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Variation in the NAT2 gene is associated with insulin resistance by affecting insulin sensitivity. Specifically, it is believed that the rs1208 loci near the NAT2 gene plays a role in insulin resistance. One study showed that when the expression of the NAT1 gene, the mouse equivalent of NAT2, is reduced there was a decrease in insulin stimulated glucose uptake and therefore decreases insulin sensitivity.  Further research has shown that loci near the GCKR and IGFI genes are linked to insulin resistance. Several other loci have also been determined to be associated with insulin insensitivity. These loci however, are estimated to only account for 25-44% of the genetic component of insulin resistance. [1]


TNF-α has been found in increased amounts in obese patients. Due to its effects on adipocytes it is possible that excessive TNF-α is one of several factors that leads to insulin resistance. TNF-α can inhibit lipogenesis, promote lipolysis, disrupt insulin signaling, and reduce the expression of GLUT4.[2] Animal studies have tested the theory by reducing the expression of TNF-α and its receptor in obese animals.[3] Beneficial results were found in some studies, supporting the idea that TNF-α plays a role in insulin resistance.


Another factor that may promote insulin resistance is Leptin, a hormone produced from the ob gene and adipocytes.[4] Its physiological role is to regulate hunger by alerting the body when it is full.[5] From an adaptation perspective, it is possible that leptin resistance was favorable for survival during periods when food was scarce.[5] Today however studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance.[6] Leptin replacement in mice with obesity and diabetes has been found to quickly decrease glucose and insulin levels and can affect insulin sensitivity.[7] Further research into the molecular mechanisms of these effects would be beneficial for increased understanding.[8]


Adaptive Mechanism[edit]

There is some prevailing thought that insulin resistance can be an evolutionary adaptation. In 1962 James Neel proposed his Thrifty Gene Hypothesis.  

This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 Diabetes, these phenotypes should be selected against.[9] Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population.[10]

Neel Postulates that originally in times of increased famine in ancient humans ancestors, that genes conferring a mechanism for increased glucose storage would be advantageous. In the modern environment today however this is not the case[9].

Evidence is contradictory to Neel in studies of the Pima Indians, which indicate that the people with higher insulin sensitives tended to weigh the most and conversely people with insulin resistance tended to weigh less on average in this demographic. [11]

Modern hypotheses suggest that insulin metabolism is a socio-ecological adaptation with insulin being the means for differentiating energy allocation to various components of the body and insulin sensitivity an adaptation to manipulate where the energy is diverted to. The Behavioral Switch Hypothesis posits that insulin resistance results in two methods to alter reproductive strategies and behavioral methods.[12] The two strategies are coined as “r to K” and “soldier to diplomat.” The r to K strategy involves diverting insulin via placenta to the fetus. This has demonstrated weight gain in the fetus, but not the mother indicating a method of increased parental investment (K strategy).[12] In the “soldier to diplomat” the insensitivity of skeletal muscle to insulin could divert the glucose to the brain, which doesn’t require insulin receptors. This has shown increased in cognitive development across various studies. [12]

See also[edit]

References[edit]

  1. ^ Brown, Audrey E.; Walker, Mark (2016). "Genetics of Insulin Resistance and the Metabolic Syndrome". Current Cardiology Reports. 18. doi:10.1007/s11886-016-0755-4. ISSN 1523-3782. PMC 4911377. PMID 27312935.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ Spiegelman, Bruce; Peraldi, Pascal (1998-05-01). "TNF-α and insulin resistance: Summary and future prospects". Molecular and Cellular Biochemistry. 182 (1–2): 169–175. doi:10.1023/A:1006865715292. ISSN 1573-4919.
  3. ^ Hotamisligil, G. S. (1999-6). "The role of TNFalpha and TNF receptors in obesity and insulin resistance". Journal of Internal Medicine. 245 (6): 621–625. ISSN 0954-6820. PMID 10395191. {{cite journal}}: Check date values in: |date= (help)
  4. ^ Friedman, J. M. (2000-04-06). "Obesity in the new millennium". Nature. 404 (6778): 632–634. doi:10.1038/35007504. ISSN 0028-0836. PMID 10766249.
  5. ^ a b Flier, J. S. (1998-5). "Clinical review 94: What's in a name? In search of leptin's physiologic role". The Journal of Clinical Endocrinology and Metabolism. 83 (5): 1407–1413. doi:10.1210/jcem.83.5.4779. ISSN 0021-972X. PMID 9589630. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Elmquist, J. K.; Maratos-Flier, E.; Saper, C. B.; Flier, J. S. (1998-10). "Unraveling the central nervous system pathways underlying responses to leptin". Nature Neuroscience. 1 (6): 445–450. doi:10.1038/2164. ISSN 1097-6256. PMID 10196541. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Halaas, J. L.; Gajiwala, K. S.; Maffei, M.; Cohen, S. L.; Chait, B. T.; Rabinowitz, D.; Lallone, R. L.; Burley, S. K.; Friedman, J. M. (1995-07-28). "Weight-reducing effects of the plasma protein encoded by the obese gene". Science (New York, N.Y.). 269 (5223): 543–546. ISSN 0036-8075. PMID 7624777.
  8. ^ Flier, Jeffrey S.; Kahn, Barbara B. (2000-08-15). "Obesity and insulin resistance". The Journal of Clinical Investigation. 106 (4): 473–481. doi:10.1172/JCI10842. ISSN 0021-9738. PMID 10953022.
  9. ^ a b Neel, James V. (1962-12). "Diabetes Mellitus: A "Thrifty" Genotype Rendered Detrimental by "Progress"?". American Journal of Human Genetics. 14 (4): 353–362. ISSN 0002-9297. PMC 1932342. PMID 13937884. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  10. ^ "Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes". Journal of Diabetes and its Complications. 21 (6): 363–370. 2007-11-01. doi:10.1016/j.jdiacomp.2006.07.005. ISSN 1056-8727.
  11. ^ Swinburn, B A; Nyomba, B L; Saad, M F; Zurlo, F; Raz, I; Knowler, W C; Lillioja, S; Bogardus, C; Ravussin, E (1991-7). "Insulin resistance associated with lower rates of weight gain in Pima Indians". Journal of Clinical Investigation. 88 (1): 168–173. ISSN 0021-9738. PMID 2056116. {{cite journal}}: Check date values in: |date= (help)
  12. ^ a b c Watve, Milind G.; Yajnik, Chittaranjan S. (2007-04-17). "Evolutionary origins of insulin resistance: a behavioral switch hypothesis". BMC evolutionary biology. 7: 61. doi:10.1186/1471-2148-7-61. ISSN 1471-2148. PMC 1868084. PMID 17437648.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

Further reading[edit]

External links[edit]

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Category:Diabetes

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