Abstract
No abstract supplied by author
Keywords: evolution, insulin paradox, insulin resistance
It has been well established that insulin resistance is associated with metabolic syndrome or diabetes resulting in higher mortality.1–6 However, recently increasing evidence has shown that blocking insulin action results in greater longevity in various life forms such as yeast, Caenorhabditis elegans, Drosophila, and vertebrate including primates.1,2,7 Therefore, it appears that the insulin paradox exists.
There are several possible explanations for the insulin paradox from an evolutionary point of view.
First, in general, there are two types of selection in evolution, K-selection and r-selection.3,8–11 The former of these acts to promote survival, whereas the latter acts to enhance reproduction (Fig. 1). In the benign environment, r-selection may predominate to shift the animal to investment in its reproduction, but in the stressful environment, K-selection may predominate causing the shift toward investment for maintaining the somatic cells of animal, that is, for maintaining its survival (Fig. 2). In evolution, insulin is thought to be a neurohormone in the brain, regulating both metabolism and growth. After the two cycles of whole genome duplications, vertebrates have emerged, which use glucose directly without changing trehalose into glucose as insects do1 (Fig. 3). Insulin is thought to have concomitantly descended down from the brain to the pancreas in order to regulate blood glucose levels. On the other hand, components of the insulin signaling system, such as insulin receptor, insulin receptor substrate (IRS), and phosphatidylinositol 3′-kinase (PI3-K), remained in the brain, especially in the hypothalamus, regulating growth,1,12 although it is unknown whether the hypothalamic insulin system may interact with the GHRH (growth hormone-releasing hormone)-GH (growth hormone)-IGF (insulin-like growth factor) system. Therefore, the action of insulin to regulate development, growth, or reproduction is more ancient that its action to regulate blood glucose levels1. In addition, incretin hormones such as glucagon-like peptide 1(GLP-1) or glucose-dependent insulinotropic peptide (GIP) have attained their ability to stimulate insulin from pancreatic beta cells as a fine-tuning mechanism of blood glucose levels.1,13 In ancient times, insulin may have acted to shift the usage of metabolic resources from survival to growth or reproduction, that is, a change in selection from K-selection to r-selection.2 Therefore, insulin resistance may have some advantage in a poor environment by shifting metabolic resources from growth or reproduction to survival.
Figure 1.
Insulin and shift between survival and growth or reproduction.
Figure 2.
Insulin/IGF-1 signal and SIRT(sirtuin)/stress response depending on the environment state.
From Stearns SC, Koella JC. Evolution in Health and Disease. 2nd ed. Oxford University Press; 2008 with modifications.
Figure 3.
Evolution of insulin signaling system.
Abbreviations: GI, gastrointestinal tract; IGF, insulin-like growth factor.
Second, insulin resistance in a tissue such as skeletal muscle allows the body to shift its priorities of glucose allocation away from the peripheral tissues and toward the fragile and energy-demanding brain10 (Fig. 4). During states associated with negative energy balance, such as starvation, infection, or trauma, insulin resistance is triggered, and free fatty acids (FFA) are mobilized from adipose tissue, which induce insulin resistance in the liver and muscle. Adipose tissue also secretes proinflammatory cytokines, further causing insulin resistance in the liver.10 These mechanisms may help to spare glucose for the brain in a poor environment.
Figure 4.
Brain protection hypothesis.
From Muhlenbein MP, editor. Human Evolutionary Biology. Cambridge, UK: Cambridge University Press; 2010 with modifications.
In summary, in ancient times at least, insulin resistance may have had some advantage from an evolutionary perspective. In this context, insulin resistance is one of the mismatches between environmental and evolutionary changes.1,2–4,14
Footnotes
Author Contributions
Conceived and designed the experiments: HK. Analysed the data: HK. Wrote the first draft of the manuscript: HK. Contributed to the writing of the manuscript: HK. Agree with manuscript results and conclusions: HK. Jointly developed the structure and arguments for the paper: HK. Made critical revisions and approved final version: HK. All authors reviewed and approved of the final manuscript.
Funding
Author(s) disclose no funding sources.
Competing Interests
HK has received a consulting fee from MSD and NovoNordisk, and has received payment for speaking from Daiichi-Sankyo Co., Astellas Co., Dainihon-Sumitomo Co. His institution has received grants from NovoNordisk and Eli Lilly.
Disclosures and Ethics
As a requirement of publication author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.
References
- 1.Imura H. Understanding of Obesity Diabetes and Life Span from the Viewpoint of Evolutionary Medicine [in Japanese] Iwanami Book Co; 2008. [Google Scholar]
- 2.Trevathan WR, Smith EO, McKenna JJ, editors. Evolutionary Medicine and Health: New Perspectives. New York; NY: Oxford University Press; 2008. [Google Scholar]
- 3.Cochran G, Harpending H. The 10,000 Year Explosion: How Civilization Accelerated Human Evolution. New York: Basic Books; 2009. [Google Scholar]
- 4.Gluckman P, Beedle A, Hanson M. Principles of Evolutionary Medicine. Oxford University Press; 2009. [Google Scholar]
- 5.Poer ML, Schulkin J. The Evolution of Obesity. Baltimore, MD: The Johns Hopkins University Press; 2009. [Google Scholar]
- 6.Cartwright J. Evolution and Human Behavior. 2nd ed. Cambridge, MA: The MIT Press; 2008. [Google Scholar]
- 7.Stearns SC, Koella JC. Evolution in Health and Disease. 2nd ed. Oxford University Press; 2008. [Google Scholar]
- 8.Flatt T, Heyland A. Mechanisms of Life History Evolution: The Genetics and Physiology of Life History Traits and Trade-offs. Oxford University Press; 2011. [Google Scholar]
- 9.Gilbert SF, Epel D. Ecological Developmental Biology: Integrating Epigenetics, Medicine, and Evolution. Sunderland, MA: Sinauer Associates; 2009. [Google Scholar]
- 10.Muhlenbein MP, editor. Human Evolutionary Biology. Cambridge, UK: Cambridge University Press; 2011. [Google Scholar]
- 11.Stearns SC, Koella JC. Evolution in Health and Disease. 2nd ed. Oxford University Press; 2008. [Google Scholar]
- 12.Koshiyama H, Honjo S, Hamamoto Y, Wada Y, Ikeda H. Hypothalamic pathogenesis of type 2 diabetes. Medical Hypotheses. 2006;67:307–10. doi: 10.1016/j.mehy.2006.02.033. [DOI] [PubMed] [Google Scholar]
- 13.Kawasaki Y, Hamamoto Y, Koshiyama H. Minireview. Species-specific Actions of Incretin: from the Evolutionary Perspective. Japanese Clinical Medicine. 2010;1:5–11. doi: 10.4137/JCM.S5915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Koshiyama H, Ogawa Y, Tanaka K, Tanaka I. Integrated network systems and evolutionary developmental endocrinology. Medical Hypotheses. 2010;74:132–8. doi: 10.1016/j.mehy.2009.07.028. [DOI] [PubMed] [Google Scholar]
- 15.Koshiyama H. Integrated Network Systems and Evolutionary Developmental Endocrinology [in Japanese] Mihara-Igaku-Sya Co; 2011. [DOI] [PubMed] [Google Scholar]