The Effect of High-Intensity Interval Training (HIIT) and Caffeine Supplementation on Brain-derived Neurotrophic Factor and Glial Line-derived Neurotrophic Factor in Streptozotocin-Induced Diabetic Rats

Document Type : Original Article


1 Assistant Professor, Department of Sport Sciences, Faculty of Social Sciences, Imam Khomeini International University, Qazvin, Iran

2 Master of exercise physiology, Allame Gazvini Institute, Qazvin, Iran

3 Assistant Professor, Department of exercise physiology, Faculty of Sport Sciences, Shahrood University of Technology, Shahrood, Iran



Background: Diabetes mellitus is a widespread disease disrupting cognitive function. We investigated the effect of eight-week high-intensity interval training (HIIT) and caffeine supplementation on Brain-derived neurotrophic factor (BDNF) and glial line-derived neurotrophic factor (GDNF) in a rat diabetic model.
Methods: In this experimental study, streptozotocin-induced diabetic rats were randomly divided into: control (C), diabetic (D), diabetic+caffeine (D+CA), diabetic+training (D+T) and diabetic+training+caffeine (D+T+CA) groups. Training groups underwent a high-intensity interval training program (5 sessions a week over 8 weeks). The supplement groups were administered with 7mg caffeine/100gr body weight for 5 days a week before each exercise session throughout the experimental period. The rat hippocampus and brainstem were removed 48 h after the last training session and blood samples were taken from left ventricle. The levels of glucose, BDNF and GDNF were measured by ELISA assay. Data were analyzed using two-way ANOVA test.
Results: Streptozotocin-induced diabetes increased blood glucose (P<0.01) whereas decreased BDNF and GDNF levels (P=0.002). The results showed that HIIT decreased blood glucose (P=0.002) but increased BDNF and GDNF levels in diabetic rats (P=0.003 and P=0.001, respectively). Even though caffeine supplementation significantly reduced blood glucose concentration (P=0.0001), it had no significant effect on BDNF and GDNF levels in diabetic rats (P>0.05). We also observed a significant interaction between treatments regarding GDNF changes (P=0.024); yet, the interaction between caffeine and HIIT on BDNF did not reach the significance level (P=0.074).
Conclusion: Based on the findings, HIIT increased BDNF and GDNF levels in rat diabetic model, but caffeine ingestion had no significant effect on neurotrophic factors. However, caffeine seems to blunt HIIT-induced increase in neurotrophic factors which remains to be further investigated.


Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007; 356(18):1842-52.
Strachan MW, Reynolds RM, Frier BM, Mitchell RJ, Price JF. The role of metabolic derangements and glucocorticoid excess in the aetiology of cognitive impairment in type 2 diabetes. Implications for future therapeutic strategies. Diabetes Obes Metab 2009; 11(5):407-14.
Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res 2009; 1280:186-94.
Rao AA. Views and opinion on BDNF as a target for diabetic cognitive dysfunction. Bioinformation 2013; 9(11):551-4.
Eyileten C, Kaplon-Cieslicka A, Mirowska-Guzel D, Malek L, Postula M. Antidiabetic effect of brain-derived neurotrophic factor and its association with inflammation in type 2 diabetes mellitus. J Diabetes Res 2017; 2017: 2823671.
McCullough MJ, Peplinski NG, Kinnell KR, Spitsbergen JM. Glial cell line-derived neurotrophic factor protein content in rat skeletal muscle is altered by increased physical activity in vivo and in vitro. Neuroscience 2011; 174:234-44.
Anitha M, Gondha C, Sutliff R, Parsadanian A, Mwangi S, Sitaraman SV, et al. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway. J Clin Invest 2006; 116(2):344-56.
Lenart L, Hodrea J, Hosszu A, Koszegi S, Zelena D, Balogh D, et al. The role of sigma-1 receptor and brain-derived neurotrophic factor in the development of diabetes and comorbid depression in streptozotocin-induced diabetic rats. Psychopharmacology (Berl) 2016; 233(7):1269-78.
Zhang D, Xiao Q, Luo H, Zhao K. Effects of angiotensin-(1-7) on hippocampal expressions of GFAP and GDNF and cognitive function in rats with diabetes mellitus. Nan Fang Yi Ke Da Xue Xue Bao 2015; 35(5):646-51. [In Chinese].
Zhao Q, Matsumoto K, Tsuneyama K, Tanaka K, Li F, Shibahara N, et al. Diabetes-induced central cholinergic neuronal loss and cognitive deficit are attenuated by tacrine and a Chinese herbal prescription, kangen-karyu: elucidation in type 2 diabetes db/db mice. J Pharmacol Sci 2011; 117(4):230-42.
Iscoe KE, Riddell MC. Continuous moderate intensity exercise with or without intermittent high‐intensity work: effects on acute and late glycaemia in athletes with Type 1 diabetes mellitus. Diabet Med 2011; 28(7):824-32.
Francois ME, Little JP. Effectiveness and safety of high-intensity interval training in patients with type 2 diabetes. Diabetes Spectr 2015; 28(1):39-44.
Lane JD. Caffeine, glucose metabolism, and type 2 diabetes. Journal of Caffeine Research 2011; 1(1):23-8.
Duarte JM, Carvalho RA, Cunha RA, Gruetter R. Caffeine consumption attenuates neurochemical modifications in the hippocampus of streptozotocin induced diabetic rats. J Neurochem 2009; 111(2):368-79.
Sasidharan SR, Joseph JA, Anandakumar S, Venkatesan V, Madhavan CN, Agarwal A. An experimental approach for selecting appropriate rodent diets for research studies on metabolic disorders. BioMed Research International 2013; 752870.
Fredholm BB. Notes on the history of caffeine use. Handb Exp Pharmacol 2011; 200:1-9.
Lao Peregrín C, Ballesteros JJ, Fernández M, Zamora Moratalla A, Saavedra A, Gómez Lázaro M, et al. Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling. Addict Biol 2017; 22(6):1706-18.
Thomas C, Bishop D, Moore-Morris T, Mercier J. Effects of high-intensity training on MCT1, MCT4, and NBC expressions in rat skeletal muscles: influence of chronic metabolic alkalosis. Am J Physiol Endocrinol Metab 2007; 293(4):E916-22.
Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a meta-analysis. Diabetes Care 2006; 29(11):2518-27.
Umpierre D, Ribeiro PA, Kramer CK, Leitão CB, Zucatti AT, Azevedo MJ, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 2011; 305(17):1790-9.
Alvarez C, Ramirez-Campillo R, Martinez-Salazar C, Mancilla R, Flores-Opazo M, Cano-Montoya J, et al. Low-volume high-intensity interval training as a therapy for type 2 diabetes. Int J Sports Med 2016; 37(09):723-9.
Mitranun W, Deerochanawong C, Tanaka H, Suksom D. Continuous vs interval training on glycemic control and macro‐and microvascular reactivity in type 2 diabetic patients. Scand J Med Sci Sports 2014; 24(2):e69-76.
Karstoft K, Winding K, Knudsen SH, Nielsen JS, Thomsen C, Pedersen BK, et al. The effects of free-living interval-walking training on glycemic control, body composition, and physical fitness in type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 2013; 36(2):228-36.
Urzua Z, Trujillo X, Huerta M, Trujillo-Hernandez B, Rios-Silva M, Onetti C, et al. Effects of chronic caffeine administration on blood glucose levels and on glucose tolerance in healthy and diabetic rats. J Int Med Res 2012; 40(6):2220-30.
Egawa T, Hamada T, Kameda N, Karaike K, Ma X, Masuda S, et al. Caffeine acutely activates 5′ adenosine monophosphate–activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles. Metabolism 2009; 58(11):1609-17.
Mukwevho E, Kohn TA, Lang D, Nyatia E, Smith J, Ojuka EO. Caffeine induces hyperacetylation of histones at the MEF2 site on the Glut4 promoter and increases MEF2A binding to the site via a CaMK-dependent mechanism. Am J Physiol Endocrinol Metab 2008; 294(3):E582-8.
Saucedo Marquez CM, Vanaudenaerde B, Troosters T, Wenderoth N. High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise. J Appl Physiol (1985) 2015; 119(12):1363-73.
Freitas DA, Rocha-Vieira E, Soares BA, Nonato LF, Fonseca SR, Martins JB, et al. High intensity interval training modulates hippocampal oxidative stress, BDNF and inflammatory mediators in rats. Physiol Behav 2018; 184:6-11.
Gomez‐Pinilla F, Zhuang Y, Feng J, Ying Z, Fan G. Exercise impacts brain‐derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci 2011; 33(3):383-90.
Vosadi E, Ravasi AA, Choobine S, Barzegar H, Borjianfard M. Effect of endurance training and omega-3 supplementation in brain-derived neurotrophic factor (BDNF) in male adult rat hippocampus. Razi Journal of Medical Sciences 2013; 20(111):50-7. [In Persian].
Zigmond MJ, Cameron JL, Leak RK, Mirnics K, Russell VA, Smeyne RJ, et al. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism Relat Disord 2009; 15(Suppl 3):S42-5.
Moy GA, McNay EC. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF. Physiol Behav 2013; 109:69-74.
Borota D, Murray E, Keceli G, Chang A, Watabe JM, Ly M, et al. Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci 2014; 17(2):201-3.
Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Simioni C, et al. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol 2007; 72(2):395-406.
Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW. Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 2008; 29(9):1380-93.
Vila-Luna S, Cabrera-Isidoro S, Vila-Luna L, Juarez-Diaz IJ, Bata-Garcia JL, Alvarez-Cervera FJ, et al. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons. Neuroscience 2012; 202:384-95.
Bairam A, Kinkead R, Lajeunesse Y, Joseph V. Neonatal caffeine treatment does not induce long-term consequences on TrkB receptors or BDNF expression in chemosensory organs of adult rats. Neurosci lett 2010; 468(3):292-6.