy providing flux and by definition glucose is preferentially stored as glycogen. Lipolysis is almost completely suppressed by high levels of insulin, meaning that the substrates for fatty acid oxidation come from stored intramyocellular lipids instead of from fatty acid uptake from the plasma compartment. Depletion of IMCL can then be followed by replenishment, indicating turnover. This could be physiological during cycles of feast and famine.



We hypothesize that peripheral insulin sensitivity increases after a period of intermittent fasting because of an increased turnover of IMCL and/or subsequent changes in the composition of intramyocellular lipids (glyco(shpingo)lipids and acylcarnitineprofiles) and by that a more favourable intramyocellular milieu with less oxidized lipids, preserved mitochondrial function and insulin signalling.

We hypothesize that peripheral insulin sensitivity increases after a period of intermittent fasting because of an increased turnover of IMCL and/or subsequent changes in the composition of intramyocellular lipids (glyco(shpingo)lipids and acylcarnitineprofiles) and by that a more favourable intramyocellular milieu with less oxidized lipids, preserved mitochondrial function and insulin signalling.

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After the first study day, volunteers are randomly assigned to:

1. Two weeks standard diet;

2. Two weeks of intermittent fasting.

After these two weeks, a study day as previously described will follow where after volunteers change diet (standard vs IF, or IF vs standard).