Insulin resistance: An adaptive mechanism becomes maladaptive in the current environment—An evolutionary perspective
Abstract
Human survival has relied upon the ability to withstand starvation through energy storage, the capacity to fight off infection by a proinflammatory immune response, and the ability to cope with physical stressors by an adaptive stress response. Energy storage, mainly as glycogen in liver and triglycerides in adipose tissue, is regulated by the anabolic actions of insulin. On the other hand, mobilization of stored energy during infection, trauma or stress is served by the temporary inhibition of insulin action (insulin resistance) in target tissues by proinflammatory cytokines and stress hormones. In the current environment, high energy intake, low physical activity, and chronic stress favor the storage of surplus fat in adipose tissue depots that far exceeds their storage capacity and liporegulation. Lipid overload in central fat depots initiates an inflammatory response and adipocyte dysfunction with resultant low-grade systemic inflammation and lipid overflow to peripheral tissues. In turn, proinflammatory cytokines and non-oxidized lipid metabolites, accumulated in liver and muscle cells, activate the mechanism of insulin resistance as would occur in the case of infection or stress. The same factors together with the ensuing insulin resistance further contribute to pancreatic β-cell dysfunction and ultimately to type 2 diabetes and cardiovascular disease. The present review supports the hypothesis that insulin resistance evolved as a physiological adaptive mechanism in human survival and that the same mechanism is inappropriately activated on a chronic basis in the current environment, leading to the manifestations of the metabolic syndrome.
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All organisms have physiological adaptive responses to deal with changing environmental conditions and the varying demands of internal physiological states.
“All organisms have physiological adaptive responses to deal with changing environmental conditions (starvation, fasting, physical threat, stress and infection) and the varying demands of internal physiological states (pregnancy, lactation and adolescence) [14,65].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
Multiple lines of evidence support the maladaptive response of human populations to rapidly changing nutritional, physical, psychological and cultural environments in the modern world.
“Multiple lines of evidence support the maladaptive response of human populations to rapidly changing nutritional, physical, psychological and cultural environments, in the modern world [5,11,14,75].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
Details of the mechanisms underlying the proposed adaptive survival advantages of insulin resistance, hyperandrogenism, enhanced energy storage and subfertility have been obtained from paleolithic records, animal models and human populations exposed to adverse environmental conditions.
“Details of the mechanisms underlying the proposed adaptive survival advantages of IR, hyperandrogenism, enhanced energy storage and subfertility have been obtained from paleolithic records, animal models and human populations exposed to adverse environmental conditions such as war and famine-inflicted starvation [14,16,62,63].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
Theories of evolutionary mismatch have been advanced to explain all of the cluster of metabolic diseases associated with PCOS and follow the same set of basic principles and explanations.
“Theories of evolutionary mismatch have also been advanced to explain all of the cluster of metabolic diseases associated with PCOS (type 2 diabetes, metabolic syndrome, NAFLD and cardiovascular disease) and follow the same set of basic principles and explanations [14,76].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
PCOS may be viewed as a conditional phenotype where a specific set of conditions has unmasked normally unexpressed or partly expressed genetic pathways, which then provide a survival advantage under certain environmental conditions.
“One common theme is that PCOS may be viewed as a “conditional phenotype” where a specific set of conditions has unmasked normally unexpressed or partly expressed genetic pathways, which then provide a survival advantage under certain environmental conditions [14,16].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
Ancient genetic polymorphisms that were aligned with the environment of that era resulted in an adaptive survival advantage in offspring in ancestral populations.
“A unified evolutionary theory of the pathogenesis of PCOS proposes that ancient genetic polymorphisms that were aligned with the environment of that era, resulted in an adaptive survival advantage in offspring in ancestral populations [14,15,16,28].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
The susceptibility alleles may be activated or functionally enhanced by a range of maternal and environmental factors.
“In addition, the susceptibility alleles may be “activated” or “functionally enhanced” by a range of maternal and environmental factors, as is usually presumed to be the case in PCOS [5,14,102].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
In evolutionary terms, women with a PCOS metabolic phenotype would have increased survival chances during times of environmental or physiological demand for altered energy metabolism, but be more vulnerable to the pathological effects of insulin resistance when exposed to modern lifestyle factors.
“In evolutionary terms, women with a PCOS metabolic phenotype would have increased survival chances during times of environmental or physiological demand for altered energy metabolism, but be more vulnerable to the pathological effects of IR when exposed to modern lifestyle factors [14,17,159].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
This switch allows free fatty acids to be mobilized from adipose tissue, converted to glucose in the liver and released into the circulation, maintaining blood sugar levels for vital metabolic processes and brain function.
“This allows free fatty acids to be mobilized from adipose tissue, which are then converted to glucose in the liver and released into the circulation [161]. As a result of this metabolic change, blood sugar levels are maintained for vital metabolic processes and brain function [14].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
Lower body SAT has a metabolic program that makes it less readily available for every-day energy needs, but it can be mobilized during pregnancy and lactation.
“Lower body SAT has a metabolic program that makes it less readily available for every-day energy needs, but it can be mobilized during pregnancy and lactation [14].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
The lower body distribution of SAT in women is hypothesized to have evolved to provide additional calorie storage for pregnancy and lactation and is unique to human females.
“The lower body distribution of SAT in women is hypothesized to have evolved to provide additional calorie storage for pregnancy and lactation and is unique to human females [14].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [14]
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- Authors
- Tsatsoulis, A., Mantzaris, M. D., Bellou, S., & Andrikoula, M.
- Affiliations
- University of Ioannina (GR)
- Foundation for Research and Technology Hellas (GR)
- Corresponding author
- Tsatsoulis, Agathocles
- ORCID
- Bellou, Sofia
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 62
- Issue
- 5
- Pages
- 622-633
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W1996129886
- Cited by
- 174
- References
- 117
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 15 · 2023: 10 · 2022: 9 · 2021: 11 · 2020: 13 · 2019: 16 · 2018: 13 · 2017: 15 · 2016: 10 · 2015: 13 · 2014: 21 · 2013: 7
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- insulin resistance, evolutionary perspective, energy storage, insulin signaling, inflammatory cytokines, stress hormones, adipose tissue dysfunction, low-grade inflammation, lipid overload, beta-cell dysfunction, type 2 diabetes, cardiovascular disease, metabolic syndrome, energy balance, physical inactivity
- MeSH terms
- Adaptation, Physiological, Adipose Tissue, Animals, Environment, Biological Evolution, Humans, Insulin Resistance, Models, Biological, Stress, Physiological, Gene-Environment Interaction
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