CRY1 polymorphism may influence the association of low carbohydrate diet (LCD) score on glucose homeostasis in overweight and obese women


  • Atieh Mirzababaei 1 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  • Farideh Shiraseb Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  • Sara Hajishizari Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  • Mena Farazi Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  • Hadith Tangestani 2 Department of Nutrition, Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Science, Bushehr, Iran
  • Leila khorraminezhad 3Endocrinology and Nephrology Unit, CHU de Québec-Laval University, Research Center, Québec (QC), Canada
  • Cain C Clark 4Centre for Intelligent Healthcare, Coventry University, Coventry, CV1 5FB, U.K.
  • Khadijeh Mirzaei 1 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran



obesity, CRY1, HOMA-IR, ISQUKI, low carbohydrate diet, interaction


Background and aims: We sought to examine the interaction between CRY1 genotypes and low carbohydrate diet (LCD) score and the effect on insulin resistance, insulin sensitivity, homeostasis model assessment of insulin resistance (HOMA- IR) and quantitative insulin sensitivity check index (ISQUKI).

Methods: This cross-sectional study was conducted with a total of 228 overweight and obese women. The data related to anthropometric and biochemical measures were collected and a food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. Based on the FFQ, we calculated an LCD score for each study participant, ranging from 0 to 70. Biochemical assessments, including TC, HDL, LDL, TG, FBS, insulin and HOMA-IR, were performed. Deoxyribonucleic acid (DNA) samples were assessed to be genotyped for the rs2287161, which was genotyped by the restriction fragment length polymorphism (PCR-RFLP) method. A generalised linear model was performed for interaction analysis.

Results: The results of the study demonstrated that, after controlling for several confounders, increased adherence to an LCD (T3 vs. T1) in the interaction with one risk allele genotype (CG) increases ISQUKI level (β: 0.001, CI: 0.00, 0.002, p=0.041). Also, there was a marginally negative interaction between higher adherence to LCD and two risk alleles genotype (CC) on insulin level (β: -0.012, CI: 0-0.024, 0.001, p=0.054).

Conclusions: This study revealed a negative interaction of CRY1 genotypes with two risk allele and higher LCD adherence on insulin level, and a positive interaction on ISQUKI. However, the mechanism of interaction between LCDs and CRY1 genotypes remains unclear.


Palou A, Bonet ML. Challenges in obesity research. Nutricion Hospitalaria 2013;28(5):144-53.

Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 2019;15(5):288-98.

Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism 2019;92:6-10.

Wells JC, Marphatia AA, Cole TJ, McCoy D. Associations of economic and gender inequality with global obesity prevalence: understanding the female excess. Soc Sci Med 2012;75(3):482-90.

Ameye H, Swinnen J. Obesity, income and gender: the changing global relationship. Global Food Security 2019;23:267-81.

Azizi F, Allahverdian S, Mirmiran P, Rahmani M, Mohammadi F. Dietary factors and body mass index in a group of Iranian adolescents: Tehran lipid and glucose study-2. Int J Vit Nutrition Research 2001;71(2):123-7.

Azizi F, Azadbakht L, Mirmiran P. Trends in overweight, obesity and central fat accumulation among Tehranian adults between 1998–1999 and 2001– 2002: Tehran lipid and glucose study. Annals Nutrition Metab 2005; 49(1):3-8.

Mohammadi-Nasrabadi M, Sadeghi R, Rahimiforushani A, Mohammadi- Nasrabadi F, Shojaeizadeh D, Montazeri A. Socioeconomic determinants of excess weight and central obesity among Iranian women: Application of information, motivation, and behavioral skills model. J Educ Health Promotion 2019;8:75.

Hajian-Tilaki K, Heidari B. Prevalence of obesity, central obesity and the associated factors in urban population aged 20–70 years, in the north of Iran: a population-based study and regression approach. Obesity Reviews 2007;8(1):3-10.

Apovian CM. Obesity: definition, comorbidities, causes, and burden. Am J Manag Care 2016;22(7 Suppl):s176-85.

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365(9468):1415-28.

Basagoudar S, Chandrashekhar R. Study of obesity and its risk factors among women of reproductive age group. Int J Current Res Review 2013;5(3):23.

Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63(25 Part B):2985-3023.

Shirani F, Esmaillzadeh A, Keshteli AH, Adibi P, Azadbakht L. Low-carbohydrate-diet score and metabolic syndrome: an epidemiologic study among Iranian women. Nutrition 2015;31(9):1124-30. j.nut.2015.04.013

Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003;348(21):2082-90.

Freedland SJ, Howard L, Allen J, et al. A lifestyle intervention of weight loss via a low-carbohydrate diet plus walking to reduce metabolic disturbances caused by androgen deprivation therapy among prostate cancer patients: carbohydrate and prostate study 1 (CAPS1) randomized controlled trial. Prostate Cancer Prostatic Dis 2019;22(3):428-37.

Frost G, Keogh B, Smith D, Akinsanya K, Leeds A. Preliminary report; the effect of low-glycemic carbohydrate on insulin and glucose response in vivo and in vitro in patients with coronary heart disease. Metabolism 1996; 45(6):669-72.

Halton TL, Liu S, Manson JE, Hu FB. Low-carbohydrate-diet score and risk of type 2 diabetes in women. American J Clin Nutrition 2008;87(2):339- 46.

Muller M, Paschen U, Seitz H. Effect of ketone bodies on glucose production and utilization in the miniature pig. J Clin Investig 1984;74(1):249-61.

Krishnaiah SY, Wu G, Altman BJ, et al. Clock regulation of metabolites reveals coupling between transcription and metabolism. Cell metabolism 2017;25(4):961-74.

Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002;418(6901):935-41.

Duguay D, Cermakian N. The crosstalk between physiology and circadian clock proteins. Chronobiol Int 2009;26(8):1479-513.

Quintero JE, Kuhlman SJ, McMahon DG. The biological clock nucleus: a multiphasic oscillator network regulated by light. J Neurosci 2003; 23(22):8070-6.

Schibler U, Ripperger J, Brown SA. Peripheral circadian osacillators in mammals: time and food. J Biol Rhythms 2003;18(3):250-60.

Shi S-q, Ansari TS, McGuinness OP, Wasserman DH, Johnson CH. Circadian disruption leads to insulin resistance and obesity. Current Biol 2013; 23(5):372-81.

Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308(5724):1043-5.

Bouatia-Naji N, Bonnefond A, Cavalcanti-Proença C, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nature Genetics 2009;41(1):89-94.

Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42(2):105-16.

Hatori M, Panda S. CRY links the circadian clock and CREB-mediated gluconeogenesis. Cell Res 2010; 20(12):1285-8.

Zhang EE, Liu Y, Dentin R, et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med 2010; 16(10):1152-6.

Mirmiran P, Esfahani FH, Mehrabi Y, Hedayati M, Azizi F. Reliability and relative validity of an FFQ for nutrients in the Tehran lipid and glucose study. Public Health Nutr 2010;13(5):654-62.

Atkinson FS, Foster-Powell K, Brand-Miller JC. International tables of glycemic index and glycemic load values: 2008. Diabetes Care 2008; 31(12):2281-3.

Eslamian G, Mirmiran P, Asghari G, Hosseini-Esfahani F, Youzbashian E, Azizi F. Low carbohydrate diet score does not predict metabolic syndrome in children and adolescents: Tehran Lipid and Glucose study. Archives Iranian Med 2014;17(6):0-0.

Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and beta-cell function fron fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412-19.

Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85(7):2402-10. jcem.85.7.6661

Moghaddam MB, Aghdam FB, Jafarabadi MA, Allahverdipour H, Nikookheslat SD, Safarpour S. The Iranian version of International Physical Activity Questionnaire (IPAQ) in Iran: validity, factor structure, internal consistency and stability. World Applied Sci J 2012;18(8):1073-80.

Ainsworth BE, Haskell WL, Herrmann SD, et al. 2011 compendium of physica activities; a second update of codes and MET values. Med Sci Sports Exercise 2011;43(8):1575-81.

Huisman SA, Oklejewicz M, Ahmadi AR, et al. Colorectal liver metastases with a disrupted circadian rhythm phase shift the peripheral clock in liver and kidney. Int J Cancer 2015;136(5):1024-32. ijc.29089

Feng D, Lazar MA. Clocks, metabolism and the epigenome. Molecular Cell 2012;47(2):158-67.

Rajaratnam SM, Howard ME, Grunstein RR. Sleep loss and circadian disruption in shift work: health burden and management. Med J Australia 2013;199:S11-S15.

Corella D, Qi L, Tai ES, et al. Perilipin gene variation determines higher susceptibility to insulin resistance in Asian women when consuming a highasaturated fat, low-carbohydrate diet. Diabetes Care 2006;29(6):1313-19.

Dashti HS, Smith CE, Lee Y-C, et al. CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American. Chronobiol Int 2014; 31(5):660-7.

Stenvers DJ, Scheer FA, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Reviews Endocrinol 2019;15(2):75-89.

Jordan SD, Lamia KA. AMPK at the crossroads of circadian clocks and metabolism. Molec Cell Endocrinol 2013;366(2):163-9.

Tseng H-L, Yang S-C, Yang S-H, Shieh K-R. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice. PLoS One 2015;10(3):e0120380.

Bass J. High glucose, no cry. Nature Med 2010;16(10):1074-6.

El Khoury D, Hwalla N. Metabolic and appetite hormone responses of hyperinsulinemic normoglycemic males to meals with varied macronutrient compositions. Ann Nutr Metab 2010;57(1):59-67.

Krebs M, Brehm A, Krssak M, et al. Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia 2003; 46(7):917-25.

Marshall JA, Hamman RF, Baxter J. High-fat, low-carbohydrate diet and the etiology of non-insulin-dependent diabetes mellitus: the San Luis Valley Diabetes Study. Am J Epidemiol 1991;134(6):590-603.

Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. N Engl J Med 1988;318(19):1217-25.

Kraegen E, Storlien L, Jenkins A, James D. Chronic exercise compensates for insulin resistance induced by a high-fat diet in rats. Am J Physiol Endocrinol Metab 1989;256(2):E242-E249.

Kiens B, Essen-Gustavsson B, Gad P, Lithell H. Lipoprotein lipase activity and intramuscular triglyceride stores after long-term high-fat and high-carbohydrate diets in physically trained men. Clin Physiol 1987;7(1):1-9.

Gannon MC, Nuttall FQ. Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes 2004; 53(9):2375-82.

Fernström M, Fernberg U, Hurtig-Wennlöf A. Insulin resistance (HOMA-IR) and body fat (%) are associated to low intake of fruit and vegetables in Swedish young adults: the cross-sectional lifestyle, biomarkers and atherosclerosis study. BMC Nutrition 2019;5(1):15.

Miller V, Yusuf S, Chow CK, et al. Availability, affordability and consumption of fruits and vegetables in 18 countries across income levels: findings from the Prospective Urban Rural Epidemiology (PURE) study. Lancet Global Health 2016;4(10):e695-e703.

Du H, Li L, Bennett D, Guo Y, et al. Fresh fruit consumption in relation to incident diabetes and diabetic vascular complications: a 7-y prospective study of 0.5 million Chinese adults. PLoS Medicine 2017;14(4):e1002279.

Zhang Z, Lanza E, Mitchell D, Mentor-Marcel R, Colburn N, Hartman T. A legume-enriched diet facilitates weight loss and improves biomarkers of insulin resistance and inflammation. The FASEB J 2010;24:931-4.

Venn B, Mann J. Cereal grains, legumes and diabetes. European J Clinical Nutrition 2004;58(11):1443-61.

Gadgil MD, Appel LJ, Yeung E, Anderson CA, Sacks FM, Miller III ER. The effects of carbohydrate, unsaturated fat, and protein intake on measures of insulin sensitivity: results from the OmniHeart trial. Diabetes Care 2013; 36(5):1132-7.

Imamura F, Micha R, Wu JH, et al. Effects of saturated fat, polyunsaturated fat, monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: a systematic review and meta-analysis of randomised controlled feeding trials. PLoS Medicine 2016;13(7):e1002087.

Mirzababaei A, Daneshzad E, Shiraseb F, et al. Variants of the cry 1 gene may influence the effect of fat intake on resting metabolic rate in women with overweight or obesity: a cross-sectional study. BMC Endocrine Disorders 2021;21(1):196.

Frayn K, Tan G, Karpe F. Adipose tissue: a key target for diabetes pathophysiology and treatment? Hormone Metabolic Res 2007;39(10):739-42.

Sun X, Zemel MB. Role of uncoupling protein 2 (UCP2) expression and 1α, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. The FASEB J 2004;18(12):1430-2.

Dubey P, Thakur V, Chattopadhyay M. Role of minerals and trace elements in diabetes and insulin resistance. Nutrients 2020;12(6):1864.






Original Research