Insulin resistance has no single known cause. Researchers don’t fully understand why it develops, but they have identified many factors that raise the risk (NIDDK). These factors can act together, and the combination differs from person to person (James et al. 2021).
Excess body fat plays a role for many people, but body size alone doesn’t explain who develops insulin resistance. Where fat is stored matters, and so do physical activity, sleep, certain medicines, hormonal changes, age, and genetics. Some of these links have been tested in experiments, while others come only from observing people.
Why there is no single cause
Insulin resistance has no single universal cause. The National Institute of Diabetes and Digestive and Kidney Diseases presents insulin resistance in terms of risk factors and states that scientists do not fully understand why it develops (NIDDK). Reviews of the underlying biology reach a similar conclusion: insulin resistance is not one disease with one origin, but a shared endpoint reached through several different routes (James et al. 2021).
Those routes fall into recognizable groups. Some are biological, such as how much fat a person stores and where it ends up. Some are environmental and behavioral, such as physical activity and sleep. Some are medication-related. Some are hormonal, including normal states such as pregnancy. Some are inherited. Because several of these can operate at once, and in different combinations in different people, researchers describe insulin resistance as multifactorial.
Excess body fat contributes to insulin resistance in many people, but it doesn’t explain every case. People at a normal weight can develop insulin resistance, and some people with a lot of body fat keep fairly normal insulin sensitivity. Researchers generally see insulin resistance as the result of several processes interacting, rather than one trigger (Johnson & Olefsky 2013). So there’s usually no single reason one person develops it, and no single risk factor has to be present. How insulin resistance develops in the body’s tissues is covered in the overview of insulin resistance.
Body fat and where it is stored
Body fat contributes to insulin resistance, but the location of the fat seems to matter more than total body size. Visceral fat sits deep inside the abdomen and surrounds the organs. Ectopic fat is fat stored inside tissues that are not designed to store it, such as the liver and skeletal muscle. Neither is measured well by weight or BMI alone (Levelt et al. 2016).
Waist circumference is often used as a stand-in for visceral fat, but it is imperfect: a waist measurement includes subcutaneous fat as well as deeper visceral fat, and the two are not metabolically interchangeable. Reviews of insulin-resistance biology describe adipose tissue dysfunction and the spillover of lipid into non-fat tissues as central features of how metabolic risk develops, rather than fat mass alone (James et al. 2021).
Liver fat illustrates the point. In a cross-sectional study of 113 non-obese, non-diabetic Caucasian adults, researchers measured liver fat by 3T proton magnetic resonance spectroscopy and estimated insulin resistance using HOMA-IR; hepatic triglyceride content tracked insulin resistance more closely than BMI or waist circumference (r=0.76; p<0.0001) (Gonzalez-Cantero et al. 2018). Three limitations accompany that number. The study was cross-sectional, so it cannot establish that liver fat caused the insulin resistance or that the sequence ran in that direction. HOMA-IR is a calculated surrogate, not a direct clamp measurement of insulin action. And the participants were non-obese, non-diabetic, and of a single ancestry, so the correlation should not be read as universal.
When liver fat accumulates to the level of a diagnosed condition, it is called metabolic dysfunction-associated steatotic liver disease (MASLD); older studies called it NAFLD (AASLD 2024). For readers with a normal BMI who have been told they may be insulin resistant, this body of work offers a plain explanation: standard body-size measures were never designed to detect fat stored inside the liver or muscle.
Daily patterns
Everyday patterns can change insulin sensitivity independently of weight change, and two of them have been tested experimentally rather than only observed: physical activity and sleep duration. Diet is also part of daily patterns and contributes to fat accumulation and metabolic risk, but food specifics are outside the scope of this page. The value of the experiments below is that they deliberately manipulated one exposure, which observational studies cannot do.
Physical inactivity
Being less active can lower insulin sensitivity. In one experiment, 10 healthy young men cut their daily steps from about 10,500 to about 1,300 for two weeks. Afterward, their insulin sensitivity had dropped by 17%, measured with the most accurate research method available (Krogh-Madsen et al. 2010). The study was small, short, and included only young men, but it shows that a change in activity alone can make a measurable difference within weeks.
Sleep
Cutting sleep short can lower insulin sensitivity. In a small trial, 9 postmenopausal women were tested after four nights of restricted sleep and after four nights of their usual sleep. After restricted sleep, their insulin sensitivity was 20% lower on one measure and 12% lower on another (Singh et al. 2023). The trial showed that losing sleep can harm insulin sensitivity. It didn’t test whether sleeping more improves it.
The link may also run the other way. In a study that followed adults for 10 years, those with insulin resistance at the start were more likely to report sleep problems later (Podlipskyte et al. 2022).
Medical contributors
Some insulin resistance comes from medical factors. Certain medicines can lower insulin sensitivity in some people, and several hormonal conditions can too. Pregnancy also reduces insulin sensitivity, as a normal part of how the body changes.
Medications
Certain medicines can worsen insulin sensitivity or blood sugar control in some people. The National Institute of Diabetes and Digestive and Kidney Diseases lists several, including glucocorticoids (steroid medicines), some antipsychotics, and some medicines used to treat HIV (NIDDK). Other drug classes have also been linked to insulin resistance, though the evidence behind them varies (Freeman & Pennings).
These medicines don’t cause insulin resistance in everyone who takes them. They’re prescribed for serious conditions, and whether to use them is a decision for the prescribing clinician. For someone taking one long term, the medicine may be part of the explanation for their insulin resistance.
Hormonal conditions
Several hormonal conditions involve insulin resistance. One is polycystic ovary syndrome (PCOS), recently renamed polyendocrine metabolic ovarian syndrome (PMOS). Insulin resistance is a recognized feature of PCOS, and the new name was chosen through a global consensus process to better reflect the condition’s metabolic and hormonal nature (Teede et al. 2026; Teede et al. 2023).
Excess cortisol, as occurs in Cushing syndrome, can also promote insulin resistance (NIDDK Symptoms & Causes of Diabetes).
Pregnancy is different. Insulin sensitivity normally decreases as pregnancy progresses, and this is expected, not a disorder (Hodson et al. 2013). This normal change is not the same as gestational diabetes and doesn’t mean a person has it.
Genetics, family history, and age
Genes play a part in insulin resistance, but they don’t decide the outcome. Insulin resistance runs in families, and genetic studies support an inherited tendency (James et al. 2021). No single common gene explains typical insulin resistance. Instead, many gene variants each seem to add a small amount of risk, and they interact with the other factors on this page. Having a parent or sibling with insulin resistance or diabetes raises a person’s risk, but it doesn’t mean they will develop it.
Risk also rises with age (NIDDK), but insulin resistance is not an inevitable part of getting older.
A few rare conditions work differently. Type A insulin resistance syndrome is a genetic disorder caused by changes in the insulin receptor gene (MedlinePlus Genetics; Semple et al. 2011). Type B insulin resistance is not inherited. It’s an autoimmune disorder in which the immune system attacks the insulin receptor (Lee et al. 2026). Both are far rarer and more severe than common insulin resistance, and a family history of type 2 diabetes doesn’t point to either.
What has held up, what hasn’t, and what remains disputed
The evidence on causes of insulin resistance is uneven. Some conclusions are stable, some popular claims outrun their data, and at least one central question about liver fat is genuinely unresolved.
Held up. No single cause accounts for every case of insulin resistance (James et al. 2021). Excess adiposity, physical inactivity, certain medicines, hormonal states, increasing age, and inherited susceptibility can each contribute, in varying combinations. Controlled experiments support a causal direction for two exposures specifically: two weeks of sharply reduced ambulatory activity lowered clamp-measured insulin sensitivity by 17% in 10 healthy young men (Krogh-Madsen et al. 2010), and four nights of sleep restriction lowered clamp glucose infusion rates in the 9 postmenopausal women analyzed in a randomized crossover trial (Singh et al. 2023). Separately, in a cross-sectional study of 113 non-obese, non-diabetic Caucasian adults, hepatic triglyceride content was more strongly associated with HOMA-IR than BMI or waist circumference (Gonzalez-Cantero et al. 2018). That is prediction and association, not demonstrated causation.
Hasn’t held up, or at least not yet. Broad claims that everyday psychological stress causes insulin resistance are stronger than the evidence supports. Stress hormones affect glucose metabolism, and excess cortisol in Cushing syndrome can promote insulin resistance (NIDDK Symptoms & Causes of Diabetes), but biological plausibility is not proof that ordinary life stress produces insulin resistance on its own. When researchers isolate a specific exposure experimentally, such as sleep restriction, the evidence is considerably stronger (Singh et al. 2023). Low-grade inflammation and gut microbiota are proposed contributors still under active investigation, not established stand-alone causes (Johnson & Olefsky 2013).
Disputed: liver fat and insulin action. A common genetic variant provides a natural experiment. In a genome-wide association study within the Dallas Heart Study, with n=2,111 in the liver-fat scan, the PNPLA3 variant rs738409[G] (I148M) was strongly associated with hepatic fat content. That cross-sectional study also described a dissociation between hepatic triglyceride content and BMI and insulin-resistance indices (Romeo et al. 2008). One proposed explanation is that differences in specific lipid species, particularly diacylglycerol FA18:1, rather than total stored triglyceride, help account for preserved insulin sensitivity in I148M carriers (Franko et al. 2018).
The reasonable reading is that total stored liver triglyceride is not sufficient on its own to explain insulin resistance, and that which lipids accumulate and what signals they trigger may matter more than bulk quantity. This does not mean liver fat is irrelevant. Evidence suggests otherwise: in a normoglycemic Taiwanese population, the I148M polymorphism was associated with fasting insulin and HOMA-IR, as well as NAFLD (Wang et al. 2011). The literature is inconsistent, and population differences may explain why.
Disputed: genetics versus environment. Both inherited susceptibility and acquired exposures matter, and no credible method assigns a percentage split to an individual. Claims that insulin resistance is “mostly genetic” or “mostly lifestyle” describe populations at best, and typically overstate what can be measured in one person.
Conclusion
Insulin resistance usually develops from several factors acting together, not from one cause. Where the body stores fat matters, not just how much fat there is, which may help explain why some people at a normal weight develop insulin resistance. Being less active and sleeping too little can both lower insulin sensitivity. Certain medicines, hormonal changes including normal pregnancy, age, and genetics can also contribute, though genes and age raise risk without determining it. Whether fat in the liver directly causes insulin resistance is still an open question.
Frequently asked questions
Is insulin resistance genetic?
Partly. Genetic susceptibility contributes, and insulin resistance clusters in families, but no single gene explains common insulin resistance, and no variant identified so far accounts for typical cases (James et al. 2021). Inherited risk shifts probability; it does not determine your outcome, and it interacts with activity, sleep, medicines, and hormonal states.
Does stress cause insulin resistance?
The broad claim that everyday psychological stress causes insulin resistance is stronger than the current evidence supports. The hormonal pathway is biologically plausible, and pathological cortisol excess in Cushing syndrome can promote insulin resistance (NIDDK Symptoms & Causes of Diabetes). In a randomized crossover trial, four nights of restricted sleep reduced clamp-measured insulin sensitivity in the 9 postmenopausal women analyzed (Singh et al. 2023). But that does not establish psychological stress by itself as a universal cause of insulin resistance in the general population.
Does insulin resistance get worse with age?
Risk rises with age. Increasing age is listed among the risk factors for insulin resistance and prediabetes (NIDDK). That statement reflects population-level probability, not a guarantee for any individual. Aging does not make insulin resistance inevitable, and age sits alongside other contributors rather than overriding them.
Does fatty liver cause insulin resistance, or the other way around?
It’s not yet clear, and the relationship may run in both directions. Liver fat and insulin resistance are strongly associated: in 113 non-obese, non-diabetic Caucasian adults, hepatic triglyceride content measured by 3T proton magnetic resonance spectroscopy correlated with HOMA-IR at r=0.76 (p<0.0001), more closely than BMI or waist circumference did (Gonzalez-Cantero et al. 2018). Because that study measured everything at one point in time, it cannot tell you which came first.
Genetics complicate the simple story. The PNPLA3 I148M variant is strongly associated with hepatic fat, yet dissociation between hepatic triglyceride content and insulin-resistance indices has been described (Romeo et al. 2008), with lipid-species differences proposed as an explanation (Franko et al. 2018). Contrary findings exist in a normoglycemic Taiwanese population (Wang et al. 2011). Historical studies use NAFLD; current terminology is MASLD.
References
- National Institute of Diabetes and Digestive and Kidney Diseases. Insulin Resistance & Prediabetes. National Institutes of Health. Last reviewed March 2025. Accessed September 27, 2026.
- James DE, Stöckli J, Birnbaum MJ. The aetiology and molecular landscape of insulin resistance. Nature Reviews Molecular Cell Biology. 2021;22(11):751-771. doi:10.1038/s41580-021-00390-6
- Johnson AMF, Olefsky JM. The origins and drivers of insulin resistance. Cell. 2013;152(4):673-684. doi:10.1016/j.cell.2013.01.041
- Levelt E, Pavlides M, Banerjee R, et al. Ectopic and Visceral Fat Deposition in Lean and Obese Patients With Type 2 Diabetes. Journal of the American College of Cardiology. 2016;68(1):53-63. doi:10.1016/j.jacc.2016.03.597
- Gonzalez-Cantero J, et al. Insulin resistance in lean and overweight non-diabetic Caucasian adults: Study of its relationship with liver triglyceride content, waist circumference and BMI. PLOS ONE. 2018;13(2). doi:10.1371/journal.pone.0192663
- American Association for the Study of Liver Diseases. New MASLD nomenclature. Accessed September 9, 2026.
- Krogh-Madsen R, et al. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity. Journal of Applied Physiology. 2010;108(5):1034-1040. doi:10.1152/japplphysiol.00977.2009
- Singh P, et al. Effect of sleep restriction on insulin sensitivity and energy metabolism in postmenopausal women: A randomized crossover trial. Obesity. 2023;31(5):1204-1215. doi:10.1002/oby.23739. PMID: 36998155.
- Podlipskyte A, et al. Association of Insulin Resistance With Cardiovascular Risk Factors and Sleep Complaints: A 10-Year Follow-Up. Frontiers in Public Health. 2022;10:848284. doi:10.3389/fpubh.2022.848284
- Freeman AM, Pennings N. Insulin Resistance. StatPearls. NCBI Bookshelf NBK507839
- Teede HJ, et al. Polyendocrine metabolic ovarian syndrome, the new name for polycystic ovary syndrome: a multistep global consensus process. The Lancet. 2026;407(10545):2329-2339. doi:10.1016/S0140-6736(26)00717-8
- Teede HJ, et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Journal of Clinical Endocrinology & Metabolism. 2023;108(10):2447-2469. doi:10.1210/clinem/dgad463
- National Institute of Diabetes and Digestive and Kidney Diseases. Symptoms & Causes of Diabetes. National Institutes of Health. Last reviewed October 2024. Accessed September 11, 2026.
- Hodson K, et al. Mechanism of insulin resistance in normal pregnancy. Hormone and Metabolic Research. 2013;45(8):567-571. doi:10.1055/s-0033-1337988
- National Library of Medicine. Type A insulin resistance syndrome. MedlinePlus Genetics. Updated December 1, 2014. Accessed September 11, 2026.
- Semple RK, et al. Genetic syndromes of severe insulin resistance. Endocrine Reviews. 2011;32(4):498-514. doi:10.1210/er.2010-0020
- Lee JE, et al. Insulin Receptor Family Autoantibodies in Patients with Type B Insulin Resistance. Journal of Clinical Endocrinology & Metabolism. 2026;111(6). doi:10.1210/clinem/dgaf692
- Romeo S, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics. 2008;40(12):1461-1465. doi:10.1038/ng.257
- Franko A, et al. Dissociation of Fatty Liver and Insulin Resistance in I148M PNPLA3 Carriers: Differences in Diacylglycerol (DAG) FA18:1 Lipid Species as a Possible Explanation. Nutrients. 2018;10(9):1314. doi:10.3390/nu10091314
- Wang CW, et al. The PNPLA3 I148M polymorphism is associated with insulin resistance and nonalcoholic fatty liver disease in a normoglycaemic population. Liver International. 2011;31(9):1326-1331. doi:10.1111/j.1478-3231.2011.02526.x