The effect of increased core body temperature on the vasomotor and sudomotor responses of patients with type 2 diabetes: Protocol of a systematic literature review and meta-analysis

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Flouris This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7204080/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Dec, 2025 Read the published version in Systematic Reviews → Version 1 posted 5 You are reading this latest preprint version Abstract Background Type 2 diabetes has been associated with impaired thermoregulatory responses to increased core body temperature, making patients more vulnerable to heat-related disorders. Although recent studies have investigated these diabetes-related impairments in heat loss mechanisms, our understanding of the occurring phenomena remains unclear due to the complexity of results and the various factors contributing to increased core body temperature. Objective To address the following Population/Exposure/Comparator/Outcome (PECO) question: what is the effect of an increase in core body temperature level (E) on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these responses (O) within individuals with type 2 diabetes (P) compared to healthy individuals at the same level of core body temperature and/or type 2 diabetes patients at lower or normal core body temperature level (C)? Methods This protocol will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A thorough database search will be conducted in PubMed and Embase using tested and validated search algorithms. Experimental (randomized and non-randomized controlled trial) or observational studies with type 2 diabetes populations and have measured core body temperature will be included. A narrative synthesis will be conducted and if possible, meat-analysis will be performed. Risk of bias will be assessed using the Office of Health Assessment and Translation tool. Discussion The results from this review will expand our knowledge of the physiological mechanisms through which type 2 diabetes impairs heat loss under hyperthermic conditions and inform guidelines to mitigate heat-related risks in type 2 diabetes populations. Protocol registration This study was registered at the International Prospective Registry for Systematic Reviews (PROSPERO) #CRD42023471939. Type 2 diabetes core body temperature hyperthermia heat loss sudomotor vasomotor systematic review protocol Background Climate change has driven the world to an emergency due to global warming, with the average surface air temperature having increased by 1.48°C since the pre-industrial period [ 1 ], a trend that will continue at least until 2040 according to the Intergovernmental Panel on Climate Change [ 2 ]. The accelerated pace of global warming is shown by the fact that the last eight years have been the hottest on record [ 1 , 3 ]. As a result, people are being more exposed to heat and extreme heat events (i.e., heatwaves), which have direct impacts on their health [ 4 ]. Heat-related disorders, such as heat exhaustion and heatstroke, increase the risk of morbidity and mortality, and amplify the complications of pre-existing health conditions [ 5 ]. Type 2 diabetes mellitus (T2D) is a chronic health condition characterized by elevated levels of blood glucose that has reached pandemic levels [ 6 ]. According to the International Diabetes Federation, 483 million people globally (9% of total population) live with T2D and this figure will surpass 700 million by 2045 [ 7 ]. T2D contributes to an impaired thermoregulatory system, resulting in patients storing more heat when they rest or are physically active in a hot environment, resulting in a higher core body temperature (CBT) [ 8 , 9 ]. On this basis, patients with T2D are among the most vulnerable population groups during heat exposure [ 8 – 10 ]. A number of studies published within the last decade have investigated different physiological and molecular mechanisms to understand the vulnerability of T2D patients to rising CBT. However, at present these mechanisms remain only partly understood, primarily because the results are too complex to interpret by examining single studies/trials in specific settings. In the era of climate change, rising global temperature, and increasing prevalence of T2D, a systematic review approach is necessary to determine how the thermoregulatory system of patients with T2D responds to rising CBT. In the present paper, we describe the protocol for a systematic review of primary studies on heat loss mechanisms during hyperthermia in individuals with T2D. Specifically, the objective of this review is to address the following Population/Exposure/Comparator/Outcome (PECO) [ 11 ] question: what is the effect of an increase in CBT level (E) on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these responses (O) within individuals with T2D (P) compared to healthy individuals at the same level of CBT and/or T2D patients at lower or normal CBT level (C)? Methods Registration The systematic review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42023471939. The study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (Additional file 1) [ 12 ]. In case any amendments to this protocol are made during the review process, changes and related reasons will be reported in the final article. Eligibility criteria The PECO criteria [ 11 ] are listed in Table 1 and are outlined in the subsequent sections. Types of population We will consider for inclusion studies reporting on the outcomes of interest in patients with T2D with or without comparison against healthy individuals, regardless of sex, gender, age, or geographical region. Description and types of exposure The CBT refers to the temperature of deep body tissues such as the heart, brain, and lungs, and it is typically measured in the following sites: sublingual, ear canal, tympanic, forehead, axilla, rectum, esophagus, gastrointestinal tract, blood, artery, bladder, brain [ 13 – 16 ]. The CBT can be regulated via thermoregulatory mechanisms within a narrow range, around 37°C, which is considered optimum for enzyme efficiency, biological procedures, and organ function [ 17 ]. This requires a heat balance between the human body and the environment, where the amount of internal heat production via metabolism and heat gain from the environment equal the heat dissipation to the environment [ 14 , 18 ]. An individual’s CBT can increase due to three main factors [ 18 – 20 ]: 1. High heat exposure from the environment (for example, increased air temperature and humidity, radiant heat sources, limited air flow); 2. Increased metabolic heat production from performing physically demanding tasks; 3. Thermal insulation from clothing. Increased CBT can be dangerous to everyone, and especially to patients with T2D [ 21 ] because they have a limited capacity to regulate CBT when they are under heat stress [ 8 , 22 ]. In turn, this raises the risk for health complications, which may explain the increased morbidity and mortality of T2D patients during heatwaves [ 23 , 24 ]. In the proposed systematic review, we will consider an increased CBT as the exposure in question. As such, we will include all studies that provide data for the effects of increased CBT level on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these thermoregulatory responses. Types of comparators We will compare our population under investigation (i.e., T2D patients) with the following comparator populations: (1) healthy individuals at the same level of CBT, and (2) patients with T2D with lower or normal CBT level. Description and types of outcomes Increased CBT activates autonomic responses to dissipate heat to the environment by two major mechanisms: cutaneous vasodilation (vasomotor response) and sweat production (sudomotor response) [ 18 , 25 , 26 ]. Patients with T2D are at increased risk of hyperthermia as a result of attenuated vasomotor and sudomotor responses [ 8 , 27 ]. This has been attributed to a number of factors, including diabetic neuropathy and microvascular dysfunction [ 17 , 28 , 29 ]. Other potential contributors include poor glycemic control, disease duration, and T2D-related complications [ 8 ]. The outcomes analyzed below contribute to attenuated vasomotor and sudomotor responses in T2D patients and will be analysed as part of this systematic review. Vasomotor responses Cutaneous vasodilation channels blood flow to the small skin capillaries to dissipate heat to the environment by convection, conduction, and radiation [ 25 , 26 , 30 ]. This way of dissipating heat is often termed “dry heat loss” and it is crucial for thermoregulation, especially during periods of rest. To function, the vasomotor response requires an increased cardiac output and redistribution of the blood flow from the body core to the skin surface [ 27 ]. Cutaneous vasodilation during hyperthermia is driven primarily by sympathetic vasodilator nerve activity in response to the release of acetylcholine and other co-transmitters via cholinergic nerve transmission [ 27 , 30 , 31 ]. Nitric oxide, substance P, vasoactive intestinal peptide (VIP), prostaglandins, and histamine hold key roles in the vasomotor response due to increased CBT [ 27 , 31 – 33 ]. We will derive data from the mostly used techniques for measuring skin blood flow including venous occlusion plethysmography, Doppler ultrasound, and laser-doppler flowmetry. If present, other validated and objective measures will be also considered in the identified studies. We will also consider all physiological and molecular parameters that may play a role in the mechanisms that control vasomotor responses of T2D patients and healthy individuals. Sudomotor responses In circumstances where the ambient temperature exceeds skin temperature, dry heat loss cannot function and another mechanism is needed to dissipate heat from the body to the environment [ 30 , 31 ]. In these conditions as well as during periods of physical work, the sudomotor response is the major mechanism of heat loss from the body to the environment [ 18 , 30 , 31 ]. It is often termed “wet heat loss” and results in sweat secretion on the skin surface which, if evaporated, leads to cooling at a rate of 2426 J per g [ 34 ]. Sweat is secreted in response to increased CBT by eccrine sweat glands that are distributed over the skin surface [ 18 , 31 , 35 ]. Eccrine glands are cholinergically innervated tubular glands controlled sympathetically from the hypothalamus through peripheral and central thermoaffector neural signals. Acetylcholine is the principal neurotransmitter, released by sudomotor nerves, which connects to muscarinic receptors on the eccrine sweat glands to activate sweat production [ 18 , 25 , 30 , 35 , 36 ]. The most common physiological measurements of sudomotor function include the thermoregulatory sweat testing, the quantitative sudomotor axon reflex sweat testing, silicone impressions (patches), the sympathetic skin response, electrochemical skin conductance, sweat sensitive test, quantitative direct and indirect axon reflex testing, whole-body sweat rate, as well as local sweat rate [ 25 , 37 , 38 ]. If present, other validated and objective measures will be also considered in the identified studies. We will also consider all physiological and molecular parameters that may play a role in the mechanisms that control sudomotor responses of T2D patients and healthy individuals. Types of studies Inclusion criteria Studies included in this review will investigate T2D patients, with or without a healthy control group, at different levels of CBT. For all outcomes we will consider papers that have measured CBT regardless of the factor contributing to elevated CBT. We will include both randomized and non-randomized controlled trials with parallel groups or with a crossover study design. Single group design studies will be also considered. In any type of observational studies (e.g., cohort; case-control studies), the researcher observes/records people with T2D at different levels of CBT without manipulation or intervention. Exclusion criteria We will exclude case reports, editorials, opinion papers, reviews, conference proceedings, letters to editors and modelling approaches (i.e., studies that estimate the effect of ambient conditions on humans with mathematical models, without involving human participants). In addition, animal studies or in vitro experiments will be excluded from this systematic review. Years considered The selected scientific databases will be searched from the date of their inception to present. No restrictions in the year of publication will be applied. Publication language No articles will be excluded based on language, but our search will be conducted using English terms. We will include studies written in any language, provided that an English translation can be obtained using Google Translate. Publication types Quantitative peer-reviewed publications. Types of effect measures For dichotomous data, risk ratios will be computed as the measure of the effect. When hazard ratios are presented, we will consider them to be similar to risk ratios. If odds ratios (OR) are provided and the prevalence of the outcome is less than 10%, we will assume that OR are similar to risk ratios. However, if the prevalence is higher, we will convert OR into risk ratios. For continuous data we will calculate mean differences. When outcomes are assessed but in different scales, we will calculate standardized mean difference. Search strategy A keyword algorithmic search, according to the PECO approach, will be performed in two scientific databases: Pubmed and Embase. The algorithm for the search for the two databases has been already developed and has been formed using the Boolean OR, AND, NOT and possibly truncations (ie, *) and wildcards (Additional file 1). Alerts will be created in each database to identify new publications. To identify other eligible publications related to our research question, reference lists of included studies will be screened for a manual search. To test the validity of the search algorithm, we created a “golden library” by using the following procedure: (1) we applied the above-mentioned search algorithm in PubMed, which retrieved 11,037 publications (02-07-2025); (2) we screened the initial 200 articles and identified two narrative reviews on the topic of heat stress in T2D patients [ 8 , 39 ]); (3) we checked the titles and abstracts of the 287 references of the two identified narrative reviews to determine their eligibility against the eligibility criteria of the PECO question in the proposed systematic review, resulting in a total of 3 eligible studies [ 9 , 40 , 41 ]; (4) to increase the size of our “golden library”, we manually searched the PubMed database through a trial-and-error approach using keywords related to the PECO question in the proposed systematic review (e.g., heat, type 2 diabetes, sudomotor, skin blood flow, sweat rate, etc.) to identify relevant studies, resulting in a total of 6 eligible studies [ 42 – 47 ]. The outcome of this process resulted in a “golden library” of 9 eligible studies. Subsequently, we searched whether the publications of the “golden library” were detected by the searching algorithm in PubMed. We found that the searching algorithm detects 8 out of the 9 publications of the “golden library”. The calculated sensitivity of the searching algorithm [eligible studies detected (n) / gold standard eligible (n)] was 0.89, suggesting that the search algorithm is sensitive enough to capture an adequate number of eligible publications. Study selection All the retrieved publications will be saved on an Endnote software file. Initially, all duplicate records will be excluded. Thereafter, two investigators will, independently, screen all titles and abstracts of the retrieved publications for eligibility using the above-mentioned inclusion and exclusion criteria. Articles that will be marked as unclear will be moved at the full-text review screening step. Eligible publications with unavailable access to full-text will be requested through email to the lead author or the journal. Any disagreements regarding eligibility will be resolved by a third investigator who will act as a referee and make the final decision. Finally, the full text of the articles that passed the first stage of eligibility check (based on title and abstract) will be screened to ensure they fulfill the present eligibility criteria. At the end of this process, a complete list of eligible publications will be presented. A PRISMA flow chart will be created to describe in detail all procedures of identification and exclusion. A full list of the excluded publications will also be included in the in a supplementary file of the systematic review. Data Extraction For each eligible study we will extract the following data: first author names, year of publication, study design and characteristics, location, patient sample size, age, sex, health status, co-morbidities, body mass index, body surface area, exposure assessment, definition and measurement of the main outcomes, baseline differences, sampling time frame, inclusion/exclusion criteria. When necessary, the reviewers will contact via email the corresponding author if full text required data of an article are unclear or missing. All extracted data will be recorded in Excel format agreed among the investigators. Any discrepancies will be resolved with consensus by a third reviewer. Risk of bias assessment The included publications will be evaluated for risk of bias using the Office of Health Assessment and Translation (OHAT) tool. Two review authors will independently assess the risk of bias in the included studies and conflicts in the risk of bias assessment will be resolved by an independent referee investigator. In cases where eligible publications have been co-authored by any of these investigators, the assessment will be performed by the other researchers in the team. To address inconsistencies and questions, all assessors will be trained in the approach used to assess the risk of bias, during a pilot study performed after completion of the study selection. Synthesis of results We will use a narrative synthesis of the available data by using the qualitative and/or the numerical results (means and standard deviations, F, R and P values) of the included studies to form our conclusion. However, if possible, means and standard deviations of the indices in the included studies will be used for a continuous meta-analysis setting. Homogeneity of the included studies will be examined and a fixed or random meta-analysis model will be adapted. Assessment of heterogeneity We will consider studies comparing different groups of T2D patients separately from studies comparing T2D patients against healthy controls. Moreover, we will consider CBT increase from all sources as similar. We will consider the different outcomes separately. We will assess the statistical heterogeneity between studies via the tau2 statistic and its 95% prediction interval. We will consider statistical heterogeneity as considerable if the tau2 prediction interval includes 1 as a measure of no effect for risk ratios and 0 for mean differences and if the prediction interval is twice as wide as the confidence interval. Subgroup analyses Depended on the nature and availability of the extracted data, we will conduct subgroup analyses where relevant. Potential subgroups may include, but not restricted, to: Age : middle-aged adults (31–55 years old) vs. older adults (> 55 years old) [ 48 ]. The aging process has an impact on thermoregulatory mechanisms with older people being more vulnerable to heat [ 49 ]. Older individuals exhibit less efficient sudomotor and vasomotor responses and reduced thermoreceptor sensitivity, resulting in increased risk of developing hyperthermia [ 49 – 51 ]. Sex : males vs. females. As a population, females seem to experience a weaker capacity to dissipate heat compared to male population, particularly in sudomotor activity. Also, women have less body weight, body surface area and absolute maximum oxygen consumption (VO 2max ) compared to men, all of each can interfere with heat loss capacity. [ 52 ]. Body composition : above vs. below a body fat percentage of 28.8 (for men) 34.9 (for women) [ 48 ]. Fat and free-fat tissues exhibit different thermodynamic characteristics, specifically in heat capacity and conductivity [ 53 ]. Fat tissue has lower specific heat capacity and conductivity than lean tissue [ 17 ]. Although research observations are controversial, individuals with greater amounts of fat mass are more likely to have a decreased capacity to dissipate heat to the environment [ 53 , 54 ]. Body morphology : above vs. below a body surface area of 2.0 (for men) 1.7 (for women) m 2 [ 48 ]. Heat is dissipated to the environment through the body surface area [ 51 ]. Therefore, dimensions of the body surface have a crucial effect on whole-body heat exchange [ 55 ]. Individuals with larger surface area have more beneficial sudomotor responses and experience higher rates of heat loss [ 17 , 48 , 51 ]. However, in diseases that hinder sweat production (e.g. T2D), the total surface area that effectively participates in evaporative heat loss mechanisms may be lower than the total body surface [ 17 , 55 ]. Aerobic fitness level : above vs. below a peak oxygen uptake of 48.3 (for men) 41.4 (for women) mlO2/kg fat free mass/min [ 48 ]. Several studies have reported that aerobic fitness levels, typically characterized by VO 2max values, enhance heat loss capacity by lowering internal CBT thresholds for the onset of vasomotor and sudomotor responses [ 51 , 56 ]. In other words, trained individuals exhibit increased heat tolerance and evaporative heat loss capacity and decreased physiological and thermoregulatory strain compared to untrained individuals during heat stress [ 57 , 58 ]. Acclimatization/acclimation status : acclimatized/acclimated vs. non- acclimatized/acclimated. Heat acclimatization is referred as the physiological adaptations in response to high core temperature and is shown to enhance thermoregulatory responses during heat stress [ 59 ]. These physiological adaptations include increases in vasomotor and sudomotor responses, decreased skin and core temperature and improved fluid balance and cardiovascular stability [ 59 , 60 ]. Certainty of evidence assessment To assess the quality of evidence, we will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool, following existing guidelines [ 61 ]. Patient and public involvement As this will be a systematic review of published data, no patients will be involved in any stage of this review. Discussion With the increasing incidence and prevalence of type 2 diabetes and the ongoing global warming, individuals with T2D face a higher risk of heat-related illnesses. Although impairments in heat loss responses are evident in T2D population, the underlying mechanisms remain insufficiently understood. To improve our understanding on the issue at hand, our planned systematic review will encompass a wide range of factors contributing to elevated CBT and its effect on sweat production and skin blood flow mechanisms in T2D patients. Our review aims to highlight and summarise the available scientific data, as well as assess the strengths and limitations of the current evidence. We also aim to identify related knowledge gaps for further research. We hope that our findings will have significant implications for healthcare professionals, policymakers, and researchers, by providing a better understanding of the extent of heat-related risks in individuals with T2D. Thus, the proposed systematic review could contribute to the development of effective, evidence-based strategies and guidelines to mitigate heat-related risks for this vulnerable population. If any amendments are made to this protocol during the review process, they will be outlined in PROSPERO and reported in the final manuscript. Limitations of the study design The limited number of studies, along with between-study variations in methodology and exposure may prevent the ability to conduct a quantitative synthesis in all outcomes of interest. Abbreviations T2D: Type 2 diabetes CBT: Core body temperature PECO: Population/Exposure/Comparator/Outcome PROSPERO: International Prospective Register of Systematic Reviews PRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols VIP: Vasoactive intestinal peptide OR: odds ratio Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. Competing interests The authors have declared that no competing interests exist. Funding The author(s) received no specific funding for this work. Authors’ contributions Conceptualization: Paraskevi Gkiata, Andreas D. Flouris Investigation: Paraskevi Gkiata, Andreas D. Flouris Methodology: Paraskevi Gkiata, Andreas D. Flouris Project administration: Andreas D. Flouris Supervision: Andreas D. Flouris Validation: Maria Vliora, Andreas D. Flouris Writing – original draft: Paraskevi Gkiata, Andreas D. Flouris Writing – review & editing:Maria Vliora, Andreas D. Flouris, Alexandra Bargiota Supplementary information Additional file 1: PRISMA-P 2015 checklist. Additional file 2:Search strategy algorithm References World Meteorological Organization. State of the Global Climate 2023. Geneva;2024 [Available from: https://library.wmo.int/idurl/4/68835. Lee H, Romero J. IPCC, 2023: Summary for Policymakers. In: Climate Change 2023: Synthesis Report. Contribution of Working Groups I, II and III to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change. 2023. van Daalen KR, Romanello M, Rocklov J, Semenza JC, Tonne C, Markandya A, et al. The 2022 Europe report of the Lancet Countdown on health and climate change: towards a climate resilient future. Lancet Public Health. 2022;7(11):e942-e65. Cuschieri S, Calleja Agius J. The interaction between diabetes and climate change - A review on the dual global phenomena. Early Hum Dev. 2021;155:105220. Romanello M, Di Napoli C, Drummond P, Green C, Kennard H, Lampard P, et al. The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels. Lancet. 2022;400(10363):1619-54. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21(17). Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119. Kenny GP, Sigal RJ, McGinn R. Body temperature regulation in diabetes. Temperature (Austin). 2016;3(1):119-45. Kenny GP, Stapleton JM, Yardley JE, Boulay P, Sigal RJ. Older adults with type 2 diabetes store more heat during exercise. Med Sci Sports Exerc. 2013;45(10):1906-14. Lam HCY, Chan JCN, Luk AOY, Chan EYY, Goggins WB. Short-term association between ambient temperature and acute myocardial infarction hospitalizations for diabetes mellitus patients: A time series study. PLoS Med. 2018;15(7):e1002612. Morgan RL, Whaley P, Thayer KA, Schunemann HJ. Identifying the PECO: A framework for formulating good questions to explore the association of environmental and other exposures with health outcomes. Environ Int. 2018;121(Pt 1):1027-31. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. Lim CL, Byrne C, Lee JK. Human thermoregulation and measurement of body temperature in exercise and clinical settings. Ann Acad Med Singap. 2008;37(4):347-53. Lim CL. Fundamental Concepts of Human Thermoregulation and Adaptation to Heat: A Review in the Context of Global Warming. Int J Environ Res Public Health. 2020;17(21). Hymczak H, Gołąb A, Mendrala K, Plicner D, Darocha T, Podsiadło P, et al. Core Temperature Measurement-Principles of Correct Measurement, Problems, and Complications. Int J Environ Res Public Health. 2021;18(20). Moran DS, Mendal L. Core Temperature Measurement. Sports Medicine. 2002;32(14):879-85. Cramer MN, Gagnon D, Laitano O, Crandall CG. Human temperature regulation under heat stress in health, disease, and injury. Physiol Rev. 2022;102(4):1907-89. Flouris AD. Human Thermoregulation. In: Périard JD, Racinais S, editors. Heat Stress in Sport and Exercise: Thermophysiology of Health and Performance. Cham: Springer International Publishing; 2019. p. 3-27. Flouris A. Human Thermoregulation: Thermophysiology of Health and Performance. 2019. p. 3-27. Kenny GP, Groeller H, McGinn R, Flouris AD. Age, human performance, and physical employment standards. Appl Physiol Nutr Metab. 2016;41(6 Suppl 2):S92-S107. Kovats RS, Hajat S. Heat stress and public health: a critical review. Annu Rev Public Health. 2008;29:41-55. Notley SR, Poirier MP, Sigal RJ, D'Souza A, Flouris AD, Fujii N, et al. Exercise Heat Stress in Patients With and Without Type 2 Diabetes. Jama. 2019;322(14):1409-11. Moon J. The effect of the heatwave on the morbidity and mortality of diabetes patients; a meta-analysis for the era of the climate crisis. Environmental Research. 2021;195:110762. Ospelt E, Hardison H, Mungmode A, Noor N, Bankole K, Anikpezie N, et al. The Impact of Climate Change on People Living with Diabetes: A Scoping Review. Clinical Diabetology. 2023;12(3):186-200. Buchmann SJ, Penzlin AI, Kubasch ML, Illigens BM, Siepmann T. Assessment of sudomotor function. Clin Auton Res. 2019;29(1):41-53. Charkoudian N. Human thermoregulation from the autonomic perspective. Auton Neurosci. 2016;196:1-2. Charkoudian N. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol (1985). 2010;109(4):1221-8. Wick DE, Roberts SK, Basu A, Sandroni P, Fealey RD, Sletten D, et al. Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. J Appl Physiol (1985). 2006;100(2):637-41. Akbar M, Wandy A, Soraya GV, Goysal Y, Lotisna M, Basri MI. Sudomotor dysfunction in diabetic peripheral neuropathy (DPN) and its testing modalities: A literature review. Heliyon. 2023;9(7):e18184. Saghiv MS, Sagiv MS. Thermoregulation. Basic Exercise Physiology: Clinical and Laboratory Perspectives. Cham: Springer International Publishing; 2020. p. 437-63. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-48. Johnson JM, Minson CT, Kellogg DL, Jr. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol. 2014;4(1):33-89. Johnson JM, Kellogg DL, Jr. Thermoregulatory and thermal control in the human cutaneous circulation. Front Biosci (Schol Ed). 2010;2(3):825-53. Wenger CB. Heat of evaporation of sweat: thermodynamic considerations. J Appl Physiol. 1972;32(4):456-9. Shibasaki M, Wilson TE, Crandall CG. Neural control and mechanisms of eccrine sweating during heat stress and exercise. J Appl Physiol (1985). 2006;100(5):1692-701. Gagnon D, Crandall CG. Chapter 13 - Sweating as a heat loss thermoeffector. In: Romanovsky AA, editor. Handbook of Clinical Neurology. 156: Elsevier; 2018. p. 211-32. Illigens BM, Gibbons CH. Sweat testing to evaluate autonomic function. Clin Auton Res. 2009;19(2):79-87. Low PA, Caskey PE, Tuck RR, Fealey RD, Dyck PJ. Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol. 1983;14(5):573-80. Petrofsky JS. The effect of type-2-diabetes-related vascular endothelial dysfunction on skin physiology and activities of daily living. Journal of diabetes science and technology. 2011;5(3):657-67. Wick DE, Roberts SK, Basu A, Sandroni P, Fealey RD, Sletten D, et al. Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. Journal of Applied Physiology. 2006;100(2):637-41. Petrofsky JS, Besonis C, Rivera D, Schwab E, Lee S. Impairment in orthostatic tolerance during heat exposure in individuals with Type I and Type II diabetes. Medical science monitor : international medical journal of experimental and clinical research. 2005;11(4):Cr153-9. Kirby NV, Meade RD, Poirier MP, Sigal RJ, Boulay P, Kenny GP. Association between haemoglobin A(1c) and whole-body heat loss during exercise-heat stress in physically active men with type 2 diabetes. Experimental physiology. 2023;108(3):338-43. Poirier MP, Notley SR, Boulay P, Sigal RJ, Friesen BJ, Malcolm J, et al. Type 2 diabetes does not exacerbate body heat storage in older adults during brief, extreme passive heat exposure. Temperature (Austin, Tex). 2020;7(3):263-9. Fujii N, Meade RD, Akbari P, Louie JC, Alexander LM, Boulay P, et al. No effect of ascorbate on cutaneous vasodilation and sweating in older men and those with type 2 diabetes exercising in the heat. Physiological reports. 2017;5(7). McGarr GW, Fujii N, McNeely BD, Hatam K, Nishiyasu T, Sigal RJ, et al. Superoxide and NADPH oxidase do not modulate skin blood flow in older exercising adults with and without type 2 diabetes. Microvascular research. 2019;125:103886. Kirby NV, Meade RD, Poirier MP, Notley SR, Sigal RJ, Boulay P, et al. Exercise intensity- and body region-specific differences in sweating in middle-aged to older men with and without type 2 diabetes. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2024;326(6):R588-R98. Behzadi P, Ravanelli N, Gravel H, Barry H, Debray A, Chaseling GK, et al. Acute effect of passive heat exposure on markers of cardiometabolic function in adults with type 2 diabetes mellitus. Journal of applied physiology (Bethesda, Md : 1985). 2022;132(5):1154-66. Flouris AD, McGinn R, Poirier MP, Louie JC, Ioannou LG, Tsoutsoubi L, et al. Screening criteria for increased susceptibility to heat stress during work or leisure in hot environments in healthy individuals aged 31-70 years. Temperature (Austin). 2018;5(1):86-99. Meade RD, Akerman AP, Notley SR, McGinn R, Poirier P, Gosselin P, et al. Physiological factors characterizing heat-vulnerable older adults: A narrative review. Environ Int. 2020;144:105909. Blatteis CM. Age-dependent changes in temperature regulation - a mini review. Gerontology. 2012;58(4):289-95. Periard JD, Eijsvogels TMH, Daanen HAM. Exercise under heat stress: thermoregulation, hydration, performance implications, and mitigation strategies. Physiol Rev. 2021;101(4):1873-979. Gagnon D, Kenny GP. Does sex have an independent effect on thermoeffector responses during exercise in the heat? J Physiol. 2012;590(23):5963-73. Morrissey MC, Wu Y, Zuk EF, Livingston J, Casa DJ, Pescatello LS. The impact of body fat on thermoregulation during exercise in the heat: A systematic review and meta-analysis. J Sci Med Sport. 2021;24(8):843-50. Dervis S, Coombs GB, Chaseling GK, Filingeri D, Smoljanic J, Jay O. A comparison of thermoregulatory responses to exercise between mass-matched groups with large differences in body fat. J Appl Physiol (1985). 2016;120(6):615-23. Cramer MN, Jay O. Biophysical aspects of human thermoregulation during heat stress. Auton Neurosci. 2016;196:3-13. Lamarche DT, Notley SR, Poirier MP, Kenny GP. Fitness-related differences in the rate of whole-body total heat loss in exercising young healthy women are heat-load dependent. Exp Physiol. 2018;103(3):312-7. Cheung SS, McLellan TM, Tenaglia S. The thermophysiology of uncompensable heat stress. Physiological manipulations and individual characteristics. Sports Med. 2000;29(5):329-59. Cheung SS, McLellan TM. Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress. J Appl Physiol (1985). 1998;84(5):1731-9. Kenny GP, Wilson TE, Flouris AD, Fujii N. Chapter 31 - Heat exhaustion. In: Romanovsky AA, editor. Handbook of Clinical Neurology. 157: Elsevier; 2018. p. 505-29. Periard JD, Racinais S, Sawka MN. Adaptations and mechanisms of human heat acclimation: Applications for competitive athletes and sports. Scand J Med Sci Sports. 2015;25 Suppl 1:20-38. Schünemann H, Brożek J, Guyatt G, Oxman A. The GRADE handbook: Cochrane Collaboration; 2013. Supplementary Files Additionalfile1PRISMAP2015checklist.docx Additional file 1: PRISMA-P 2015 checklist. Additionalfile2Searchstrategyalgortihm.docx Additional file 2: Search strategy algorithm Cite Share Download PDF Status: Published Journal Publication published 12 Dec, 2025 Read the published version in Systematic Reviews → Version 1 posted Editorial decision: Minor revision 17 Sep, 2025 Reviewers agreed at journal 07 Aug, 2025 Reviewers invited by journal 07 Aug, 2025 Editor assigned by journal 07 Aug, 2025 First submitted to journal 24 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7204080","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":497066418,"identity":"1587340e-4b5f-44db-bae4-28bd95df8924","order_by":0,"name":"Paraskevi Gkiata","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACHsYGMM3GwNj4AMTnI0rLAYiWZgMQn42wFiA+AGGySUCsIwDkfQ43fv5Qw5DYJ5HcVvk1x06GjYH54aMbeLQYnm1sljhwjCGxTSKx7bbstmSgw9iMjXPwaelnbJA4wMZgzMZzsO225DZmoBYeNmkCWpp/HPgH0VIsua2esBZ53sY2iYNtDHJs7I1tjB+3HSasxQBouMXZPgmQlmZpxm3HediYCfhFvif98Y2KbzY88s3sDz/+3FZtz8/e/PAxXlsOgClwjDAw84BJPMrBtjQgcRh/EFA9CkbBKBgFIxMAAEpzQwQc6IoeAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0006-4965-3768","institution":"FAME Laboratory, Department of Physical Educarion and Sport Science, University of Thessaly, Trikala, Greece","correspondingAuthor":true,"prefix":"","firstName":"Paraskevi","middleName":"","lastName":"Gkiata","suffix":""},{"id":497066419,"identity":"379c05a5-6350-4804-b019-1a8731ac53a5","order_by":1,"name":"Maria Vliora","email":"","orcid":"","institution":"FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, Greece","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Vliora","suffix":""},{"id":497066420,"identity":"cd96eff2-59d9-4d71-93b4-9fa673585217","order_by":2,"name":"Alexandra Bargiota","email":"","orcid":"","institution":"Department of Endocrinology and Metabolic Diseases, University General Hospital of Larissa, Larissa, Greece","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Bargiota","suffix":""},{"id":497066421,"identity":"902cadd5-578d-4fbd-b7fb-cab615f2375b","order_by":3,"name":"Andreas D. Flouris","email":"","orcid":"","institution":"FAME Laboratory, Department of Physical Education and Sport Science, University of Thessaly, Trikala, Greece","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"D.","lastName":"Flouris","suffix":""}],"badges":[],"createdAt":"2025-07-24 09:40:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7204080/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7204080/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-025-02991-0","type":"published","date":"2025-12-12T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":98243526,"identity":"8c594c40-95f3-4deb-9be8-821a7935e718","added_by":"auto","created_at":"2025-12-15 16:08:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":703527,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7204080/v1/fd789084-f7c6-44c2-bd94-f5a7572601a9.pdf"},{"id":88931233,"identity":"cfd51f50-76d2-4bcb-b776-2b1bdc1b1a84","added_by":"auto","created_at":"2025-08-12 21:45:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34770,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1: PRISMA-P 2015 checklist.\u003c/p\u003e","description":"","filename":"Additionalfile1PRISMAP2015checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7204080/v1/a2f15ae78354e95f4680bd1e.docx"},{"id":88931017,"identity":"44ad8d00-131f-4e87-9d15-d268bad7c8e4","added_by":"auto","created_at":"2025-08-12 21:37:00","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14732,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 2:\u003cstrong\u003e \u003c/strong\u003eSearch strategy algorithm\u003c/p\u003e","description":"","filename":"Additionalfile2Searchstrategyalgortihm.docx","url":"https://assets-eu.researchsquare.com/files/rs-7204080/v1/53f462b6ee670ae9d0cb3bb8.docx"}],"financialInterests":"","formattedTitle":"The effect of increased core body temperature on the vasomotor and sudomotor responses of patients with type 2 diabetes: Protocol of a systematic literature review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eClimate change has driven the world to an emergency due to global warming, with the average surface air temperature having increased by 1.48°C since the pre-industrial period [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], a trend that will continue at least until 2040 according to the Intergovernmental Panel on Climate Change [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The accelerated pace of global warming is shown by the fact that the last eight years have been the hottest on record [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. As a result, people are being more exposed to heat and extreme heat events (i.e., heatwaves), which have direct impacts on their health [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Heat-related disorders, such as heat exhaustion and heatstroke, increase the risk of morbidity and mortality, and amplify the complications of pre-existing health conditions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eType 2 diabetes mellitus (T2D) is a chronic health condition characterized by elevated levels of blood glucose that has reached pandemic levels [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. According to the International Diabetes Federation, 483\u0026nbsp;million people globally (9% of total population) live with T2D and this figure will surpass 700\u0026nbsp;million by 2045 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. T2D contributes to an impaired thermoregulatory system, resulting in patients storing more heat when they rest or are physically active in a hot environment, resulting in a higher core body temperature (CBT) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. On this basis, patients with T2D are among the most vulnerable population groups during heat exposure [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A number of studies published within the last decade have investigated different physiological and molecular mechanisms to understand the vulnerability of T2D patients to rising CBT. However, at present these mechanisms remain only partly understood, primarily because the results are too complex to interpret by examining single studies/trials in specific settings. In the era of climate change, rising global temperature, and increasing prevalence of T2D, a systematic review approach is necessary to determine how the thermoregulatory system of patients with T2D responds to rising CBT.\u003c/p\u003e\u003cp\u003eIn the present paper, we describe the protocol for a systematic review of primary studies on heat loss mechanisms during hyperthermia in individuals with T2D. Specifically, the objective of this review is to address the following Population/Exposure/Comparator/Outcome (PECO) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] question: what is the effect of an increase in CBT level (E) on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these responses (O) within individuals with T2D (P) compared to healthy individuals at the same level of CBT and/or T2D patients at lower or normal CBT level (C)?\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eRegistration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe systematic review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42023471939. The study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (Additional file 1) [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. In case any amendments to this protocol are made during the review process, changes and related reasons will be reported in the final article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PECO criteria [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e] are listed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and are outlined in the subsequent sections.\u003c/p\u003e\n\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003cimg 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\"\u003e\u003c/div\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will consider for inclusion studies reporting on the outcomes of interest in patients with T2D with or without comparison against healthy individuals, regardless of sex, gender, age, or geographical region.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription and types of exposure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CBT refers to the temperature of deep body tissues such as the heart, brain, and lungs, and it is typically measured in the following sites: sublingual, ear canal, tympanic, forehead, axilla, rectum, esophagus, gastrointestinal tract, blood, artery, bladder, brain [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. The CBT can be regulated via thermoregulatory mechanisms within a narrow range, around 37\u0026deg;C, which is considered optimum for enzyme efficiency, biological procedures, and organ function [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. This requires a heat balance between the human body and the environment, where the amount of internal heat production via metabolism and heat gain from the environment equal the heat dissipation to the environment [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. An individual\u0026rsquo;s CBT can increase due to three main factors [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1. High heat exposure from the environment (for example, increased air temperature and humidity, radiant heat sources, limited air flow);\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e2. Increased metabolic heat production from performing physically demanding tasks;\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e3. Thermal insulation from clothing.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eIncreased CBT can be dangerous to everyone, and especially to patients with T2D [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] because they have a limited capacity to regulate CBT when they are under heat stress [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. In turn, this raises the risk for health complications, which may explain the increased morbidity and mortality of T2D patients during heatwaves [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eIn the proposed systematic review, we will consider an increased CBT as the exposure in question. As such, we will include all studies that provide data for the effects of increased CBT level on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these thermoregulatory responses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of comparators\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will compare our population under investigation (i.e., T2D patients) with the following comparator populations: (1) healthy individuals at the same level of CBT, and (2) patients with T2D with lower or normal CBT level.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription and types of outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIncreased CBT activates autonomic responses to dissipate heat to the environment by two major mechanisms: cutaneous vasodilation (vasomotor response) and sweat production (sudomotor response) [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. Patients with T2D are at increased risk of hyperthermia as a result of attenuated vasomotor and sudomotor responses [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. This has been attributed to a number of factors, including diabetic neuropathy and microvascular dysfunction [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. Other potential contributors include poor glycemic control, disease duration, and T2D-related complications [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. The outcomes analyzed below contribute to attenuated vasomotor and sudomotor responses in T2D patients and will be analysed as part of this systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVasomotor responses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCutaneous vasodilation channels blood flow to the small skin capillaries to dissipate heat to the environment by convection, conduction, and radiation [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. This way of dissipating heat is often termed \u0026ldquo;dry heat loss\u0026rdquo; and it is crucial for thermoregulation, especially during periods of rest. To function, the vasomotor response requires an increased cardiac output and redistribution of the blood flow from the body core to the skin surface [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. Cutaneous vasodilation during hyperthermia is driven primarily by sympathetic vasodilator nerve activity in response to the release of acetylcholine and other co-transmitters via cholinergic nerve transmission [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. Nitric oxide, substance P, vasoactive intestinal peptide (VIP), prostaglandins, and histamine hold key roles in the vasomotor response due to increased CBT [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eWe will derive data from the mostly used techniques for measuring skin blood flow including venous occlusion plethysmography, Doppler ultrasound, and laser-doppler flowmetry. If present, other validated and objective measures will be also considered in the identified studies. We will also consider all physiological and molecular parameters that may play a role in the mechanisms that control vasomotor responses of T2D patients and healthy individuals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSudomotor responses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn circumstances where the ambient temperature exceeds skin temperature, dry heat loss cannot function and another mechanism is needed to dissipate heat from the body to the environment [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. In these conditions as well as during periods of physical work, the sudomotor response is the major mechanism of heat loss from the body to the environment [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. It is often termed \u0026ldquo;wet heat loss\u0026rdquo; and results in sweat secretion on the skin surface which, if evaporated, leads to cooling at a rate of 2426 J per g [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. Sweat is secreted in response to increased CBT by eccrine sweat glands that are distributed over the skin surface [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Eccrine glands are cholinergically innervated tubular glands controlled sympathetically from the hypothalamus through peripheral and central thermoaffector neural signals. Acetylcholine is the principal neurotransmitter, released by sudomotor nerves, which connects to muscarinic receptors on the eccrine sweat glands to activate sweat production [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe most common physiological measurements of sudomotor function include the thermoregulatory sweat testing, the quantitative sudomotor axon reflex sweat testing, silicone impressions (patches), the sympathetic skin response, electrochemical skin conductance, sweat sensitive test, quantitative direct and indirect axon reflex testing, whole-body sweat rate, as well as local sweat rate [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. If present, other validated and objective measures will be also considered in the identified studies. We will also consider all physiological and molecular parameters that may play a role in the mechanisms that control sudomotor responses of T2D patients and healthy individuals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies included in this review will investigate T2D patients, with or without a healthy control group, at different levels of CBT. For all outcomes we will consider papers that have measured CBT regardless of the factor contributing to elevated CBT. We will include both randomized and non-randomized controlled trials with parallel groups or with a crossover study design. Single group design studies will be also considered. In any type of observational studies (e.g., cohort; case-control studies), the researcher observes/records people with T2D at different levels of CBT without manipulation or intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will exclude case reports, editorials, opinion papers, reviews, conference proceedings, letters to editors and modelling approaches (i.e., studies that estimate the effect of ambient conditions on humans with mathematical models, without involving human participants). In addition, animal studies or \u003cem\u003ein vitro\u003c/em\u003e experiments will be excluded from this systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYears considered\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe selected scientific databases will be searched from the date of their inception to present. No restrictions in the year of publication will be applied.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication language\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo articles will be excluded based on language, but our search will be conducted using English terms. We will include studies written in any language, provided that an English translation can be obtained using Google Translate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication types\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQuantitative peer-reviewed publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTypes of effect measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor dichotomous data, risk ratios will be computed as the measure of the effect. When hazard ratios are presented, we will consider them to be similar to risk ratios. If odds ratios (OR) are provided and the prevalence of the outcome is less than 10%, we will assume that OR are similar to risk ratios. However, if the prevalence is higher, we will convert OR into risk ratios. For continuous data we will calculate mean differences. When outcomes are assessed but in different scales, we will calculate standardized mean difference.\u003c/p\u003e\n\u003cp\u003eSearch strategy\u003c/p\u003e\n\u003cp\u003eA keyword algorithmic search, according to the PECO approach, will be performed in two scientific databases: Pubmed and Embase. The algorithm for the search for the two databases has been already developed and has been formed using the Boolean OR, AND, NOT and possibly truncations (ie, *) and wildcards (Additional file 1). Alerts will be created in each database to identify new publications. To identify other eligible publications related to our research question, reference lists of included studies will be screened for a manual search.\u003c/p\u003e\n\u003cp\u003eTo test the validity of the search algorithm, we created a \u0026ldquo;golden library\u0026rdquo; by using the following procedure: (1) we applied the above-mentioned search algorithm in PubMed, which retrieved 11,037 publications (02-07-2025); (2) we screened the initial 200 articles and identified two narrative reviews on the topic of heat stress in T2D patients [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]); (3) we checked the titles and abstracts of the 287 references of the two identified narrative reviews to determine their eligibility against the eligibility criteria of the PECO question in the proposed systematic review, resulting in a total of 3 eligible studies [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]; (4) to increase the size of our \u0026ldquo;golden library\u0026rdquo;, we manually searched the PubMed database through a trial-and-error approach using keywords related to the PECO question in the proposed systematic review (e.g., heat, type 2 diabetes, sudomotor, skin blood flow, sweat rate, etc.) to identify relevant studies, resulting in a total of 6 eligible studies [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. The outcome of this process resulted in a \u0026ldquo;golden library\u0026rdquo; of 9 eligible studies. Subsequently, we searched whether the publications of the \u0026ldquo;golden library\u0026rdquo; were detected by the searching algorithm in PubMed. We found that the searching algorithm detects 8 out of the 9 publications of the \u0026ldquo;golden library\u0026rdquo;. The calculated sensitivity of the searching algorithm [eligible studies detected (n) / gold standard eligible (n)] was 0.89, suggesting that the search algorithm is sensitive enough to capture an adequate number of eligible publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the retrieved publications will be saved on an Endnote software file. Initially, all duplicate records will be excluded. Thereafter, two investigators will, independently, screen all titles and abstracts of the retrieved publications for eligibility using the above-mentioned inclusion and exclusion criteria. Articles that will be marked as unclear will be moved at the full-text review screening step. Eligible publications with unavailable access to full-text will be requested through email to the lead author or the journal. Any disagreements regarding eligibility will be resolved by a third investigator who will act as a referee and make the final decision. Finally, the full text of the articles that passed the first stage of eligibility check (based on title and abstract) will be screened to ensure they fulfill the present eligibility criteria. At the end of this process, a complete list of eligible publications will be presented. A PRISMA flow chart will be created to describe in detail all procedures of identification and exclusion. A full list of the excluded publications will also be included in the in a supplementary file of the systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each eligible study we will extract the following data:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003efirst author names,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eyear of publication,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003estudy design and characteristics,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003elocation,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003epatient sample size,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eage,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003esex,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ehealth status,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eco-morbidities,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ebody mass index,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ebody surface area,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eexposure assessment,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003edefinition and measurement of the main outcomes,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ebaseline differences,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003esampling time frame,\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003einclusion/exclusion criteria.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWhen necessary, the reviewers will contact via email the corresponding author if full text required data of an article are unclear or missing. All extracted data will be recorded in Excel format agreed among the investigators. Any discrepancies will be resolved with consensus by a third reviewer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe included publications will be evaluated for risk of bias using the Office of Health Assessment and Translation (OHAT) tool. Two review authors will independently assess the risk of bias in the included studies and conflicts in the risk of bias assessment will be resolved by an independent referee investigator. In cases where eligible publications have been co-authored by any of these investigators, the assessment will be performed by the other researchers in the team. To address inconsistencies and questions, all assessors will be trained in the approach used to assess the risk of bias, during a pilot study performed after completion of the study selection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis of results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will use a narrative synthesis of the available data by using the qualitative and/or the numerical results (means and standard deviations, F, R and P values) of the included studies to form our conclusion. However, if possible, means and standard deviations of the indices in the included studies will be used for a continuous meta-analysis setting. Homogeneity of the included studies will be examined and a fixed or random meta-analysis model will be adapted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of heterogeneity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will consider studies comparing different groups of T2D patients separately from studies comparing T2D patients against healthy controls. Moreover, we will consider CBT increase from all sources as similar. We will consider the different outcomes separately. We will assess the statistical heterogeneity between studies via the tau2 statistic and its 95% prediction interval. We will consider statistical heterogeneity as considerable if the tau2 prediction interval includes 1 as a measure of no effect for risk ratios and 0 for mean differences and if the prediction interval is twice as wide as the confidence interval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepended on the nature and availability of the extracted data, we will conduct subgroup analyses where relevant. Potential subgroups may include, but not restricted, to:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAge\u003c/span\u003e: middle-aged adults (31\u0026ndash;55 years old) vs. older adults (\u0026gt;\u0026thinsp;55 years old) [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. The aging process has an impact on thermoregulatory mechanisms with older people being more vulnerable to heat [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]. Older individuals exhibit less efficient sudomotor and vasomotor responses and reduced thermoreceptor sensitivity, resulting in increased risk of developing hyperthermia [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSex\u003c/span\u003e: males vs. females. As a population, females seem to experience a weaker capacity to dissipate heat compared to male population, particularly in sudomotor activity. Also, women have less body weight, body surface area and absolute maximum oxygen consumption (VO\u003csub\u003e2max\u003c/sub\u003e) compared to men, all of each can interfere with heat loss capacity. [\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBody composition\u003c/span\u003e: above vs. below a body fat percentage of 28.8 (for men) 34.9 (for women) [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. Fat and free-fat tissues exhibit different thermodynamic characteristics, specifically in heat capacity and conductivity [\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e]. Fat tissue has lower specific heat capacity and conductivity than lean tissue [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although research observations are controversial, individuals with greater amounts of fat mass are more likely to have a decreased capacity to dissipate heat to the environment [\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBody morphology\u003c/span\u003e: above vs. below a body surface area of 2.0 (for men) 1.7 (for women) m\u003csup\u003e2\u003c/sup\u003e [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. Heat is dissipated to the environment through the body surface area [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]. Therefore, dimensions of the body surface have a crucial effect on whole-body heat exchange [\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e]. Individuals with larger surface area have more beneficial sudomotor responses and experience higher rates of heat loss [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]. However, in diseases that hinder sweat production (e.g. T2D), the total surface area that effectively participates in evaporative heat loss mechanisms may be lower than the total body surface [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAerobic fitness level\u003c/span\u003e: above vs. below a peak oxygen uptake of 48.3 (for men) 41.4 (for women) mlO2/kg fat free mass/min [\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. Several studies have reported that aerobic fitness levels, typically characterized by VO\u003csub\u003e2max\u003c/sub\u003e values, enhance heat loss capacity by lowering internal CBT thresholds for the onset of vasomotor and sudomotor responses [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e]. In other words, trained individuals exhibit increased heat tolerance and evaporative heat loss capacity and decreased physiological and thermoregulatory strain compared to untrained individuals during heat stress [\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAcclimatization/acclimation status\u003c/span\u003e: acclimatized/acclimated vs. non- acclimatized/acclimated. Heat acclimatization is referred as the physiological adaptations in response to high core temperature and is shown to enhance thermoregulatory responses during heat stress [\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e]. These physiological adaptations include increases in vasomotor and sudomotor responses, decreased skin and core temperature and improved fluid balance and cardiovascular stability [\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eCertainty of evidence assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the quality of evidence, we will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool, following existing guidelines [\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and public involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs this will be a systematic review of published data, no patients will be involved in any stage of this review.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWith the increasing incidence and prevalence of type 2 diabetes and the ongoing global warming, individuals with T2D face a higher risk of heat-related illnesses. Although impairments in heat loss responses are evident in T2D population, the underlying mechanisms remain insufficiently understood. To improve our understanding on the issue at hand, our planned systematic review will encompass a wide range of factors contributing to elevated CBT and its effect on sweat production and skin blood flow mechanisms in T2D patients. Our review aims to highlight and summarise the available scientific data, as well as assess the strengths and limitations of the current evidence. We also aim to identify related knowledge gaps for further research. We hope that our findings will have significant implications for healthcare professionals, policymakers, and researchers, by providing a better understanding of the extent of heat-related risks in individuals with T2D. Thus, the proposed systematic review could contribute to the development of effective, evidence-based strategies and guidelines to mitigate heat-related risks for this vulnerable population. If any amendments are made to this protocol during the review process, they will be outlined in PROSPERO and reported in the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations of the study design\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe limited number of studies, along with between-study variations in methodology and exposure may prevent the ability to conduct a quantitative synthesis in all outcomes of interest.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eT2D: Type 2 diabetes\u003c/p\u003e\n\u003cp\u003eCBT: Core body temperature\u003c/p\u003e\n\u003cp\u003ePECO: Population/Exposure/Comparator/Outcome\u003c/p\u003e\n\u003cp\u003ePROSPERO: International Prospective Register of Systematic Reviews\u003c/p\u003e\n\u003cp\u003ePRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols\u003c/p\u003e\n\u003cp\u003eVIP: Vasoactive intestinal peptide\u003c/p\u003e\n\u003cp\u003eOR: odds ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no competing interests exist.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe author(s) received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eConceptualization: Paraskevi Gkiata, Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eInvestigation: Paraskevi Gkiata, Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eMethodology: Paraskevi Gkiata, Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eProject administration: Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eSupervision: Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eValidation: Maria Vliora, Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; original draft: Paraskevi Gkiata, Andreas D. Flouris\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; review \u0026amp; editing:Maria Vliora, Andreas D. Flouris, Alexandra Bargiota\u003c/p\u003e\n\u003cp\u003eSupplementary information\u003c/p\u003e\n\u003cp\u003eAdditional file 1: PRISMA-P 2015 checklist.\u003c/p\u003e\n\u003cp\u003eAdditional file 2:Search strategy algorithm\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Meteorological Organization. State of the Global Climate 2023. Geneva;2024 [Available from: https://library.wmo.int/idurl/4/68835.\u003c/li\u003e\n\u003cli\u003eLee H, Romero J. IPCC, 2023: Summary for Policymakers. In: Climate Change 2023: Synthesis Report. Contribution of Working Groups I, II and III to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change. 2023.\u003c/li\u003e\n\u003cli\u003evan Daalen KR, Romanello M, Rocklov J, Semenza JC, Tonne C, Markandya A, et al. The 2022 Europe report of the Lancet Countdown on health and climate change: towards a climate resilient future. Lancet Public Health. 2022;7(11):e942-e65.\u003c/li\u003e\n\u003cli\u003eCuschieri S, Calleja Agius J. The interaction between diabetes and climate change - A review on the dual global phenomena. Early Hum Dev. 2021;155:105220.\u003c/li\u003e\n\u003cli\u003eRomanello M, Di Napoli C, Drummond P, Green C, Kennard H, Lampard P, et al. The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels. Lancet. 2022;400(10363):1619-54.\u003c/li\u003e\n\u003cli\u003eGalicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21(17).\u003c/li\u003e\n\u003cli\u003eSun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.\u003c/li\u003e\n\u003cli\u003eKenny GP, Sigal RJ, McGinn R. Body temperature regulation in diabetes. Temperature (Austin). 2016;3(1):119-45.\u003c/li\u003e\n\u003cli\u003eKenny GP, Stapleton JM, Yardley JE, Boulay P, Sigal RJ. Older adults with type 2 diabetes store more heat during exercise. Med Sci Sports Exerc. 2013;45(10):1906-14.\u003c/li\u003e\n\u003cli\u003eLam HCY, Chan JCN, Luk AOY, Chan EYY, Goggins WB. Short-term association between ambient temperature and acute myocardial infarction hospitalizations for diabetes mellitus patients: A time series study. PLoS Med. 2018;15(7):e1002612.\u003c/li\u003e\n\u003cli\u003eMorgan RL, Whaley P, Thayer KA, Schunemann HJ. Identifying the PECO: A framework for formulating good questions to explore the association of environmental and other exposures with health outcomes. Environ Int. 2018;121(Pt 1):1027-31.\u003c/li\u003e\n\u003cli\u003eMoher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.\u003c/li\u003e\n\u003cli\u003eLim CL, Byrne C, Lee JK. Human thermoregulation and measurement of body temperature in exercise and clinical settings. Ann Acad Med Singap. 2008;37(4):347-53.\u003c/li\u003e\n\u003cli\u003eLim CL. Fundamental Concepts of Human Thermoregulation and Adaptation to Heat: A Review in the Context of Global Warming. Int J Environ Res Public Health. 2020;17(21).\u003c/li\u003e\n\u003cli\u003eHymczak H, Gołąb A, Mendrala K, Plicner D, Darocha T, Podsiadło P, et al. Core Temperature Measurement-Principles of Correct Measurement, Problems, and Complications. Int J Environ Res Public Health. 2021;18(20).\u003c/li\u003e\n\u003cli\u003eMoran DS, Mendal L. Core Temperature Measurement. Sports Medicine. 2002;32(14):879-85.\u003c/li\u003e\n\u003cli\u003eCramer MN, Gagnon D, Laitano O, Crandall CG. Human temperature regulation under heat stress in health, disease, and injury. Physiol Rev. 2022;102(4):1907-89.\u003c/li\u003e\n\u003cli\u003eFlouris AD. Human Thermoregulation. In: P\u0026eacute;riard JD, Racinais S, editors. Heat Stress in Sport and Exercise: Thermophysiology of Health and Performance. Cham: Springer International Publishing; 2019. p. 3-27.\u003c/li\u003e\n\u003cli\u003eFlouris A. Human Thermoregulation: Thermophysiology of Health and Performance. 2019. p. 3-27.\u003c/li\u003e\n\u003cli\u003eKenny GP, Groeller H, McGinn R, Flouris AD. Age, human performance, and physical employment standards. Appl Physiol Nutr Metab. 2016;41(6 Suppl 2):S92-S107.\u003c/li\u003e\n\u003cli\u003eKovats RS, Hajat S. Heat stress and public health: a critical review. Annu Rev Public Health. 2008;29:41-55.\u003c/li\u003e\n\u003cli\u003eNotley SR, Poirier MP, Sigal RJ, D\u0026apos;Souza A, Flouris AD, Fujii N, et al. Exercise Heat Stress in Patients With and Without Type 2 Diabetes. Jama. 2019;322(14):1409-11.\u003c/li\u003e\n\u003cli\u003eMoon J. The effect of the heatwave on the morbidity and mortality of diabetes patients; a meta-analysis for the era of the climate crisis. Environmental Research. 2021;195:110762.\u003c/li\u003e\n\u003cli\u003eOspelt E, Hardison H, Mungmode A, Noor N, Bankole K, Anikpezie N, et al. The Impact of Climate Change on People Living with Diabetes: A Scoping Review. Clinical Diabetology. 2023;12(3):186-200.\u003c/li\u003e\n\u003cli\u003eBuchmann SJ, Penzlin AI, Kubasch ML, Illigens BM, Siepmann T. Assessment of sudomotor function. Clin Auton Res. 2019;29(1):41-53.\u003c/li\u003e\n\u003cli\u003eCharkoudian N. Human thermoregulation from the autonomic perspective. Auton Neurosci. 2016;196:1-2.\u003c/li\u003e\n\u003cli\u003eCharkoudian N. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol (1985). 2010;109(4):1221-8.\u003c/li\u003e\n\u003cli\u003eWick DE, Roberts SK, Basu A, Sandroni P, Fealey RD, Sletten D, et al. Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. J Appl Physiol (1985). 2006;100(2):637-41.\u003c/li\u003e\n\u003cli\u003eAkbar M, Wandy A, Soraya GV, Goysal Y, Lotisna M, Basri MI. Sudomotor dysfunction in diabetic peripheral neuropathy (DPN) and its testing modalities: A literature review. Heliyon. 2023;9(7):e18184.\u003c/li\u003e\n\u003cli\u003eSaghiv MS, Sagiv MS. Thermoregulation. Basic Exercise Physiology: Clinical and Laboratory Perspectives. Cham: Springer International Publishing; 2020. p. 437-63.\u003c/li\u003e\n\u003cli\u003eTansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-48.\u003c/li\u003e\n\u003cli\u003eJohnson JM, Minson CT, Kellogg DL, Jr. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol. 2014;4(1):33-89.\u003c/li\u003e\n\u003cli\u003eJohnson JM, Kellogg DL, Jr. Thermoregulatory and thermal control in the human cutaneous circulation. Front Biosci (Schol Ed). 2010;2(3):825-53.\u003c/li\u003e\n\u003cli\u003eWenger CB. Heat of evaporation of sweat: thermodynamic considerations. J Appl Physiol. 1972;32(4):456-9.\u003c/li\u003e\n\u003cli\u003eShibasaki M, Wilson TE, Crandall CG. Neural control and mechanisms of eccrine sweating during heat stress and exercise. J Appl Physiol (1985). 2006;100(5):1692-701.\u003c/li\u003e\n\u003cli\u003eGagnon D, Crandall CG. Chapter 13 - Sweating as a heat loss thermoeffector. In: Romanovsky AA, editor. Handbook of Clinical Neurology. 156: Elsevier; 2018. p. 211-32.\u003c/li\u003e\n\u003cli\u003eIlligens BM, Gibbons CH. Sweat testing to evaluate autonomic function. Clin Auton Res. 2009;19(2):79-87.\u003c/li\u003e\n\u003cli\u003eLow PA, Caskey PE, Tuck RR, Fealey RD, Dyck PJ. Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol. 1983;14(5):573-80.\u003c/li\u003e\n\u003cli\u003ePetrofsky JS. The effect of type-2-diabetes-related vascular endothelial dysfunction on skin physiology and activities of daily living. Journal of diabetes science and technology. 2011;5(3):657-67.\u003c/li\u003e\n\u003cli\u003eWick DE, Roberts SK, Basu A, Sandroni P, Fealey RD, Sletten D, et al. Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. Journal of Applied Physiology. 2006;100(2):637-41.\u003c/li\u003e\n\u003cli\u003ePetrofsky JS, Besonis C, Rivera D, Schwab E, Lee S. Impairment in orthostatic tolerance during heat exposure in individuals with Type I and Type II diabetes. Medical science monitor : international medical journal of experimental and clinical research. 2005;11(4):Cr153-9.\u003c/li\u003e\n\u003cli\u003eKirby NV, Meade RD, Poirier MP, Sigal RJ, Boulay P, Kenny GP. Association between haemoglobin A(1c) and whole-body heat loss during exercise-heat stress in physically active men with type 2 diabetes. Experimental physiology. 2023;108(3):338-43.\u003c/li\u003e\n\u003cli\u003ePoirier MP, Notley SR, Boulay P, Sigal RJ, Friesen BJ, Malcolm J, et al. Type 2 diabetes does not exacerbate body heat storage in older adults during brief, extreme passive heat exposure. Temperature (Austin, Tex). 2020;7(3):263-9.\u003c/li\u003e\n\u003cli\u003eFujii N, Meade RD, Akbari P, Louie JC, Alexander LM, Boulay P, et al. No effect of ascorbate on cutaneous vasodilation and sweating in older men and those with type 2 diabetes exercising in the heat. Physiological reports. 2017;5(7).\u003c/li\u003e\n\u003cli\u003eMcGarr GW, Fujii N, McNeely BD, Hatam K, Nishiyasu T, Sigal RJ, et al. Superoxide and NADPH oxidase do not modulate skin blood flow in older exercising adults with and without type 2 diabetes. Microvascular research. 2019;125:103886.\u003c/li\u003e\n\u003cli\u003eKirby NV, Meade RD, Poirier MP, Notley SR, Sigal RJ, Boulay P, et al. Exercise intensity- and body region-specific differences in sweating in middle-aged to older men with and without type 2 diabetes. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2024;326(6):R588-R98.\u003c/li\u003e\n\u003cli\u003eBehzadi P, Ravanelli N, Gravel H, Barry H, Debray A, Chaseling GK, et al. Acute effect of passive heat exposure on markers of cardiometabolic function in adults with type 2 diabetes mellitus. Journal of applied physiology (Bethesda, Md : 1985). 2022;132(5):1154-66.\u003c/li\u003e\n\u003cli\u003eFlouris AD, McGinn R, Poirier MP, Louie JC, Ioannou LG, Tsoutsoubi L, et al. Screening criteria for increased susceptibility to heat stress during work or leisure in hot environments in healthy individuals aged 31-70 years. Temperature (Austin). 2018;5(1):86-99.\u003c/li\u003e\n\u003cli\u003eMeade RD, Akerman AP, Notley SR, McGinn R, Poirier P, Gosselin P, et al. Physiological factors characterizing heat-vulnerable older adults: A narrative review. Environ Int. 2020;144:105909.\u003c/li\u003e\n\u003cli\u003eBlatteis CM. Age-dependent changes in temperature regulation - a mini review. Gerontology. 2012;58(4):289-95.\u003c/li\u003e\n\u003cli\u003ePeriard JD, Eijsvogels TMH, Daanen HAM. Exercise under heat stress: thermoregulation, hydration, performance implications, and mitigation strategies. Physiol Rev. 2021;101(4):1873-979.\u003c/li\u003e\n\u003cli\u003eGagnon D, Kenny GP. Does sex have an independent effect on thermoeffector responses during exercise in the heat? J Physiol. 2012;590(23):5963-73.\u003c/li\u003e\n\u003cli\u003eMorrissey MC, Wu Y, Zuk EF, Livingston J, Casa DJ, Pescatello LS. The impact of body fat on thermoregulation during exercise in the heat: A systematic review and meta-analysis. J Sci Med Sport. 2021;24(8):843-50.\u003c/li\u003e\n\u003cli\u003eDervis S, Coombs GB, Chaseling GK, Filingeri D, Smoljanic J, Jay O. A comparison of thermoregulatory responses to exercise between mass-matched groups with large differences in body fat. J Appl Physiol (1985). 2016;120(6):615-23.\u003c/li\u003e\n\u003cli\u003eCramer MN, Jay O. Biophysical aspects of human thermoregulation during heat stress. Auton Neurosci. 2016;196:3-13.\u003c/li\u003e\n\u003cli\u003eLamarche DT, Notley SR, Poirier MP, Kenny GP. Fitness-related differences in the rate of whole-body total heat loss in exercising young healthy women are heat-load dependent. Exp Physiol. 2018;103(3):312-7.\u003c/li\u003e\n\u003cli\u003eCheung SS, McLellan TM, Tenaglia S. The thermophysiology of uncompensable heat stress. Physiological manipulations and individual characteristics. Sports Med. 2000;29(5):329-59.\u003c/li\u003e\n\u003cli\u003eCheung SS, McLellan TM. Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress. J Appl Physiol (1985). 1998;84(5):1731-9.\u003c/li\u003e\n\u003cli\u003eKenny GP, Wilson TE, Flouris AD, Fujii N. Chapter 31 - Heat exhaustion. In: Romanovsky AA, editor. Handbook of Clinical Neurology. 157: Elsevier; 2018. p. 505-29.\u003c/li\u003e\n\u003cli\u003ePeriard JD, Racinais S, Sawka MN. Adaptations and mechanisms of human heat acclimation: Applications for competitive athletes and sports. Scand J Med Sci Sports. 2015;25 Suppl 1:20-38.\u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;nemann H, Brożek J, Guyatt G, Oxman A. The GRADE handbook: Cochrane Collaboration; 2013.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 2 diabetes, core body temperature, hyperthermia, heat loss, sudomotor, vasomotor, systematic review protocol","lastPublishedDoi":"10.21203/rs.3.rs-7204080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7204080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eType 2 diabetes has been associated with impaired thermoregulatory responses to increased core body temperature, making patients more vulnerable to heat-related disorders. Although recent studies have investigated these diabetes-related impairments in heat loss mechanisms, our understanding of the occurring phenomena remains unclear due to the complexity of results and the various factors contributing to increased core body temperature.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo address the following Population/Exposure/Comparator/Outcome (PECO) question: what is the effect of an increase in core body temperature level (E) on the vasomotor and sudomotor responses and the physiological and molecular mechanisms that control these responses (O) within individuals with type 2 diabetes (P) compared to healthy individuals at the same level of core body temperature and/or type 2 diabetes patients at lower or normal core body temperature level (C)?\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis protocol will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A thorough database search will be conducted in PubMed and Embase using tested and validated search algorithms. Experimental (randomized and non-randomized controlled trial) or observational studies with type 2 diabetes populations and have measured core body temperature will be included. A narrative synthesis will be conducted and if possible, meat-analysis will be performed. Risk of bias will be assessed using the Office of Health Assessment and Translation tool.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e\u003cp\u003eThe results from this review will expand our knowledge of the physiological mechanisms through which type 2 diabetes impairs heat loss under hyperthermic conditions and inform guidelines to mitigate heat-related risks in type 2 diabetes populations.\u003c/p\u003e\u003ch2\u003eProtocol registration\u003c/h2\u003e\u003cp\u003eThis study was registered at the International Prospective Registry for Systematic Reviews (PROSPERO) #CRD42023471939.\u003c/p\u003e","manuscriptTitle":"The effect of increased core body temperature on the vasomotor and sudomotor responses of patients with type 2 diabetes: Protocol of a systematic literature review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-12 21:36:55","doi":"10.21203/rs.3.rs-7204080/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-09-17T09:30:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-08-07T09:54:18+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-07T09:37:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-07T06:24:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2025-07-24T05:39:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a71c2c35-ef89-411c-a55b-6c8508d77da7","owner":[],"postedDate":"August 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T16:01:19+00:00","versionOfRecord":{"articleIdentity":"rs-7204080","link":"https://doi.org/10.1186/s13643-025-02991-0","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2025-12-12 15:57:32","publishedOnDateReadable":"December 12th, 2025"},"versionCreatedAt":"2025-08-12 21:36:55","video":"","vorDoi":"10.1186/s13643-025-02991-0","vorDoiUrl":"https://doi.org/10.1186/s13643-025-02991-0","workflowStages":[]},"version":"v1","identity":"rs-7204080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7204080","identity":"rs-7204080","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}