The evolutionary benefit of insulin resistance

doi:10.1016/j.clnu.2012.05.011

Clinical Nutrition

Volume 31, Issue 6, December 2012, Pages 1002-1007

https://doi.org/10.1016/j.clnu.2012.05.011 Get rights and content

Summary

Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in various states such as starvation, immune activation, growth and cancer, to spare glucose for different biosynthetic purposes such as the production of NADPH, nucleotides in the pentose phosphate pathway and oxaloacetate for anaplerosis. In these conditions, total glucose oxidation by the tricarboxylic acid cycle is actually low and energy demands are largely met by fatty acid and ketone body oxidation.

This beneficial role of insulin resistance has consequences for treatment and research. Insulin resistance should be investigated at the cellular, tissue and whole organism level. The metabolic pathways discussed here, should be integrated in the accepted and valid mechanistic events of insulin resistance before interfering with them to promote insulin sensitivity at any cost.

Introduction

“Insulin resistance” is generally regarded as a deleterious condition associated with the metabolic syndrome, type 2 diabetes mellitus and critical illness; disorders that lead to hyperglycemia. In turn, chronically elevated glucose levels are causing many of the ill effects of these conditions. Consequently, much effort has been invested into treating hyperglycemia on its own: glucose targets have not only been set for patients with type 2 diabetes mellitus, but also for critically ill patients. In the latter tight glucose control has been advocated until very recently. Likewise efforts have been performed to feed carbohydrates to patients until very shortly before surgery to decrease insulin resistance.

The bad image of insulin resistance has obscured its potential benefits as an adaptive mechanism. Insulin resistance (or the ability to selectively modulate the cellular/tissue response to insulin) is evolutionarily well preserved in insects, worms, and vertebrates including humans.¹ Having been under so much evolutionary pressure, its persistence suggests that it benefits survival of the species. Here we shortly review old and recent experimental evidence regarding the important role of insulin resistance in various states (e.g. starvation, immune activation, growth) to finally hypothesize on the evolutionary importance of insulin resistance.

Section snippets

Insulin resistance in starvation

A century ago Benedict demonstrated in his classic work "A study on long term fasting" that the human organism could limit its nitrogen losses during long term starvation.² Starvation is accompanied by insulin resistance as shown by targeted inhibition of the action of insulin in oral glucose tolerance tests and clamp studies. Glucose uptake and oxidation are decreased by mechanisms like decreased phosphorylation of insulin signaling intermediates in muscle such as AKT and the AKT substrate 160.

Insulin resistance in stress starvation

In stress starvation (starvation associated with trauma or illness) most metabolic processes occurring in pure starvation intensify due to higher energy requirements. This energy is largely derived from fatty acid and ketone body oxidation. However, peripheral organs become more catabolic (skin, bone, muscle) resulting in net protein loss with amino acids taken up and utilized in protein synthesis by central organs (liver, spleen, immune cells, healing tissues) for stress responses (e.g.

Glucose serves biosynthetic purposes

In the first step of the oxidative part of the pentose phosphate pathway (PPP), glucose 6-phosphate is partly oxidized via glucose 6-phosphate dehydrogenase, producing the reducing equivalent NADPH. NADPH is necessary to maintain the redox potential of different substrates such as glutathione, but is also required for macrophages/neutrophils to produce radicals killing bacteria, and possibly to facilitate phagocytosis, and for fatty acid synthesis.20, 21 Further down the oxidative part of the

Changes in metabolism during immune response activation (Fig. 1)

Glucose uptake in leukocytes and spleen is enhanced by endotoxin administration, sepsis, trauma, and all other inflammatory conditions. Although leukocytes have a full TCA cycle, they shift from complete oxidation of glucose in the fed non-activated state to glycolysis and increased PPP flux once activated.18, 21 In Kupffer and endothelial cells, in vitro studies show that glucose flux through the PPP is approximately half of palmitate oxidation and one third of glutamine breakdown.³² These

Insulin resistance and growth

Channeling glucose into the PPP and the TCA cycle is also necessary during growth: this has been demonstrated in pregnancy and during lactation.37, 38 In these conditions dietary carbohydrates are available but glucose is still preferentially used for biogenesis. To metabolize glucose, pregnant, lactating women and pubertal humans need to secrete increased amounts of insulin, reflecting insulin resistance.39, 40, 41

The same mechanisms apply to malignant tumor growth: the well known “Warburg

Insulin resistance in obesity

If we accept that insulin resistance benefits limitation of net degradation of protein in long-term starvation and stress while facilitating PPP and anaplerosis, the role of insulin resistance in overfeeding is enigmatic.

Accumulation of fat and muscle mass for hibernation (or very likely also for migration) leaves animals severely insulin resistant due to a pro-inflammatory drive induced by abundant amounts of fat as well as to synthesize muscle and fat.⁴⁴ Similarly, high fat feeding for 11

Evolutionary purpose of insulin resistance

The benefit of insulin resistance in prolonging survival and meeting requirements of tissue proliferation is supported by the finding that in the Drosophila fly insulin sensitivity is upregulated and life span is shortened by knocking out FoxO genes (required to resist amino acid starvation as described above).⁵⁰ Similar findings have been reported in nematodes and in mice.¹ FoxO1 expression combats oxidative stress, preserving cellular function and promoting the switch from carbohydrate to

Hypothesis

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. This mechanism is evolutionarily well preserved in multiple species, including the human organism. It is also likely that in other insulin resistance states like chronic inflammatory

Funding

None.

Conflict of interest

None.

Disclosure

The authors have nothing to disclose.

Statement of authorship

Both authors have participated sufficiently and intellectually in the work to take public responsibility for the conception, content and writing of the article. The authors have nothing to declare.

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During the follow-up period, 349 (6.3%) patients succumbed within 28 days. A U-shaped correlation between SHR and mortality persisted, even after adjusting for other confounding variables, with a discernible inflection point at 0.95. When SHR surpassed 0.95, each standard deviation (SD) increase corresponded to a 1.41-fold elevation in the risk of mortality (odds ratio [OR]: 1.41, 95% CI: 1.25 to 1.59). In contrast, when SHR fell below 0.95, each SD increment correlated with a significantly reduced risk of mortality (OR: 0.56, 95% CI: 0.34 to 0.91).
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Opinion paperThe evolutionary benefit of insulin resistance

Summary

Introduction

Section snippets

Insulin resistance in starvation

Insulin resistance in stress starvation

Glucose serves biosynthetic purposes

Changes in metabolism during immune response activation (Fig. 1)

Insulin resistance and growth

Insulin resistance in obesity

Evolutionary purpose of insulin resistance

Hypothesis

Funding

Conflict of interest

Disclosure

Statement of authorship

Current Topics in Cellular Regulation

Cell

FEBS Letters

The Journal of Biological Chemistry

Metabolism: Clinical and Experimental

Journal of Biotechnology

Biochimica Et Biophysica Acta

The American Journal of Clinical Nutrition

Biochemical Medicine and Metabolic Biology

Clinical Anaesthesiology

Domestic Animal Endocrinology

Trends in Endocrinology & Metabolism

The role of insulin and IGF-1 signaling in longevity

Cellular and Molecular Life Sciences: CMLS

An experiment on a fasting man

Science (New York, N.Y.)

Muscle adaptation to short-term fasting in healthy lean humans

The Journal of Clinical Endocrinology and Metabolism

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle

American Journal of Physiology Endocrinology and Metabolism

Brain metabolism during fasting

The Journal of Clinical Investigation

Regulation of ketone body flux in septic patients

American Journal of Physiology

Fuel metabolism in starvation

Annual Review of Nutrition

Relationships between lipid availability and protein utilization during prolonged fasting

Journal of Comparative Physiology B, Biochemical, Systemic and Environmental Physiology

Energy and protein requirements for molt in the king penguin Aptenodytes patagonicus

The American Journal of Physiology

Contributions of gluconeogenesis to glucose production in the fasted state

The Journal of Clinical Investigation

Alanine and inter-organ relationships in branched-chain amino and 2-oxo acid metabolism

Bioscience Reports

Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans

Physiological Reviews

Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1

Nature Genetics

The role of FoxO in the regulation of metabolism

Oncogene

Post-operative changes in hepatic, intestinal, splenic and muscle fluxes of amino acids and ammonia in pigs

Clinical Science (London, England: 1979)

Insulin sensitivity of glucose and fat metabolism in severe sepsis

Clinical Science (London, England: 1979)

Opinion paper
The evolutionary benefit of insulin resistance