Insulin and insulin sensitivity during a fast

Insulin is released by pancreatic beta cells in response to rising glucose, and to amino acids and the gut incretin hormones. It is the storage signal. It moves glucose into muscle and fat by bringing the GLUT4 transporter to the cell surface, promotes glycogen and fat synthesis, suppresses the liver's glucose output, activates mTORC1, and, most importantly for a fast, potently suppresses the breakdown of stored fat.

That last effect is exceptionally sensitive. Insulin restrains lipolysis at concentrations well below those needed to move muscle glucose uptake. Which means the fall in insulin is the permissive event for everything else: fat mobilisation, ketogenesis, the shift in fuel selection.

Then there is the part that confuses people. Measure insulin sensitivity during a fast with the standard method, and you will find it reduced. The person has become insulin resistant in a strictly operational sense. Understanding why that is the correct physiological answer, rather than a warning sign, requires one specific human experiment.

Insulin falls early and it falls a long way. Across a 72 hour fast in six healthy men sampled at seven timepoints, plasma insulin fell about 50%, from 64.6 plus or minus 12.9 to 30.1 plus or minus 7.9 pmol/L, and 70% of that entire decline had already happened inside the first 24 hours. Glucose fell about 25% over the same window. Glycerol and palmitic acid rates of appearance both roughly doubled, and 60% of that rise happened between 12 and 24 hours, with the single largest interval change between 18 and 24 hours. The authors' own conclusion is that early lipid mobilisation tracks the fall in insulin and is not driven by changes in glucose concentration or glucose kinetics.

The resistance that develops is selective, and that was measured directly. Six lean subjects underwent sequential euglycaemic clamps at four insulin infusion rates, before and after a 48 hour fast. Fasting markedly reduced glucose utilisation at every insulin infusion rate. But the decline in free fatty acids at an insulin concentration of 30 microunits per mL was virtually identical before and after the fast. Glucose disposal became resistant. Suppression of fat release did not.

That is exactly the arrangement a fasting body needs. Glucose has to be preserved for the tissues that can use nothing else, principally the brain early on, plus red blood cells and the renal medulla, which are obligately glycolytic under all conditions. Making muscle and fat less responsive to insulin's glucose signal is how that preservation happens. Meanwhile the antilipolytic effect must stay intact, because unrestrained fat release would produce runaway ketogenesis.

Rising free fatty acids are themselves part of the mechanism. Fatty acid oxidation raises acetyl-CoA and citrate, which inhibit pyruvate dehydrogenase and phosphofructokinase, and lipid intermediates interfere with insulin signal transduction in muscle. This is substrate competition, and it reverses when carbohydrate returns.

Falling blood glucose withdraws the stimulus to beta cells. Rising free fatty acids and rising counter-regulatory hormones then produce the selective resistance in peripheral tissue.

Two opposite errors circulate about this, and the selectivity finding disposes of both. One is alarm: fasting causes insulin resistance, therefore fasting is metabolically harmful. The other is dismissal: the resistance seen in a fast proves that insulin resistance in general is benign. Neither survives contact with the measurement.

The fasting version and the pathological version differ on three checkable points. Duration: fasting resistance resolves within hours to a day of carbohydrate refeeding, while pathological resistance persists for months or years. Insulin level: fasting resistance occurs with low circulating insulin, pathological resistance with high circulating insulin, because the beta cell is compensating. Selectivity: fasting spares insulin's suppression of fat release, pathological resistance impairs it, which is why free fatty acids stay elevated in the fed state in metabolic disease, the opposite of the fasting picture.

There is a practical consequence worth knowing. An oral glucose tolerance test done on someone who has recently completed a multi-day fast, or who has been eating very low carbohydrate, will look abnormal for reasons that have nothing to do with disease. The standard mitigation is several days of adequate carbohydrate before testing.