Obesity is believed to be the major cause of insulin resistance, although many other obesity-independent signals are shown to affect insulin sensitivity.
We address the degree to which variation in insulin resistance is explained by morphometric and biochemical measures of obesity.
PubMed and Google Scholar were searched for epidemiological studies published between 1994 and 2015 that report correlations between at least one measure of obesity and that of insulin resistance.
A total of 63 studies satisfied inclusion criteria. Frequency distribution of coefficients of determination between morphometric measures of obesity and insulin resistance was skewed with the mode being less than 10%, class and median being 17.3%. Plasma leptin concentration, but not plasma non-esterified fatty acid level, was better correlated with insulin resistance, the median variance explained being 33.29%. Morphometric measures alone had a median variance explained of 16%. Ethnicity explained part of the variance across studies with the correlation being significantly poorer in Asians.
The extremely limited predictive power of morphometric and biochemical measures of obesity suggests that more research needs to focus on the obesity-independent signals that affect insulin sensitivity as well as leptin expression.
Obesity is currently believed to be the major cause of type 2 diabetes mellitus (T2DM) characterised by insulin resistance. Among the currently perceived risk factors for T2DM, overweight and obesity are strongest.
Obese and metabolically normal individuals exist
Apart from adipocyte-derived signals, a number of other signals have been shown to affect insulin sensitivity partly or completely independent of obesity. They include autonomic and other neuronal signals,
We address a part of this broader question by asking how much of the variance in measures of insulin resistance (i.e. fasting plasma insulin, homeostatic model assessment – insulin resistance/insulin sensitivity (HOMA – IR/IS), hyperinsulinaemic clamp and frequently sampled intravenous glucose tolerance test) is explained by obesity indices, namely body mass index (BMI), waist–hip ratio (WHR), waist circumference (WC), total fat (TF), plasma non-esterified fatty acids (NEFA) and plasma leptin, in epidemiological studies published between 1994 and 2015. The systematic review was registered with the International Prospective Register of Systematic Reviews (registration number CRD42016047499). The review design followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
We conducted a literature search using PubMed (Medline) and Google Scholar for studies examining correlation between obesity and insulin resistance or risk of type 2 diabetes published between 1994 and 2015. The key words used in combination for the search included: Type 2 diabetes mellitus (T2DM), Homeostatic model assessment – insulin resistance/ insulin sensitivity (HOMA – IR/IS), Frequently sampled intravenous glucose tolerance test (FSIVGTT), hyperinsulinaemic clamp, obesity, waist circumference (WC), non-esterified fatty acid (NEFA), leptin, waist-hip ratio (WHR), body mass index (BMI) and total fat (TF). The key word combinations used for search included (1) obesity or one of the specific measures of obesity, (2) insulin resistance or one of the specific measures of insulin resistance and (3) the word ‘correlation’. We did not include pro-inflammatory cytokines in the study. Although adipocytes are known to secrete cytokines, they are not specific to adipose tissue. Because many different types of cells secrete pro-inflammatory cytokines, it would be difficult to draw clear-cut inferences from their correlations. Adiponectin is more specific to adipose tissue; however, its plasma level is not directly proportional to obesity. Therefore, we did not consider adiponectin as a surrogate of obesity.
The number of patients per study ranged from 21 to 4800. The studies covered different age groups, the net range being from 2 to 95 years.
Papers reporting Pearson’s correlation, Spearman’s correlation or multiple regression including one or more measures of obesity and one or more measures of insulin resistance were included in the meta-analysis. Studies that divided the population in groups such as tertiles or quartiles and used group comparison statistics were excluded because different studies make different number of groups making comparisons across studies difficult. Two researchers screened all papers identified in the initial search, based on the inclusion criteria. In addition, the corresponding authors of 35 studies that did not report any correlations between measures of obesity and insulin resistance but had measured these parameters in a population were contacted to request access to raw data from which we could have calculated the required statistics. Four data sets coming from two research groups could be accessed, from which we could obtain 16 relevant correlations.
Many publications reported more than one correlation based on different measures of obesity and insulin resistance or based on distinct patient groups separated by gender, treatment, ethnicity, etc. As one approach to analysis, every correlation between a measure of obesity and that of insulin resistance was treated as an independent data point. In an alternative approach, to avoid pseudo-replication, we also analysed the data taking only the best correlation from each study. The coefficient of determination (
Sixty-three studies were identified using the inclusion and exclusion criteria (see Appendix 1 for the complete list), which gave us 164 correlations between obesity measures and insulin resistance measures. In 10 studies, variance explained was reported, and
The 164
Frequency distribution of
Among various obesity-related parameters, leptin had better
Not all studies report
Of 164
The age group under study had a significant effect on the strength of the correlations.
Variance in insulin resistance explained by obesity is dependent upon age and age range of the study group. (a) Correlation between mid-point of age range and
The frequency distribution of
Among the various measures of obesity, all morphometric parameters performed poorly. The notion that central obesity is better correlated with insulin resistance
It is important to note that among the studies that had not published the
Overall, in the majority of the studies, both morphometric and biochemical measures of obesity seem to explain only a small part of the variation in insulin resistance. This suggests that there can be other causal factors for insulin resistance independent of obesity. In experimental physiology, a number of signals have been demonstrated that affect insulin sensitivity independent of obesity.
Our analysis reveals the limited role of obesity and thereby highlights the importance of investigating alternative possibilities. A possible clinical implication of our finding is that obesity control will have only a limited success in preventing type 2 diabetes. More research needs to be focused on the other possible causes of insulin resistance and their importance at the clinical level. Any effort in this direction can be extremely enlightening and useful for the prevention, control and treatment of type 2 diabetes.
The authors would like to thank Manawa Diwekar, Shubhankar Kulkarni and Pramod Patil for useful comments on an earlier draft of the manuscript. They would also like to thank Raj Bhopal and others of the Newcastle Heart project, England, and Chittaranjan Yajnik and others of the Pune Maternal Nutrition study and Coronary Risk of Insulin Sensitivity in Indian Subjects, Pune, study for giving them access to their raw data and also for their useful comments on the manuscript.
The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.
H.B.V. and M.G.W. designed the study. H.B.V. did the search. H.B.V. and M.G.W. did the screening and analysis and wrote the article.
Abate N, Chandalia M, Snell P, Grundy S. Adipose Tissue Metabolites and Insulin Resistance in Nondiabetic Asian Indian Men. J Clin Endocrinol Metab. 2004 Jun;89(6):2750–5.
Ades A, Savage P, Toth M, Schneider D, Audelin M, Bunn J, Ludlow M. The influence of obesity and consequent insulin resistance on coronary risk factors in medically treated patients with coronary disease. International Journal of Obesity. 2008; 32:967–974.
Baldeweg S, Golay A, Natali A, Balkau B, Del Prato S, Coppack SW. Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR). Eur J Clin Invest. 2000 Jan;30(1):45–52.
Bhopal R, Unwin N, White M, Yallop J, Walker L, Alberti K, Harland J, Patel S, Ahmad N, Turner C. Heterogeneity of coronary heart disease risk factors in Indian, Pakistani, Bangladeshi, and European origin populations: Cross sectional study. BMJ. 1999;319:215–220.
Broussard J, Chapotot F, Abraham V, Day A, Delebecque F, Whitmore H, Tasali E. Sleep restriction increases free fatty acids in healthy men. Diabetologia. 2015; 58:791–798. DOI:10.1007/s00125-015-3500-4
Calcutt N, Jolivalt C, Fernyhough P. Growth factors as therapeutics for diabetic neuropathy. Curr Drug Targets. 2008;9(1):47–59.
Carey D, Jenkins A, Campbell L, Freund J, Chisholm D. Abdominal Fat and Insulin Resistance in Normal and Overweight Women Direct Measurements Reveal a Strong Relationship in Subjects at Both Low and High Risk of NIDDM. DIABETES. 1996;45:633–638.
Cho Y, Kang J, Hur Y, Song J, Lee K. Related Factors of Insulin Resistance in Korean Children: Adiposity and Maternal Insulin Resistance Int. J. Environ. Res. Public Health. 2011;8:4596–4607.
Contreras P, Zura M, Aguirre C, Sepúlveda A, Depix M, Mella I. The clinical estimate of adiposity is not a good predictor of insulin tissue sensitivity measured with a minimal model analysis. Rev Med Chil. 1994 Mar;122(3):241–7.
Coutinho P, Leite N, Lopes W, Rosa da Silva L, Consentino C, Araújo C, Moraes Jr F, de Jesus I, Cavaglieri C, Radominski R. Association between adiposity indicators, metabolic parameters and inflammatory markers in a sample of female adolescents. Arch Endocrinol Metab. 2015;59(4):325–334.
Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. Plasma Leptin and Insulin Relationships in Obese and Nonobese Humans. Diabetes. 1996;45(5):695–698.
Daruka K. Correlation of body fat index with insulin resistance across normal, overweight and obese individuals. Journal of Evidence based Medicine and Healthcare. 2015;23(2):3422–3426.
Fischer S, Hanefeld M, Haffner S, Fusch C, Schwanebeck U, Köhler C, Fücker K, Julius U. Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass. Acta Diabetol 2002;39(3):105–10.
Fris S, Rössner S, Norgren S, Arvidson J, Gustafsson J. Bone Marrow Transplantation, Glucose metabolism and body composition in young adults treated with TBI during childhood. 2011;46:1303–1308.
Gannar F, Cabrera L, Marzougui F, Sakly M, Attia N. Leptin, Insulin and Lipid Profiles in Obese Subjects with and without Metabolic Syndrome in the Region of Cap-Bon: Tunisia, Endocrinol Metab Synd. 2015;4:3.
García-Estévez D, Araú jo-Vilar D, Saavedra-González A, Fiestras-Janeiro G, Cabezas-Cerrato J. Analysis of the Relationship Between Body Mass Index, Insulin Resistance, and Beta-Cell Function: A Cross-Sectional Study Using the Minimal Model. Metabolism. 2004;53(11):1462–1466.
Goto M, Morita A, Goto A, Deura K, Sasaki S, Aiba N. Reduction in Adiposity, β-Cell Function, Insulin Sensitivity, and Cardiovascular Risk Factors: A Prospective Study among Japanese with Obesity. PLoS ONE. 2013;8(3):e57964.
Hattori A, Iwata A, Uemura K, Miura H, Ueda M, Tamaya T, Muraguchi M, Ohmoto Y, Iguchi A. Gender-Related Difference in Relationship between Insulin Resistance and Serum Leptin Level in Japanese Type 2 Diabetic and Non-Diabetic Subjects. Endocrine Journal. 2000;47(5):615–621.
Haupt D, Fahnestock P, Flavin K, Schweiger J, Stevens A, Hessler M, Maeda J, Yingling M, Newcomer J. Adiposity and insulin sensitivity derived from intravenous glucose tolerance tests in antipsychotic-treated patients. Neuropsychopharmacology.2007;32(12):2561–9.
Hayashi T, Boyko E, McNeely M, Leonetti D, Kahn S, Fujimoto W. Visceral Adiposity, Not Abdominal Subcutaneous Fat Area, Is Associated With an Increase in Future Insulin Resistance in Japanese Americans. Diabetes. 2008;57:1269–1275.
Henderson D,Fan X, Sharma S, Copeland P, Borba C, Freudenreich O, Cather C, Evin E, Donald D. Waist Circumference Is the Best Anthropometric Predictor for Insulin Resistance in Nondiabetic Patients with Schizophrenia Treated with Clozapine But Not Olanzapine J Psychiatr Pract. 2009 Jul;15(4):251–261.
Hettehewa L, Dharmasiri L, Ariyaratne C, Jayasinghe S, Weeraratne T, Kotapola I. Correlation between BMI and Insulin resistance in type 2 diabetes mellitus patients pioglitozone in treatment. Galle Medical Journal. 2007;12(1):18–24.
Innocent O, ThankGod O, Sandra E, Josiah I. Correlation between body mass index and blood glucose levels among some Nigerian undergraduates. HOAJ Biology. 2013;2(4):1–4.
Karpe F, Dickmann J, Frayn K. Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation. DIABETES. 2011;60:2441–2449.
Khokhar K, Sidhu S, Kaur G. Relationship between serum leptin and type 2 diabetes mellitus and their association with obesity and menopausal status. Archives of Applied Science Research. 2013;5(5):38–44.
Kiani A. Temporal Changes in Plasma Concentration of Leptin, IGF-1, Insulin and Metabolites Under Extended Fasting and Re-Feeding Conditions in Growing Lambs. Int J Endocrinol Metab. 2013:11.
Koebnick C, Roberts C, Shaibi G, Kelly L, Lane L, Toledo-Corral C, Davis C, Ventura E, Alexander K, Weigensberg M, Goran M. Adiponectin and Leptin are Independently Associated with Insulin Sensitivity, but not with Insulin Secretion or Beta-cell Function in Overweight Hispanic Adolescents. Horm Metab Res. 2008.
Krekoukia M, Nassis G, Psarra G, Skenderi K, Chrousos G, Sidossis L. Elevated total and central adiposity and low physical activity are associated with insulin resistance in children. Metabolism. 2007;56(2):206–13.
Lalia A, Dasari S, Johnson M, Robinson M, Konopka A, Distelmaier K, Port J, Glavin M, Esponda R, Nair K, Lanza I. Predictors of whole-body insulin sensitivity across ages and adiposity in adult humans. J Clin Endocrinol Metab. 2016; 101(2):626–634.
Lichnovska C, Gwozdziewiczova S, Chlup R, Hřebiček J, Lichnovska R, Gwozdziewiczova S, Chlup R, Hřebiček J. Serum leptin in the development of insulin resistance and other disorders in the metabolic syndrome. Biomed. Papers 2005;149(1):119–126.
Lofgren I, Herron K, Zern T, West T, Patalay M, Shachter N, Koo S, Fernandez M. Waist Circumference Is a Better Predictor than Body Mass Index of Coronary Heart Disease Risk in Overweight Premenopausal Women. J. Nutr. 2004;134(5):1071–1076.
Maffeis C, Corciulo N, Livieri C, Rabbone I, Trifirò G, Falorni A, Guerraggio L, Peverelli P, Cuccarolo G, Bergamaschi G, Di Pietro M, Grezzani A. Waist circumference as a predictor of cardiovascular and metabolic risk factors in obese girls European Journal of Clinical Nutrition. 2003;57:566–572.
Mari A, Ludvik B, Pacini G, Nolan J, Murphy E. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24: 539–548.
Maria Do Carmo M, Martins, Faleiro L, Fonseca F. Relationship between leptin and body mass and metabolic syndrome in an adult population Rev Port Cardiol. 2012; 31:711–9.
Maryam K, Nahid Arian pour N, Aghdas Safari A, Roozegar R. Body mass index (BMI) related insulin resistance in polycystic ovarian syndrome among patients referred to gynecology clinic of Imam Reza Hospital, Tehran, Iran. Journal of Clinical Medicine and Research. 2012;4(7):84–88.
Matos L, De Vieira Giorelli G, Dias C. Correlation of anthropometric indicators for identifying insulin sensitivity and resistance. Med J. 2011;129(1):30–5.
McLachlan K, Boston R, Alford P. Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: A dominant role for decreased insulin secretion rather than insulin resistance Diabetologia. 2005;48:1373–1379.
Mohammadzadeh G, Zarghami N. Serum leptin level is reduced in non-obese subjects with type 2 diabetes. Endocrinol Met b. 2013;11(1):3–10.
Mohiti J, Afkhami M, Babaei A. Relation Between Leptin and Insulin In Patients With Type II Diabetes Mellitus. Int J Endocrinol Metab. 2005;3:121–125.
Nomair A, Aref N, Rizwan F, Ezzo O, Hassan A. Serum leptin level in obese women with polycystic ovary syndrome, and its relation to insulin resistance. Asian Pacific Journal of Reproduction. 2014;3(4):288–294.
Okumura T, Taniguchi A, Nagasaka S, Sakai M, Fukushima M, Kuroe A, Yoshii S, Nakamura T, Ogura M, Atarashi T, Nishida S, Nakai Y. Relationship of regional adiposity to serum leptin level in nonobese Japanese type 2 diabetes patients. Diabetes Metab. 2003;29(1):15–8.
Pehlivanov B, Mitkov M. Serum leptin levels correlate with clinical and biochemical indices of insulin resistance in women with polycystic ovary syndrome. The European Journal of Contraception & Reproductive Health Care. 2009;14(2):153–159.
Pitteloud N, Mootha V, Dwyer A, Hardin M, Lee H, Eriksson K, Tripathy K, Yialamas M, Groop L, Elahi D, Hayes F. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28:1636–1642.
Racette S, Evans E, Weiss E, Hagberg J, Holloszy J. Abdominal Adiposity Is a Stronger Predictor of Insulin Resistance Than Fitness Among 50–95 Year Olds. Diabetes Care. 2006;29(3):673–678.
Ramakrishnan G, Unni U, Raj T, Thomas T, Vaz M, Kurpad A. A pilot study on hyperinsulinaemic euglycaemic clamp based insulin sensitivity in young adult Indian males with low body mass index. Indian J Med Res. 2009;129:409–417.
Rasmussen-Torvik L, Pankow J, David R. Jacobs, Jr, Julia Steinberger, Antoinette Moran, Alan R. Sinaiko Influence of waist on adiponectin and insulin sensitivity in adolescence. Obesity (Silver Spring). 2009;17(1):156–161.
Reyes M, Gahagan S, Díaz E, Blanco E, Leiva L, Lera L, Raquel Burrows R. Relationship of Adiposity and Insulin Resistance Mediated by Inflammation in a Group of Overweight and Obese Chilean Adolescents. Nutrition Journal. 2011;10(1):4.
Shea S, Aymong E, Zybert P, Shamoon H, Tracy R, Deckelbaum R, Basch C. Obesity, Fasting Plasma Insulin, and C – reactive protein Levels in Healthy Children. Obesity Research. 2003;11(1):95–103.
Sierra-Johnson J, Johnson B, Bailey K, Turner S. Relationships between Insulin Sensitivity and Measures of Body Fat in Asymptomatic Men and Women. Obesity Research. 2004;12(12):2070–2079.
Sivitz W, Wayson S, Bayless M, Larson L, Sinkey C, Bar R, Haynes W. Leptin and Body Fat in Type 2 Diabetes and Monodrug Therapy. The Journal of Clinical Endocrinology & Metabolism. 2003;88(4):1543–1553.
Tabata S, Yoshimitsu S, Hamachi T, Abe I, Ohnaka K, Kono S. Waist circumference and insulin resistance: A cross-sectional study of Japanese men. BMC Endocrine Disorders. 2009;9:1.
Temel I, Celik O, Hascalik S, Celik N, Sahin I, Aydin S. Serum nonesterified fatty acids, ghrelin, and homocysteine levels in women with polycystic ovary syndrome. Turk J Med Sci. 2010;40(2):221–228.
Thompson D, Boyne M, Ferguson T, Reid M, Wilks R, Barnett A, Forrester T. Limitations of fasting indices in the measurement of insulin sensitivity in Afro-Caribbean adults. BMC. Research Notes 2014:7:98.
Toft I, Bønaa K, Jenssen T. Insulin Resistance in Hypertension Is Associated With Body Fat Rather Than Blood Pressure. Hypertension. 1998;32:115–122.
Trirogoff M, Shintani A, Himmelfarb J, Ikizler T. Body mass index and fat mass are the primary correlates of insulin resistance in nondiabetic stage 3–4 chronic kidney disease patients. Am J Clin Nutr. 2007;86:1642–8.
Valtueña S, Numeroso F, Ardigò D, Pedrazzoni M, Franzini L, Piatti P, Monti L, Zavaroni I. Relationship between leptin, insulin, body composition and liver steatosis in non-diabetic moderate drinkers with normal transaminase levels. European Journal of Endocrinology. 2005;153:283–290.
Venkataraman K, Khoo C, Leow M, Khoo E, Isaac A. New Measure of Insulin Sensitivity Predicts Cardiovascular Disease Better than HOMA Estimated Insulin Resistance. PLoS ONE. 2013;8(9):e74410.
Virtanen K, Iozzo P, Hällsten K, Huupponen R, Parkkola R, Janatuinen T, Lönnqvist F, Viljanen T, Rönnemaa T, Lönnroth P, Knuuti J, Ferrannini E, Nuutila. Increased fat mass compensates for insulin resistance in abdominal obesity and type 2 diabetes: A positron-emitting tomography study. Diabetes. 2005;54(9):2720–6
Yadav A, Jyoti P, Jain S, Bhattacharjee S. Correlation of Adiponectin and Leptin with Insulin Resistance: A Pilot Study in Healthy North Indian Population. Indian J Clin Biochem. 2011 Apr;26(2):193–196.
Yajnik C, Joglekar C, Lubree H, Rege S, Naik, S, Bhat D, Uradey B, Raut K, Shetty P, Yudkin J. Adiposity, inflammation and hyperglycaemia in rural and urban Indian men: Coronary Risk of Insulin Sensitivity in Indian Subjects (CRISIS) Study. Diabetologia. 2008;51:39–46.
Yajnik C. Early Life Origins of Insulin Resistance and Type 2 Diabetes in India and Other Asian Countries. J. Nutr. 2008;134:205–210.
Zimmet P, Hodge A, Nicolson M, Staten M, De Courten M, Moore J, Morawiecki A, Lubina J, Collier G, Alberti G, Dowse G. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 1996;313(7063):965–9.
Johns I, Goff L, Bluck L, Griffin B, Jebb S, Lovegrove J, Sanders T, Frost G, Dornhorst A. Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study. Diabet Med. 2014;31(11):1310–5.