Thermoregulatory function, that is, heat dissipative responses such as skin blood flow (SkBF) and sweating to an increased body temperature, is critical during physical work or exercise in warm and hot conditions and during hyperthermia. Thermoregulatory function is associated with individual somatotype, fitness level, normal aging, and physiological status and diseases. Individuals with type 2 diabetes have decreased thermoregulatory responses compared with healthy counterparts, characterized by decreased SkBF and sweating. The decreased SkBF and sweating would be associated with the reduction in nitric oxide bioavailability and endothelial functions in skin vasculatures, also with central mechanisms, and so on. Aerobic exercise training and/or acclimation to the heat improve heat dissipative responses in healthy subjects. The effects of exercise training in type 2 diabetics on glycemic control are well established while it remains unclear that high levels of aerobic fitness or exercise training in diabetics improve thermoregulatory function during heat stress.
- sweat rate
- skin blood flow
- plasma volume
Individuals are more likely to become exhausted and to develop heat-related illnesses when physical work or sporting activities are performed for a prolonged time in warm and hot conditions or direct sunlight compared to in cooler conditions. Thermoregulation is one of the most important physiological functions for when individuals are exposed to extreme hot environments. The incidence of heat-related illnesses is particularly great if physical work or exercise is performed at higher intensities and in higher ambient temperatures (Ta) and relative humidity (RH) . In addition, the incidence is greater in persons who are dehydrated, who are not acclimated to hot environments, or who have low levels of physical fitness and daily activity even if they are healthy . More importantly, the incidence is greater in individuals with obesity, diabetes mellitus, and cardiovascular diseases, due to impaired thermoregulatory responses [1, 2]. It is also greater in individuals with attenuated thermoregulatory responses, such as those with skin grafts, spinal cord injuries, and multiple sclerosis [3, 4, 5]. Moreover, an extreme hot environment can be dangerous for the elderly (even those who are healthy) because of the normal aging process [1, 2]. Over the last two decades, the morbidity and mortality of heat-related illnesses has rapidly increased in Japan because of the rapidly aging population and global warming . This chapter first discusses thermoregulation during work and exercise in warm and hot conditions and the possible physiological effects of humoral and other important factors on thermoregulation. Second, the effects of diseases such as diabetes on thermoregulatory responses are discussed.
2. Thermoregulation in warm and hot conditions
Core body temperature is determined by the heat equilibrium between heat gain and loss . Typically, core body temperature is elevated when we face continuous whole-body work and exercise. This is because only approximately 20% of the energy produced in contracting muscles is used for muscle contraction; the remaining 80% is converted to heat energy, and therefore exercise causes an increase in muscle temperature. The heat is distributed to the body by the circulation and increases body temperatures. Therefore, greater exercise intensities are associated with greater heat production during exercise. However, although core body temperature elevates rapidly within several minutes of starting exercise, heat dissipation mechanisms are activated sufficiently to balance heat production and eventually the increase in core body temperature reaches a steady state. The cutaneous vasculature and sweat glands are thermoregulatory effectors of the skin and promote heat loss by increasing skin blood flow (SkBF) via cutaneous vasodilation and by sweating, respectively . The heat generated in contracting muscles is transferred, because of circulation of blood, to the skin surface; thus, skin surface temperature is elevated by the increased SkBF. The heat transferred to the skin surface is released to the surrounding air according to the thermal gradient between the skin and the air (non-evaporative heat dissipation). Therefore, in a cool environment, non-evaporative heat dissipation is effective; however, in warm environments, when Ta is higher than skin temperatures (~30°C), it becomes ineffective or even negative and acts as a source of heat gain. Conversely, sweating enhances heat loss via sweat evaporation from the skin surface to the air (evaporative heat dissipation). Evaporative heat dissipation is determined according to the gradient of water vapor between the skin surface and the surrounding air. Therefore, it is available regardless of Ta and is the main and critical heat loss mechanism when Ta exceeds ~30°C; however, it is attenuated in a humid environment. Consequently, when heat gain exceeds heat loss during high-intensity work and/or exercise in a hot and humid environment, core body temperature increases rapidly. Therefore, these conditions increase susceptibility to heat-related illnesses.
Physiologically, SkBF and sweating are regulated by body core and skin temperatures (thermal factors) and also other (non-thermal) factors . Body core temperature is monitored continuously by central thermoreceptors. On the other hand, skin temperatures are monitored continuously by the peripheral thermoreceptors. These receptors send received thermal information through an afferent pathway to the thermoregulatory center in the preoptic/anterior hypothalamus . When the hypothalamic thermoregulatory center determines that core and skin temperatures are elevated compared to the set point, SkBF and sweating are increased through the reflex efferent pathways of sympathetic nerve systems . In humans, SkBF and sweating are neutrally controlled via two distinct skin sympathetic nerves. A sympathetic adrenergic vasoconstrictor system is one of the neural control mechanisms for SkBF and the other is a separate sympathetic cholinergic vasodilator system . Sweating is controlled by sympathetic cholinergic nerves . In addition, non-thermal factors modify the thermal reflex, including central commands, mechano- and metabo-reflexes, arterial and cardiopulmonary baroreflexes, blood volume and osmolality, and mental stimuli . During exercise, they exert different effects on SkBF and sweating responses . Typically, SkBF at the same levels of core and skin temperatures is lower during exercise than resting conditions, and this restriction is greater at higher exercise intensities. Conversely, sweating at the same levels of core and skin temperatures is likely to be higher during exercise than resting conditions.
When levels of dehydration worsen, the risk of heat-related illnesses is much higher during work or exercise in a hot environment . Rothstein and Towbin  described for the first time the effects of dehydration on thermoregulation in humans. They reported that an ~0.3°C increase in rectal temperature is caused by every 1% body weight loss by sweating in breaks between exercises when soldiers march in the desert. This is because, as non-thermal factors, dehydration-induced hypovolemia and hyperosmolality limit the response to enhance SkBF and sweating to increased body temperature. Decreased body fluid volume and increased osmolality change dramatically during exercise even in a cool environment. Indeed, plasma volume (PV) is decreased with an increased intensity of exercise. In maximal exercise, the decrease in PV is reached by approximately 300–500 mL (8–15%). Increased capillary fluid filtration from the intravascular to the extravascular spaces due to an increase in blood pressure and peripheral vasodilation during exercise causes the PV change. Additionally, metabolites accumulated in the intracellular fluid of contracting muscles such as lactic acid increases free-water shift from the plasma to the intracellular fluid through the interstitium based on the osmotic gradient . It is estimated to be ~1 L of the volume shifted to the contracting muscles at maximal exercise. About half of this water is from PV . In addition, plasma osmolality (Posm) is increased from ~285 mosmol/kgH2O at rest to over 300 mosmol/kgH2O at maximal exercise due to accumulated metabolites. These humoral changes are not caused by dehydration due to sweating; rather, they are associated with the exercise itself. Because they are observed within several minutes after the start of exercise, in addition, when exercise is performed in warm and hot conditions, hypohydration due to the decrease in PV and hyperosmolality due to the increase in Posm during exercise is exacerbated because of increased SkBF and sweating for thermoregulation. Enhanced SkBF induces a reduction in venous return to the heart due to pooling of excessive blood in dilated peripheral vasculature of the skin . Additionally, ~10% of the sweat volume is lost from plasma fluids, and Posm is increased according to sweat rate because sweat is hypotonic compared to body fluids. These humoral changes enhance the load on the circulation and act as limiting factors for thermoregulation.
Nadel et al.  first showed that isotonic hypovolemia (change in PV, −700 mL; body weight, −2.7%) achieved by diuretic administration before exercise induced upward shift of the esophageal temperature (Tes) threshold for the onset of cutaneous vasodilation by 0.4°C during exercise at 55% of maximal oxygen consumption rate (VO2max) in a hot environment (Ta 35°C). It also reduced the SkBF at peak value by about 50% compared to control condition. Besides, Mack et al.  reported that an acute reduction in venous return to the heart induced by application of −40 mmHg lower body negative pressure (LBNP) decreased SkBF and elevated Tes during exercise at an intensity corresponding to a heart rate of 125 beats/min in a warm environment (Ta, 28°C). In contrast, all techniques to acutely increase venous return during exercise, including isotonic hypervolemia with saline infusion , postural change from upright to supine position [14, 15], head-out water immersion , or continuous negative pressure breathing , enhanced the response to increase SkBF to an increased core body temperature during exercise. From these observations, the response to increase SkBF to an increased core body temperature during exercise is attenuated by dehydration-induced hypovolemia via the cardiopulmonary baroreflex. Recently, Ogawa et al.  reported that the efferent sympathetic signals to skin vasculature, that is, the skin sympathetic nerve activity (SSNA), component synchronized with the cardiac cycle was decreased by postural change from supine to 30° head-up tilt during hyperthermia (Tes increased ~0.7°C) with passive heating and that the responses were correlated with the decrease in cutaneous vasodilation. With these data, they suggested that the SSNA component synchronized with the cardiac cycle was likely to contribute to the suppression of cutaneous vasodilatation.
Previous studies have suggested that the response to increase sweat rate during exercise is also attenuated by hypovolemia. Fortney et al.  presented that the ability to enhance sweating of the chest and forearm to an increase in Tes, but not the Tes threshold at the start of sweating during cycle ergometer exercise (65–70% VO2max) in a warm environment (Ta, 30°C; RH, 40%), was attenuated by isotonic hypovolemia (9% reduction in plasma volume induced by diuretics) prior to exercise. Additionally, Mack et al.  showed that LBNP at the level of −40 mmHg during exercise dampened the sweat rate and SkBF to increased Tes. Dodt et al.  also observed decreased skin sympathetic nerve activity following LBNP in passively heated subjects. In contrast, Kamijo et al.  reported that isotonic hypovolemia induced by diuretic (−10%) before exercise dampened increases in SkBF, similar to the results of Nadel et al. . However, it did not dampen the increase in sweat rate during exercise at 60% VO2max in a warm environment (Ta, 30°C; RH, 45%). Thus, the effects of hypovolemia on sweat rate are still debatable.
Plasma hyperosmolality suppresses the response to increase SkBF and sweating during exercise. Fortney et al.  showed that 10 mosmol/kgH2O increases in Posm achieved by hypertonic saline infusion before exercise caused an increased Tes thresholds for cutaneous vasodilation and sweating by 0.2°C. In addition, the sensitivity to increase SkBF in response to increased Tes decreased during exercise at 70% VO2max in a warm environment (Ta, 30°C; RH, 40%). Additionally, onset of SkBF and sweat rate responses to increased core body temperature is delayed by plasma hyperosmolality. Takamata et al.  showed a linear upward shift of the Tes thresholds with several levels of increase in Posm by hypertonic saline infusion. They suggested with these data that Tes thresholds for cutaneous vasodilation and sweating during passive heat stress (lower-leg water immersion, 42°C) at rest shifted upward by 0.044°C and 0.034°C per 1 mosmol/kgH2O increase, respectively. More intriguingly, they also suggested that the upward shift in Tes thresholds during exercise were caused by an increased Posm induced by exercise. The increased Tes thresholds at a given increase in Posm during exercise were identical to those during resting passive heat stress . Mitono et al.  supported this evidence by indicating that when the increase in Posm during exercise was attenuated by hypotonic saline infusion prior to exercise, the delayed onset of cutaneous vasodilation in response to increased Tes during exercise was normalized. It has been suggested that the response of the thermoregulatory center was attenuated by plasma hyperosmolality via osmoreceptors.
As described above, dehydration is a limiting factor for heat loss mechanisms during exercise in the heat. These mechanisms prevent cardiovascular failure caused by reduction in venous return to the heart due to blood pooling in dilated peripheral skin vasculature and reductions in PV due to sweating. Indeed, it has been reported that, when drinking such a small amount of water so as not to change PV and Posm in dehydrated individuals, thirst sensation and plasma vasopressin secretion induced by increased Posm are released rapidly by a stimulation of oropharyngeal reflexes [25, 26]. It also simultaneously releases the dehydration-induced attenuated responses of SkBF  and SR .
3. Effects of exercise training on thermoregulation in warm and hot conditions
Thermoregulatory responses are improved by aerobic and endurance exercise training, resulting in reduced physiological strain and therefore enhanced cardiovascular and exercise capacities during exercise in warm and hot conditions. These adaptations are remarkable when exercise training is performed in the heat . After a 10-day training period in a cool condition (Ta, 20°C), SkBF and sweat rate responses to increased Tes during exercise (Ta, 25°C) are enhanced. After a subsequent 10-day training period in a hot condition (Ta, 35°C), these responses improved further . The increased SkBF and sweating responses are characterized by the early start of cutaneous vasodilation and sweating responses to increased Tes [28, 29] and the increased sensitivity to increase SkBF and sweat rate in response to an increased Tes compared with before exercise training [28, 29]. It is suggested that the mechanisms of the increase in thermoregulatory responses with exercise training are similar to those following acclimations to repeated heat exposures, including adaptations of the thermoregulatory center and thermoregulatory effectors [1, 12] as well as an increase in VO2max  and PV [28, 31, 32].
It is suggested that the exercise-induced PV expansion is primarily associated with an increase in total volume of extracellular fluid . An increase in plasma protein (mainly albumin content) also contributes by drawing fluids into the intravascular space from the interstitium [33, 34, 35]. Facilitated Na+ and water reabsorption [33, 36] and an enhancement of voluntary fluid intake with increased thirst sensation  (associated with an activated renin-angiotensin-aldosterone system and vasopressin release) during and after exercise or dehydration are suggested as mechanisms of training-induced increases in extracellular fluid volume . Increases in plasma protein may be due to activated hepatic plasma protein synthesis [39, 40] and enhanced translocation of protein to the intravascular space from the interstitium  coincide with a restricted transcapillary escape ratio of protein .
PV expansion by exercise training results in a reduction in lactic acid concentration in the blood at the same absolute intensity of exercise (an enhanced lactate threshold), which contributes to a suppression of increase in Posm during exercise. This mechanism contributes to the downward shift of the body core temperature threshold for cutaneous vasodilation and sweating after training. Moreover, expanded PV increases venous return to the heart and cardiac filling pressure and therefore enhances cardiac stroke volume. It also improves the responses of SkBF and sweat rate to increased core body temperature during exercise [11, 16, 17]. Indeed, an increase in cardiac stroke volume and also the sensitivity of increase in SkBF to increased Tes during exercise in a warm condition (Ta, 30°C) was closely correlated to a PV expansion by a 10-day endurance training (60% VO2max for 1 h/day at 30°C) . Additionally, Goto et al.  reported the influences of protein and carbohydrate (CHO) supplementation just after exercise (Pro-CHO; 0.36 g protein/kg and 3.6 kcal) during the 5-day training period (70% VO2max for 30 min/day) in a warm environment (Ta, 30°C) on PV and thermoregulatory responses. They suggested that, in the Pro-CHO group, plasma albumin content (Albcont) and therefore PV increased by ~10% and ~8%, respectively. These were significantly higher than the increase of ~4% in the placebo intake control group (CNT; 0.9 kcal and 0 g protein/kg body weight). They attributed the increase in Albcont to activated hepatic albumin synthesis following exercise due to the increased substance bioavailability [39, 40] and also the effects of insulin on protein synthesis in hepatocytes . Most notably, the sensitivity of an increase in SkBF and sweat rate to increased Tes enhanced after training more in the Pro-CHO group compared with the CNT group. Additionally, both groups showed a significant decrease in heart rate and Tes during exercise after training period. However, these adaptations were more prominent in the Pro-CHO group than in the CNT group, indicating decreased cardiovascular and thermal strains after the training period with PV expansion.
In addition, Ikegawa et al.  supported the observations by Goto et al.  by presenting an increased PV with an early shift of the onset of the cutaneous vasodilation and sweating responses to an increased Tes after the same training protocol. Further, the early shift of the onset of the cutaneous vasodilation and sweating responses was wholly or partly diminished after the expanded PV by training was reduced to the pre-training level by using the diuretics. Furthermore, Ichinose et al.  showed that 10 days of exercise training (60% VO2max for 60 min/day at 30°C) attenuated the sensitivity of the upward shift of Tes threshold for cutaneous vasodilation with the increased Posm by hypertonic saline infusion, though the threshold for sweating was not changed. Furthermore, they suggested that increased PV after training correlated with the attenuated sensitivity to hyperosmolality in each individual, suggesting that the attenuation is associated with the stretch of cardiopulmonary baroreceptors induced by PV expansion. Thus, the enhanced thermoregulation and cardiovascular capacities after exercise training are closely associated with PV expansion in addition to the neural adaptation of the thermoregulatory center and thermoregulatory effectors [1, 12].
The Na+ concentration of sweat is important to maintain PV during exercise. It decreases after exercise training or heat acclimation due to an enhanced Na+ reabsorption at the sweat gland duct induced by an enhanced sensitivity to aldosterone . To maintain PV during exercise, hypotonic sweat is advantageous because hypotonic sweat loss causes a greater increase in osmolality of extracellular fluid. It promotes the shift of water from intracellular to extracellular fluid space according to the osmotic gradient between the spaces . This therefore attenuates the decreased PV and venous return to the heart. As a result, the decreased thermoregulatory responses with a sweating loss at a given volume are attenuated with low Na+ concentration in sweat . Moreover, the delayed onset of cutaneous vasodilation and sweating responses to increased Tes at a given increase in Posm was attenuated in heat-acclimated individuals in whom an increased Posm by sweating loss at a given volume was enhanced due to low Na+ concentration in sweat .
4. Effects of biological aging on thermoregulation in warm and hot conditions
The susceptibility to heat related-illnesses in the elderly  is caused by a deterioration in thermoregulatory responses with aging [47, 48]. Previous studies have indicated that even healthy elderly individuals have an impaired thermal perception  and impaired autonomic [50, 51] and behavioral [52, 53] thermoregulatory responses. A recent study indicated that skin warmth detection thresholds in the extremities and the whole-body thermal sensation deteriorated with normal aging under both normothermic conditions and under passive heat-induced mild hyperthermic conditions . Decreased VO2max and cardiovascular capacity associate with the deteriorated thermoregulation with aging . Nevertheless, elderly individuals with a similar level of VO2max to young individuals are known to show an attenuated response of SkBF both during passive heat stress in whole-body or local-body parts and during exercise under a hot environment compared to young individuals [55, 56]. Specifically, Kenney et al.  used bretylium tosylate to block the local release of norepinephrine on the forearm skin. They suggested that the attenuated SkBF response to hyperthermia during exercise in a hot condition was caused not by an enhanced vasoconstrictor system but mainly by a decreased sensitivity of the active vasodilator system to increased Tes. In addition, the whole-body and local sweat rate in response to passive heat stress or exercise are attenuated in the elderly compared to young adults .
Several physiological changes with advancing age, for example, such as decreased PV and increased Posm at baseline , diminished thirst sensation , and responses in antidiuretic hormone and aldosterone after thermal dehydration , are suggested to be associated with the decreased thermoregulatory responses in the elderly. Decreased renal concentrating ability  and lower reabsorptive ability of sweat gland ducts  with advancing age are also suggested to be associated with the deteriorated thermoregulatory responses with aging. Vasoconstriction of splanchnic organs during exercise, which enhances the redistribution of cardiac output to the skin vasculature, is associated with increased cutaneous vasodilation in youth, which is also attenuated with aging . Furthermore, elderly individuals commonly take a variety of prescription drugs that may affect thermoregulatory responses and body fluid regulation . Exercise training and heat acclimation can improve the blunted body fluid regulation and thermoregulation with aging, although generally the improvement of these is lower or limited relative to their younger counterparts.
5. Effects of type 2 diabetes on thermoregulation in warm and hot conditions
Type 2 diabetes typically presents later in life with a mean onset age of 54 years . Type 2 diabetes is associated with multiple comorbidities, including obesity, dyslipidemia, metabolic syndrome, hypertension, and other markers of cardiovascular diseases in addition to the changes associated with aging. Most of the research examining ability of thermoregulation in type 2 diabetic patients has considered not only to estimate itself but also the responses to evaluate the severity of neuropathy along with other diabetes-related complications. Many studies have only measured the local heat dissipative responses of the hands and feet. It is generally reported that type 2 diabetic patients have attenuated SkBF responses evoked by pharmacological stimuli [62, 63], local skin heating [64, 65], and whole-body heating [64, 66]. Importantly, these effects appear to depend on physical fitness level. Type 2 diabetic engaging in physical activity has reduced impairments in skin vasodilation compared with type 2 diabetics who are not physically active . Conversely, studies of local sweating in type 2 diabetics have generally found that these individuals have impaired sweating responses compared to their healthy counterparts [64, 68, 69], despite one study reporting otherwise . The changes in regional sweating with type 2 diabetes are comparable to those observed with type 1 diabetes, such that there is relatively lower body anhidrosis along with euhydrosis or hyperhidrosis compared to the upper body . While these studies have implications for whole-body temperature regulation during heat stress, the evidence regarding the impact of heat stress (as induced by warm and hot environments, physical activity, or both) on type 2 diabetics remains limited.
Kenny et al.  recently reported that relatively active type 2 diabetics who were otherwise generally healthy (good glycemic control and no diabetes-related complications) have significantly decreased whole-body heat loss during exercise for 60 min (~370 W of metabolic heat production or ~60% of the predetermined VO2max) as assessed by whole-body direct calorimetry. During the exercise bout, due to the lower evaporative heat loss in type 2 diabetes, they stored ~1.5-fold more heat than their healthy counterparts. Regardless of the greater amount of heat accumulation during exercise, the diabetes-related impairment in the capacity to dissipate heat persisted into the 60-minute recovery. Healthy groups lost ~twofold more heat relative to the group with type 2 diabetes, which was associated with slightly and no statistically significant, but sustained difference in the rate of non-evaporative heat loss .
6. The mechanisms underlying type 2 diabetes-related impairments in heat dissipation
To date, few studies have examined the mechanisms underlying type 2 diabetes-related impairments in heat dissipation; however, some information may be gleaned from those studies aimed primarily at assessing the presence of neuropathies. The reduction in nitric oxide bioavailability in individuals with type 2 diabetes is well established [62, 63, 72, 73] and may be further exacerbated by the presence of atherosclerotic plaques which are known to adversely alter endothelial function through interfering with nitric oxide signaling . In fact, one study reported that the relative nitric oxide-dependent vasodilation during whole-body passive heating was similar between healthy controls and type 2 diabetics; however, absolute SkBF was lower in the latter group . Moreover, there is evidence to support an endothelium-independent component to the impairment in vasodilation as observed during exogenous administration of a nitric oxide donor (e.g., sodium nitroprusside) . Importantly, these diabetes-related changes in SkBF appear to be closely associated with the duration of diabetes and/or the presence of related complications [62, 63]. There is little report on the central versus peripheral mechanisms that form the basis of diabetes-related SkBF responses; one study indicated that onset of vasodilation responses to increased core body temperature was delayed and it was the primary factor, explaining lower SkBF in patients with type 2 diabetes mellitus. This indicates that central mechanisms contribute to the modulation of SkBF .
The mechanisms responsible for diabetes-related impairments in sweating during heat stress remain incompletely understood and most of the information is provided from studies which have not examined thermoregulatory control. Petrofsky et al.  indicated that, during isometric handgrip exercise to exhaustion, sweating on the arms and legs was significantly lower, but only forehead sweat rate was actually higher in type 2 diabetics than the controls. The primary factors associated with this modulation in sweating include long-term diabetes, poorly controlled glycemia, and the presence of neuropathy. Diabetic neuropathy seems to have an important role in altering the sweat gland innervations [68, 75]. Luo et al. [75, 76] showed that the sweat glands in type 2 diabetics with poor glycemic control exhibit exacerbated reductions in periglandular nerve terminals and in the innervation index. Impairments in sweating during heat stress may also be related to the reduction in nitric oxide bioavailability since the role of nitric oxide-induced sweating during exercise has recently been proven [77, 78].
7. Effects of hyperglycemia on thermoregulation during thermal stress
Hyperglycemia can have an important negative impact on body core temperature regulation. Specifically, hyperglycemia can lead to increases in Posm which have been independently associated with impairments in sweating and SkBF as described in the earlier section . Furthermore, hyperglycemia can induce dehydration through osmotic diuresis  which can lead to hypovolemia without adequate fluid replacement. Recently, studies have demonstrated that the combination of hyper osmolality and hypovolemia augments any effects to further exacerbate impairments in heat dissipation in healthy individuals [81, 82]. In contrast, acute hyperglycemia (induced by hyperinsulinemic-hyperglycemic clamp) did not result in the impairment of NO-mediated skin microvascular function .
8. Effects of exercise training on thermoregulation in the elderly individuals
Several longitudinal studies have reported that heat dissipative responses during exercise in a hot environment are enhanced when aerobic training is performed under hot or even cool to thermoneutral conditions by initially sedentary elderly individuals [30, 60, 84] and young individuals [27, 28, 29]. Thomas et al.  reported that a 16-week aerobic training program increased VO2max by ≥5% and advanced onset of cutaneous vasodilation in response to an increased mean body temperature during exercise in a hot environment (Ta, 36°C) both in young and in elderly individuals. They also suggested that an enhanced sensitivity of the active vasodilator system contributes to the enhanced cutaneous vasodilation . Additionally, Okazaki et al.  supported and extended these results by showing that onset of cutaneous vasodilation and sweating responses to an increased Tes during exercise in a warm environment (Ta, 30°C) were advanced after an 18-week aerobic and resistance training under cool to thermoneutral conditions in initially sedentary elderly individuals. The improvements in VO2max were 20 and 10%, respectively, in each study. However, both studies indicated that the sensitivity of increase in SkBF and sweat rate to an increased mean body temperature or Tes did not increase after training. Further, Okazaki et al.  indicated that a diminished increase in PV following training period in elderly individuals was associated with the unchanged sensitivity, by showing a linear correlation between changes in the sensitivities and those in PV following the training period. Similarly, in young individuals, the increase in PV is considered to be the major mechanism which contributed to the improvement of thermoregulatory responses by exercise training as described in the earlier section. This results from increased venous return to the heart by increasing cardiac stroke volume and/or by suppressing baroreflex-induced reduction of skin vasodilation . Additionally, Ho et al.  showed that splanchnic and renal vasoconstriction during exercise were increased in young individuals but not in elderly individuals following aerobic training period. Thus, in elderly people, exercise training improved VO2max but generally diminished the enhancement of thermoregulation compared with younger counterparts [60, 84].
The primary limiting factor for the blunted increase in PV with aerobic training in elderly people is an attenuated increase in Albcont with exercise [35, 84, 85]. Other factors are likely to be a reduced fluid intake after thermal dehydration [38, 58] or water deprivation  with aging. Accordingly, enhanced albumin synthesis in the liver in response to exercise is one mechanism of the increased Albcont after aerobic training in the young individuals [39, 40]. In regard to this point, the response to increase Albcont after aerobic training is smaller in the elderly individuals. It may be affected, in part, by the attenuated hepatic albumin synthesis response to exercise [87, 88] due to decreased gene expression with normal aging. However, it is also reasonable that this is caused by insufficient protein intake for albumin synthesis in elderly people. Decreased daily activity with aging may be accustomed to low energy and protein diets in elderly people. Therefore, improvements would occur if substrates for plasma albumin synthesis are given immediately after exercise when albumin synthesis is reportedly enhanced [40, 88]. In this regard, one study showed that when young and elderly individuals ingested placebo (i.e., non-energy ingestion) just after acute high-intensity interval exercise, the ability of recovery of Albcont and PV after exercise was generally blunted in elderly individuals compered to young individuals. In contrast, Albcont and PV recovered more when they consumed a protein and CHO mixture compared to consumed placebo in both individuals .
Okazaki et al.  further determined the effects of protein and CHO intake just after exercise on PV and thermoregulatory responses during 8 weeks of aerobic training under cool to thermoneutral conditions in elderly individuals. In individuals consuming protein and CHO, Albcont and PV increased by 6%, and these increases were accompanied by enhanced sensitivities of SkBF and sweat rate (18 and 80%, respectively) to increased Tes. In contrast, they remained unchanged in individuals taking the placebo immediately after exercise . Additionally, this enhanced sensitivity associated with a 10% increase in stroke volume during exercise . Consequently, the improved PV expansion response induced by exercise along with post-exercise protein and CHO intake enhances the attenuated increase in cardiovascular and thermoregulatory capacity in elderly individuals compared with young counterparts. Recently, Kataoka et al.  reported the similar results in hypertensive elderly individuals (∼160 mmHg for systolic and ∼90 mmHg for diastolic blood pressure at rest) that PV and SkBF response to increased Tes both increased after aerobic training (60–75% of VO2 peak for 60 min/day, 3 days/week, for 8 weeks) with protein (10 g) and CHO (15 g) supplementation. Furthermore, they showed that despite the increased PV, arterial blood pressures rather decreased after training with an increased carotid arterial compliance and baroreflex sensitivity.
Recent studies have presented that aerobic training improves cutaneous vasodilation by local mechanisms in aged skin . Black et al.  used L-NAME (an NO synthase inhibitor) during acetylcholine infusions to block NO production and demonstrated that, in initially sedentary elderly individuals, increase in vascular responsiveness following 12 and 24 weeks of aerobic training was induced by the increase in action of NO in the skin. There are similar results in a longitudinal study  although a cross-sectional study reported no effects .
The enhancement of the sweating function in summer occurred later and its reduction in winter occurred earlier, in an elderly group compared with a younger group despite a smaller seasonal variation range . To prevent heat disorders in elderly individuals, it is strongly recommended that they engage in exercise training prior to the summer season. Regular exercise generally improves thermoregulatory capacity alongside VO2max. Protein and CHO intake after exercise will also enable adequate training adaptations to be achieved.
9. Effects of exercise training on thermoregulation in diabetic patients
The effects of aerobic fitness along with short- and long-term exercise training have been widely studied in the context of glucoregulation in type 2 and type 1 diabetics. The effects of exercise training on glycemic control in type 2 diabetics are well established. A recent meta-analysis by Umpierre et al.  reported that structured exercise training (over 12 weeks) consisting of aerobic exercise, resistance training, or a combination is associated with enhanced glycemic control (~0.7% HbA1c reduction) in type 2 diabetics. They also reported that structured exercise training of more than 150 min per week is associated with greater HbA1c reduction (~0.9%) compared to 150 min or less per week . Structured exercise training also has beneficial effects on diabetes-related complications . Greater benefits are apparent in type 2 diabetics with higher HbA1c before the exercise intervention .
In healthy individuals, it has been suggested that higher levels of aerobic fitness and/or physically activity improve the capacity to dissipate heat during exercise [98, 99]. A recent study indicated that the age-related decline in aerobic fitness was associated with the decreased whole-body evaporative heat loss during exercise in the heat . Moreover, a group of trained middle-aged males (~48 years) exhibited greater whole-body heat loss than an untrained group during exercise . Other studies have also indicated that VO2max decreased ~7% per decade in sedentary, active, and even endurance-trained populations . Despite reports of the relationship between aerobic fitness and thermoregulatory capacity in healthy people, there are no reports in with either type 1 [102, 103, 104] or type 2  diabetics because aerobic fitness has not been considered as a potential factor influencing thermoregulatory capacities. Therefore, the increased aerobic fitness with exercise training in diabetics would improve thermoregulatory control, autonomic nervous system function, and cardiovascular responses, especially during exercise-induced heat stress, as reported in healthy counterparts, however, the situation remains unclear.
10. Oral rehydration during exercise
Based on the physiological responses to warm and hot conditions described previously, it is suggested that dehydration prior to and during exercise should be prevented or countered. This would reduce extra thermal and cardiovascular strains during exercise in the heat and the risk of developing heat-related illnesses. In general, oral rehydration with solutions containing 0.1–0.2% of NaCl and 4–8% of CHO based on thirst sensation is recommended, but, during exercise, we need to prevent the addition of 2% of body weight reduction . Elderly persons or persons who work or undertake high-intensity exercise in warm and hot conditions should start fluid ingestion prior to and during the early period of work before thirst is perceived . Special care should be taken by diabetics so that hyper and hypoglycemia are not induced with oral rehydration during exercise and hyperthermic conditions.
The morbidity and mortality of heat-related illnesses would expand in the years to come worldwide because of the rapidly aging population and global warming. The decreased thermoregulatory capacity in type 2 diabetes is associated with the presence of neuropathies, reduced nitric oxide bioavailability, central mechanisms, and so on, while it would be improved with aerobic fitness with exercise training as in healthy counterparts. Thermoregulatory adaptations after exercise training are enhanced with PV expansion with a dietary supplementation conjunction with exercise in healthy individuals. Further researches are necessary to elucidate the effective strategy to improve thermoregulatory capacity as well as glycemic control in type 2 diabetes with or without complications with exercise training.
Taylor NAS, Kondo N, Kenney WL. The physiology of acute heat exposure, with implications for human performance in the heat. In: Taylor NAS, Groeller H, editors. Physiological Bases of Human Performance during Work and Exercise. Philadelphia: Elsevier; 2008. pp. 341-358
Kenny GP, Yardley J, Brown C, Sigal RJ, Jay O. Heat stress in older individuals and patients with common chronic diseases. CMAJ. 2010; 182:1053-1060
Crandall CG, Davis SL. Cutaneous vascular and sudomotor responses in human skin grafts. Journal of Applied Physiology (Bethesda, Md.: 1985). 2010; 109:1524-1530
Davis SL, Wilson TE, White AT, Frohman EM. Thermoregulation in multiple sclerosis. Journal of Applied Physiology (Bethesda, Md.: 1985). 2010; 109:1531-1537
Price MJ, Campbell IG. Thermoregulatory responses of spinal cord injured and able-bodied athletes to prolonged upper body exercise and recovery. Spinal Cord. 1999; 37:772-779
Nakai S, Shin-ya H, Yoshida T, Yorimoto A, Inoue Y, et al. Proposal of new guidelines for prevention of heat disorders during sports and daily actibities vased on age, clothing and heat acclimatization. Japanese Journal of Physical Fitness and Sports Medicine. 2007; 56:437-444
American College of Sports Medicine, Sawka MN, Burke LM, Eichner ER, Maughan RJ, et al. American College of Sports Medicine position stand. Exercise and fluid replacement. Medicine and Science in Sports and Exercise. 2007; 39:377-390
Rothstein A, Towbin EJ. Blood circulation and temperature of men dehydrating in the heat. In: Adolph EF, editor. Physiology of Man in the Desert. New York: Interscience; 1947. pp. 172-196
Nose H, Takamata A, Mack GW, Oda Y, Okuno T, et al. Water and electrolyte balance in the vascular space during graded exercise in humans. Journal of Applied Physiology. 1991; 70:2757-2762
Lundvall J, Mellander S, Westling H, White T. Fluid transfer between blood and tissues during exercise. Acta Physiologica Scandinavica. 1972; 85:258-269
Nose H, Mack GW, Shi XR, Morimoto K, Nadel ER. Effect of saline infusion during exercise on thermal and circulatory regulations. Journal of Applied Physiology. 1990; 69:609-616
Nadel ER, Fortney SM, Wenger CB. Effect of hydration state of circulatory and thermal regulations. Journal of Applied Physiology. 1980; 49:715-721
Mack G, Nishiyasu T, Shi X. Baroreceptor modulation of cutaneous vasodilator and sudomotor responses to thermal stress in humans. The Journal of Physiology. 1995; 483(Pt 2):537-547
Johnson JM, Rowell LB, Brengelmann GL. Modification of the skin blood flow-body temperature relationship by upright exercise. Journal of Applied Physiology. 1974; 37:880-886
Gonzalez-Alonso J, Mora-Rodriguez R, Coyle EF. Supine exercise restores arterial blood pressure and skin blood flow despite dehydration and hyperthermia. The American Journal of Physiology. 1999; 277:H576-H583
Nielsen B, Rowell LB, Bonde-Petersen F. Cardiovascular responses to heat stress and blood volume displacements during exercise in man. European Journal of Applied Physiology and Occupational Physiology. 1984; 52:370-374
Nagashima K, Nose H, Takamata A, Morimoto T. Effect of continuous negative-pressure breathing on skin blood flow during exercise in a hot environment. Journal of Applied Physiology (Bethesda, Md.: 1985). 1985; 84:1845-1851
Ogawa Y, Kamijo Y, Ikegawa S, Masuki S, Nose H. Effects of postural change from supine to head-up tilt on the skin sympathetic nerve activity component synchronised with the cardiac cycle in warmed men. Journal of Physiology-London. 2017; 595:1185-1200
Fortney SM, Nadel ER, Wenger CB, Bove JR. Effect of blood volume on sweating rate and body fluids in exercising humans. Journal of Applied Physiology. 1981; 51:1594-1600
Dodt C, Gunnarsson T, Elam M, Karlsson T, Wallin BG. Central blood volume influences sympathetic sudomotor nerve traffic in warm humans. Acta Physiologica Scandinavica. 1995; 155:41-51
Kamijo Y, Okumoto T, Takeno Y, Okazaki K, Inaki M, et al. Transient cutaneous vasodilatation and hypotension after drinking in dehydrated and exercising men. The Journal of Physiology. 2005; 568:689-698
Fortney SM, Wenger CB, Bove JR, Nadel ER. Effect of hyperosmolality on control of blood flow and sweating. Journal of Applied Physiology. 1984; 57:1688-1695
Takamata A, Nagashima K, Nose H, Morimoto T. Role of plasma osmolality in the delayed onset of thermal cutaneous vasodilation during exercise in humans. The American Journal of Physiology. 1998; 275:R286-R290
Mitono H, Endoh H, Okazaki K, Ichinose T, Masuki S, et al. Acute hypoosmolality attenuates the suppression of cutaneous vasodilation with increased exercise intensity. Journal of Applied Physiology. 2005; 99:902-908
Geelen G, Keil LC, Kravik SE, Wade CE, Thrasher TN, et al. Inhibition of plasma vasopressin after drinking in dehydrated humans. The American Journal of Physiology. 1984; 247:R968-R971
Takamata A, Mack GW, Gillen CM, Jozsi AC, Nadel ER. Osmoregulatory modulation of thermal sweating in humans: Reflex effects of drinking. The American Journal of Physiology. 1995; 268:R414-R422
Roberts MF, Wenger CB, Stolwijk JA, Nadel ER. Skin blood flow and sweating changes following exercise training and heat acclimation. Journal of Applied Physiology. 1977; 43:133-137
Ichinose T, Okazaki K, Masuki S, Mitono H, Chen M, et al. Ten-day endurance training attenuates the hyperosmotic suppression of cutaneous vasodilation during exercise but not sweating. Journal of Applied Physiology. 2005; 99:237-243
Takeno Y, Kamijo YI, Nose H. Thermoregulatory and aerobic changes after endurance training in a hypobaric hypoxic and warm environment. Journal of Applied Physiology (Bethesda, Md.: 1985). 2001; 91:1520-1528
Thomas CM, Pierzga JM, Kenney WL. Aerobic training and cutaneous vasodilation in young and older men. Journal of Applied Physiology. 1999; 86:1676-1686
Ikegawa S, Kamijo Y, Okazaki K, Masuki S, Okada Y, et al. Effects of hypohydration on thermoregulation during exercise before and after 5-day aerobic training in a warm environment in young men. Journal of Applied Physiology. 2011; 110:972-980
Okazaki K, Goto M, Nose H. Protein and carbohydrate supplementation increases aerobic and thermoregulatory capacities. The Journal of Physiology. 2009; 587:5585-5590
Convertino VA, Brock PJ, Keil LC, Bernauer EM, Greenleaf JE. Exercise training-induced hypervolemia: Role of plasma albumin, renin, and vasopressin. Journal of Applied Physiology. 1980; 48:665-669
Gillen CM, Lee R, Mack GW, Tomaselli CM, Nishiyasu T, et al. Plasma volume expansion in humans after a single intense exercise protocol. Journal of Applied Physiology. 1991; 71:1914-1920
Okazaki K, Hayase H, Ichinose T, Mitono H, Doi T, et al. Protein and carbohydrate supplementation after exercise increases plasma volume and albumin content in older and young men. Journal of Applied Physiology. 2009; 107:770-779
Nagashima K, Wu J, Kavouras SA, Mack GW. Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans. Journal of Applied Physiology (Bethesda, Md.: 1985). 1985; 91:1229-1236
Greenleaf JE, Brock PJ, Keil LC, Morse JT. Drinking and water balance during exercise and heat acclimation. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology. 1983; 54:414-419
Takamata A, Ito T, Yaegashi K, Takamiya H, Maegawa Y, et al. Effect of an exercise-heat acclimation program on body fluid regulatory responses to dehydration in older men. The American Journal of Physiology. 1999; 277:R1041-R1050
Nagashima K, Cline GW, Mack GW, Shulman GI, Nadel ER. Intense exercise stimulates albumin synthesis in the upright posture. Journal of Applied Physiology. 2000; 88:41-46
Yang RC, Mack GW, Wolfe RR, Nadel ER. Albumin synthesis after intense intermittent exercise in human subjects. Journal of Applied Physiology. 1998; 84:584-592
Mack GW, Yang R, Hargens AR, Nagashima K, Haskell A. Influence of hydrostatic pressure gradients on regulation of plasma volume after exercise. Journal of Applied Physiology (Bethesda, Md.: 1985). 1998; 85:667-675
Haskell A, Gillen CM, Mack GW, Nadel ER. Albumin infusion in humans does not model exercise induced hypervolaemia after 24 hours. Acta Physiologica Scandinavica. 1998; 164:277-284
Goto M, Okazaki K, Kamijo Y, Ikegawa S, Masuki S, et al. Protein and carbohydrate supplementation during 5-day aerobic training enhanced plasma volume expansion and thermoregulatory adaptation in young men. Journal of Applied Physiology. 2010; 109:1247-1255
Ahlman B, Charlton M, Fu A, Berg C, O'Brien P, et al. Insulin's effect on synthesis rates of liver proteins. A swine model comparing various precursors of protein synthesis. Diabetes. 2001; 50:947-954
Nose H, Mack GW, Shi XR, Nadel ER. Shift in body fluid compartments after dehydration in humans. Journal of Applied Physiology (Bethesda, Md.: 1985). 1988; 65:318-324
Takamata A, Yoshida T, Nishida N, Morimoto T. Relationship of osmotic inhibition in thermoregulatory responses and sweat sodium concentration in humans. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2001; 280:R623-R629
Blatteis CM. Age-dependent changes in temperature regulation—A mini review. Gerontology. 2012; 58:289-295
Kenny GP, Poirier MP, Metsios GS, Boulay P, Dervis S, et al. Hyperthermia and cardiovascular strain during an extreme heat exposure in young versus older adults. Temperature (Austin). 2017; 4:79-88
Guergova S, Dufour A. Thermal sensitivity in the elderly: A review. Ageing Research Reviews. 2011; 10:80-92
Holowatz LA, Kenney WL. Peripheral mechanisms of thermoregulatory control of skin blood flow in aged humans. Journal of Applied Physiology (Bethesda, Md.: 1985). 2010; 109:1538-1544
Kenney WL. Thermoregulation at rest and during exercise in healthy older adults. Exercise and Sport Sciences Reviews. 1997; 25:41-76
Kenney WL, Chiu P. Influence of age on thirst and fluid intake. Medicine and Science in Sports and Exercise. 2001; 33:1524-1532
Van Someren EJ, Raymann RJ, Scherder EJ, Daanen HA, Swaab DF. Circadian and age-related modulation of thermoreception and temperature regulation: Mechanisms and functional implications. Ageing Research Reviews. 2002; 1:721-778
Takeda R, Imai D, Suzuki A, Ota A, Naghavi N, et al. Lower thermal sensation in normothermic and mildly hyperthermic older adults. European Journal of Applied Physiology. 2016; 116:975-984
Kenney WL, Tankersley CG, Newswanger DL, Hyde DE, Puhl SM, et al. Age and hypohydration independently influence the peripheral vascular response to heat stress. Journal of Applied Physiology. 1985; 68:1902-1908
Kenney WL, Morgan AL, Farquhar WB, Brooks EM, Pierzga JM, et al. Decreased active vasodilator sensitivity in aged skin. The American Journal of Physiology. 1997; 272:H1609-H1614
Inoue Y, Shibasaki M, Ueda H, Ishizashi H. Mechanisms underlying the age-related decrement in the human sweating response. European Journal of Applied Physiology and Occupational Physiology. 1999; 79:121-126
Mack GW, Weseman CA, Langhans GW, Scherzer H, Gillen CM, et al. Body fluid balance in dehydrated healthy older men: Thirst and renal osmoregulation. Journal of Applied Physiology. 1994; 76:1615-1623
Geelen G, Corman B. Relationship between vasopressin and renal concentrating ability in aging rats. The American Journal of Physiology. 1992; 262:R826-R833
Ho CW, Beard JL, Farrell PA, Minson CT, Kenney WL. Age, fitness, and regional blood flow during exercise in the heat. Journal of Applied Physiology. 1997; 82:1126-1135
Surveillance CfDCaPN. Diabetes Publich Health Resource. GA: Atlanta; 2014
Beer S, Feihl F, Ruiz J, Juhan-Vague I, Aillaud MF, et al. Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes. Vascular Health and Risk Management. 2008; 4:1449-1458
Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. Journal of the American College of Cardiology. 1996; 27:567-574
Petrofsky JS, Lee S, Patterson C, Cole M, Stewart B. Sweat production during global heating and during isometric exercise in people with diabetes. Medical Science Monitor. 2005; 11:CR515-CR521
Strom NA, Sawyer JR, Roberts SK, Kingsley-Berg SM, Charkoudian N. Local sensory nerve control of skin blood flow during local warming in type 2 diabetes mellitus. Journal of Applied Physiology (Bethesda, Md.: 1985). 2010; 108:293-297
Wick DE, Roberts SK, Basu A, Sandroni P, Fealey RD, et al. Delayed threshold for active cutaneous vasodilation in patients with type 2 diabetes mellitus. Journal of Applied Physiology (Bethesda, Md.: 1985). 2006; 100:637-641
Colberg SR, Stansberry KB, McNitt PM, Vinik AI. Chronic exercise is associated with enhanced cutaneous blood flow in type 2 diabetes. Journal of Diabetes and its Complications. 2002; 16:139-145
Fealey RD, Low PA, Thomas JE. Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clinic Proceedings. 1989; 64:617-628
Rand SPJ, Zimmermann G. Diabetes: Sweat response and heart rate variability during electrical stimulation in controls and people with diabetes. Journal of Applied Research. 2008; 8:48-54
Berghoff M, Kilo S, Hilz MJ, Freeman R. Differential impairment of the sudomotor and nociceptor axon-reflex in diabetic peripheral neuropathy. Muscle & Nerve. 2006; 33:494-499
Kenny GP, Stapleton JM, Yardley JE, Boulay P, Sigal RJ. Older adults with type 2 diabetes store more heat during exercise. Medicine and Science in Sports and Exercise. 2013; 45:1906-1914
Sokolnicki LA, Roberts SK, Wilkins BW, Basu A, Charkoudian N. Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus. American Journal of Physiology. Endocrinology and Metabolism. 2007; 292:E314-E318
Fujii N, Meade RD, Akbari P, Louie JC, Alexander LM, 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:e13238
Kawashima S, Yokoyama M. Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004; 24:998-1005
Luo KR, Chao CC, Hsieh PC, Lue JH, Hsieh ST. Effect of glycemic control on sudomotor denervation in type 2 diabetes. Diabetes Care. 2012; 35:612-616
Luo KR, Chao CC, Chen YT, Huang CM, Yang NC, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. Journal of Neuropathology and Experimental Neurology. 2011; 70:930-938
McGinn R, Paull G, Meade RD, Fujii N, Kenny GP. Mechanisms underlying the postexercise baroreceptor-mediated suppression of heat loss. Physiological Reports. 2014; 2:e12168
Welch G, Foote KM, Hansen C, Mack GW. Nonselective NOS inhibition blunts the sweat response to exercise in a warm environment. Journal of Applied Physiology (Bethesda, Md.: 1985). 2009; 106:796-803
Suzuki A, Okazaki K, Imai D, Takeda R, Naghavi N, et al. Thermoregulatory responses are attenuated after fructose but not glucose intake. Medicine and Science in Sports and Exercise. 2014; 46:1452-1461
Dhatariya K. People with type 1 diabetes using short acting analogue insulins are less dehydrated than those with using human soluble insulin prior to onset of diabetic ketoacidosis. Medical Hypotheses. 2008; 71:706-708
Kenny GP, Jay O. Thermometry, calorimetry, and mean body temperature during heat stress. Comprehensive Physiology. 2013; 3:1689-1719
Lynn AG, Gagnon D, Binder K, Boushel RC, Kenny GP. Divergent roles of plasma osmolality and the baroreflex on sweating and skin blood flow. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2012; 302:R634-R642
Naylor LH, Yusof NM, Paramalingam N, Jones TW, Davis EA, et al. Acute hyperglycaemia does not alter nitric oxide-mediated microvascular function in the skin of adolescents with type 1 diabetes. European Journal of Applied Physiology. 2014; 114:435-441
Okazaki K, Kamijo Y, Takeno Y, Okumoto T, Masuki S, et al. Effects of exercise training on thermoregulatory responses and blood volume in older men. Journal of Applied Physiology. 2002; 93:1630-1637
Zappe DH, Bell GW, Swartzentruber H, Wideman RF, Kenney WL. Age and regulation of fluid and electrolyte balance during repeated exercise sessions. The American Journal of Physiology. 1996; 270:R71-R79
Phillips PA, Rolls BJ, Ledingham JG, Forsling ML, Morton JJ, et al. Reduced thirst after water deprivation in healthy elderly men. The New England Journal of Medicine. 1984; 311:753-759
Gersovitz M, Munro HN, Udall J, Young VR. Albumin synthesis in young and elderly subjects using a new stable isotope methodology: Response to level of protein intake. Metabolism. 1980; 29:1075-1086
Sheffield-Moore M, Yeckel CW, Volpi E, Wolf SE, Morio B, et al. Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. American Journal of Physiology. Endocrinology and Metabolism. 2004; 287:E513-E522
Okazaki K, Ichinose T, Mitono H, Chen M, Masuki S, et al. Impact of protein and carbohydrate supplementation on plasma volume expansion and thermoregulatory adaptation by aerobic training in older men. Journal of Applied Physiology. 2009; 107:725-733
Kataoka Y, Kamijo YI, Ogawa Y, Sumiyoshi E, Nakae M, et al. Effects of hypervolemia by protein and glucose supplementation during aerobic training on thermal and arterial pressure regulations in hypertensive older men. Journal of Applied Physiology (Bethesda, Md.: 1985). 2016; 121:1021-1031
Simmons GH, Wong BJ, Holowatz LA, Kenney WL. Changes in the control of skin blood flow with exercise training: Where do cutaneous vascular adaptations fit in? Experimental Physiology. 2011; 96:822-828
Black MA, Green DJ, Cable NT. Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels. The Journal of Physiology. 2008; 586:3511-3524
Hodges GJ, Sharp L, Stephenson C, Patwala AY, George KP, et al. The effect of 48 weeks of aerobic exercise training on cutaneous vasodilator function in post-menopausal females. European Journal of Applied Physiology. 2010; 108:1259-1267
Tew GA, Saxton JM, Klonizakis M, Moss J, Ruddock AD, et al. Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating. Journal of Applied Physiology. 2011; 110:1264-1270
Inoue Y, Nakao M, Okudaira S, Ueda H, Araki T. Seasonal variation in sweating responses of older and younger men. European Journal of Applied Physiology and Occupational Physiology. 1995; 70:6-12
Umpierre D, Ribeiro PA, Kramer CK, Leitao CB, Zucatti AT, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: A systematic review and meta-analysis. JAMA. 2011; 305:1790-1799
Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: A meta-analysis. Diabetes Care. 2006; 29:2518-2527
Buono MJ, Sjoholm NT. Effect of physical training on peripheral sweat production. Journal of Applied Physiology (Bethesda, Md.: 1985). 1988; 65:811-814
Havenith G, van Middendorp H. The relative influence of physical fitness, acclimatization state, anthropometric measures and gender on individual reactions to heat stress. European Journal of Applied Physiology and Occupational Physiology. 1990; 61:419-427
Stapleton JM, Poirier MP, Flouris AD, Boulay P, Sigal RJ, et al. Aging impairs heat loss, but when does it matter? Journal of Applied Physiology (Bethesda, Md.: 1985). 2015; 118:299-309
Wilson TM, Tanaka H. Meta-analysis of the age-associated decline in maximal aerobic capacity in men: Relation to training status. American Journal of Physiology. Heart and Circulatory Physiology. 2000; 278:H829-H834
Stapleton JM, Yardley JE, Boulay P, Sigal RJ, Kenny GP. Whole-body heat loss during exercise in the heat is not impaired in type 1 diabetes. Medicine and Science in Sports and Exercise. 2013; 45:1656-1664
Carter MR, McGinn R, Barrera-Ramirez J, Sigal RJ, Kenny GP. Impairments in local heat loss in type 1 diabetes during exercise in the heat. Medicine and Science in Sports and Exercise. 2014; 46:2224-2233
McGinn R, Carter MR, Barrera-Ramirez J, Sigal RJ, Flouris AD, et al. Does type 1 diabetes alter post-exercise thermoregulatory and cardiovascular function in young adults? Scandinavian Journal of Medicine & Science in Sports. 2015; 25:e504-e514