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Insulin Resistance and Natural Selection Part 3

Many authors have cited the-allocation of energetic resource to the immune system as an adaptive event that occurs during insulin resistance (e.g. Odergaard 2012, Tsatsoulis 2011, Esteve, 2010).

An article by Soeters and Soeters in Clinical Nutrition (May 2012) adds another chapter to the potential evolutionary role of insulin resistance.

They write:

“Here we hypothesize that insulin resistance promotes glucose availability for the inflammatory response in the defense against starvation, disease and trauma and to promote growth during lactation, pregnancy, puberty and cancer, and in situations where the organism prepares itself for migration or hibernation.”

Soeters and Soeters (2012) observe that pentose phosphate pathway is favored during insulin resistance, adding to the potentially adaptive suite of adjustments that occur during insulin resistance. Soeters and Soeters suggest that glucose shunting through the pentose phosphate pathway during IR maximizes biosynthetic and redox regulating functions. These two features free up nucleotide substrates that support rapid cell proliferation during an immune response, and they favor oxidative killing. In addition, the increased activity of PPP relative to glycolysis increases reducing equivalents that provide cellular resistance to oxidative stress.

Improved Oxidative Killing by Macrophages

One consequence of these shifts in glucose utilization is enhanced oxidative killing by macrophages.  Glucose metabolism in the pentose phosphate pathway (PPP) involves the oxidation of glucose-6-phosphate by glucose-6-phosphate dehydrogenase, generating NADPH. NADPH is a key intermediary in the oxidative burst that macrophages use to efficiently kill bacteria.

Consequences of Insulin Therapy

Interestingly, Soeters and Soeters propose that treatment of insulin resistance with insulin interferes with these adaptive functions.

“This beneficial role of insulin resistance has consequences for treatment and research. Forcing glucose into oxidative pathways by liberal administration of insulin deprives the organism of glucose for synthetic and anti-oxidative pathways, which is actually suggested by recent findings showing that in ICU patients late initiation of parenteral nutrition was associated with lower insulin infusion rates, faster recovery and fewer complications.”

Perhaps intensive insulin treatment in the critically ill is a bad idea. Later, we will review the evidence for that idea.


Soeters MR, Soeters PB. The evolutionary benefit of insulin resistance. Clin Nutr. 2012 Dec;31(6):1002-7. doi: 10.1016/j.clnu.2012.05.011.

Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

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