Body temperature regulation in diabetes

“A recent meta-analysis by Umpierre et al.181 reported a mean decrease in HbA1c following a structured exercise intervention >12 weeks of ~0.7%.”

“The activity of brown adipose tissue has been shown to be characterized by uncoupling protein-1, a mitochondrial protein, and has been reported to have a pronounced role inwhole-body thermogenesis even under resting conditions.(155) While brown adipose tissue activity is reported to be relatively lower in individuals…”

“Advanced age is a particularly important risk factor for type 2 diabetes, with diabetes prevalence rate reaching as high as 33% in older adults who are obese.(190) Given that the mean age of the workforce is increasing rapidly, employers are faced increasingly with the challenge of accommodating individuals with chron…”

“Type 1 diabetes was formerly known as juvenile diabetes due to its common presentation in children and adolescents, and is characterized by the endocrine pancreas ceasing to produce insulin following the immune-mediated destruction of b-islet cells.(2)”

“exposure activates brown adipose tissue which is highly metabolically active and oxidizes triglycerides and glucose as fuel.(154) The activity of brown adipose tissue has been shown to be characterized by uncoupling protein-1, a mitochondrial protein, and has been reported to have a pronounced role inwhole-body thermo…”

“Type 2 diabetes tends to present later in life with a mean onset age of 54 years,(94) although the mean age at diagnosis is rapidly decreasing(95) due in part to the longstanding increase in diagnosis in the pediatric population.(96) In general, type 2 diabetes is linked to general health status and lifestyle as it ha…”

“On the other hand, non-shivering thermogenesis is primarily mediated by metabolically active brown adipose tissue.(38) Although shivering is undoubtedly the major contributor to increases in heat production, studies postulate that non-shivering thermogenesis remains an important physiological response especially durin…”

“hypertension.(139) During heat stress, especially during exercise in the heat, hypertensive individuals experience greater elevations in blood pressure due to increased peripheral resistance which can restrict heat loss due to the reductions skin blood flow, which ultimately lead to more pronounced increases in core t…”

“For instance, type 2 diabetes is associated with reduced sympathetic neural control of blood pressure(123) which manifests as greater orthostatic intolerance compared to age-matched controls.(124) In addition, individuals with type 2 diabetes exhibit a decline in baroreflex sensitivity(125) which is closely associated…”

“function]) mechanisms.(32,33) In the context of wholebody heat loss under heat stress conditions which are compensable (i.”

“In fact, individuals with type 2 diabetes have up to a 56% greater risk for hospitalization and/or mortality during a heat wave.(106) One recent study assessed the influence of age and type 2 diabetes during passive heat exposure in a room set at 43 C for 3 hours.”

“In fact, Hanssen et al.157 reported that only 10 days of cold acclimation (14- 15 C) in individuals with type 2 diabetes induced a 43% increase in insulin sensitivity which was explained by a 60% increase in GLUT-4 translocation (i.e., themembrane channel that allows glucose to enter amuscle cell or adipocyte).”

“adversely alter endothelial function through interfering with nitric oxide signaling.(110) In fact, one study reported that the relative nitric oxide-dependent vasodilation during whole-body passive heating was similar between healthy controls and those with type 2 diabetes; however, absolute skin blood flow was lower…”

“Dehydration associated with prolonged exposure to extreme heat conditions can induce significant alterations of blood composition (increased in red blood cell count, blood viscosity and platelet counts) which, if left unchecked, can increase the risk of coagulation, and subsequently cerebral and coronary thromboses.(1…”

“Individuals with types 1 and 2 diabetes are reported to be particularly vulnerable during extreme heat events as they account for a disproportionate number of hospitalizations and deaths.(19) The most recently published physical activity recommendations for individuals with diabetes highlight their susceptibility to a…”

“Surprisingly, these improvements in insulin sensitivity surpass even those of long-term exercise training which is currently regarded as the best management strategy for type 2 diabetes.(158) Taken together, it appears that mild cold exposuremay be useful for themanagement of type 2 diabetes as a third lifestyle facto…”

“Individuals with type 1 diabetes are known to be at increased risk for cardiovascular disease and hypertension;(13) however, this can be minimized by healthy habits including physical activity and good glycemic control.(75) On the other hand, baroreflex sensitivity has been reportedly reduced with type 1 diabetes in r…”

“Therefore, while any impairments in resting cardiovascular function are minimal or non-detectable, individuals with type 1 diabetes may be at increased risk for cardiovascular-related limitations under stress such as during exercise, especially when performed in the heat due to the exponential increase in the requirem…”

“, diabetes tends to accelerate any age-related changes).(45,147)”

“Minson et al.(140) showed that older men have a markedly lower increase in total blood flow directed to the skin during a passive heat stress maintained to the individual’s limit of thermal tolerance.”

“The primary factors associated with this decrease in sweating include longstanding diabetes, poor glycemic control, and the presence of neuropathy which seem to have an important role in altering the peripheral properties of the sweat glands.(54,111) For instance, the sweat glands from individuals with type 2 diabetes…”

“Importantly, these effects are strongly dependent upon glycemic control, albeit it has been postulated that episodes of acute hyperglycemia exert more damage than chronically poor management of glycemia.(118)”

“Furthermore, this blunted responsiveness is at least in part attributed to the reduction in the control of blood vessel diameter by the sympathetic nervous system.(45,123) Collectively, there is some evidence to indicate that individuals with type 2 diabetes may be less able to prevent decreases in core temperature as…”

“Taken together, it appears that mild cold exposuremay be useful for themanagement of type 2 diabetes as a third lifestyle factor (along with diet and exercise) to optimize health.(24,159) However, further examination is required to determine the long-term effects of cold exposure and the optimal exposure level that is…”

“During thermal stress, sensory information is sent from the peripheral (in the skin and muscle) and central (in the brain) thermoreceptors to the pre-optic anterior hypothalamus of the brain which is believed to coordinate thermoeffector responses to achieve heat balance.(26,27)”

“reported similar increases in skin blood flow between non-neuropathic individuals with type 1 diabetes and their healthy counterparts (albeit responses were blunted in neuropathic individuals) whereas other work has shown clear diabetesrelated impairments in skin blood flow.(47,48) In the context of eccrine sweating,…”

“One of the strongest determinants of the rate of heat loss is the level of hyperthermia as measured by mean body temperature which has traditionally been defined as a composite of core and skin temperatures.(31) Upon exposure to heat stress (i.”

“, finding shelter, adding clothing layers, making fire) must be employed in order to prevent precipitous decreases in core temperature.(34) In addition, multiple physiological processes are activated during cold exposure in order to minimize heat loss and under conditions of severe and/or prolonged cold stress, increa…”

“6 and 7).(184,185) However, some have reported no”

“cardiac output during exercise due to left ventricular diastolic dysfunction.(119,120) Moreover, a recent study has noted a ~20% reduction in exercise capacity in their participants with uncomplicated type 2 diabetes relative to their healthy counterparts.”

“especially during physically activity in the heat, is stimulated by cholinergic nerves to expel sweat onto the skin which is subsequently evaporated.(30) It is the evaporation of sweat that cools the body and as such sweat loss due to dripping provides no thermoregulatory benefit and facilitates a state of progressive…”

“6 and 7).(184,185) However, some have reported no”

“Despite this, a recent meta-analysis of the randomized trials of aerobic or resistance exercise on glycemic control in individuals with type 1 diabetes by Yardley et al.(169) concluded that there is insufficient evidence to ascertain the effect of exercise training on HbA1c.”

“In fact, the latter mechanism has received some support by observations depicting lower sweat gland nerve densities associated with sympathetic nerve impairments.(73)”

“Shivering intensity is dictated by changes in mean body temperature,(36,37) and maximal heat production of a shivering individual can increase up to 5-fold from baseline or to ~40% of maximal aerobic capacity.(36) On the other hand, non-shivering thermogenesis is primarily mediated by metabolically active brown adipos…”

“differences in heat loss following short-term exercise training(186) or between independent groups with large differences in aerobic fitness in young individuals.(187) A recent study by Stapleton and colleagues(188) showed that the age-related decline in aerobic fitness (~7% per decade(189)) explained some of the age-…”

“These agerelated changes in cardiovascular function to heat stress is further impaired in individuals with pre-existing cardiac dysfunction(127) such that increases in skin blood flow and therefore heat exchange is severely compromised.(130,133) Heart failure and peripheral arterial disease are the most common initial…”

“For instance, a study by Arora et al.46 reported similar increases in skin blood flow between non-neuropathic individuals with type 1 diabetes and their healthy counterparts (albeit responses were blunted in neuropathic individuals) whereas other work has shown clear diabetesrelated impairments in skin blood flow.47,4…”

“In contrast, the differences in glycemia in a colder environment may be related to counter-regulatory hormone signaling such as increases in plasma cortisol production together with greater glucocorticoid responsiveness which results in lower insulin sensitivity.(170) While no studies have yet assessed the direct impa…”

“In fact, infusion of C-peptide in those with type 1 diabetes was successful in reversing the group’s impairment in skin blood flow relative to healthy individuals.(61) Others have noted impairments in endothelium-dependent and endothelium–independent vasodilation 62 along with reduced nitric oxide bioavailability due…”

“This is exacerbated by reductions in whole-body heat exchange associated with the smaller body surface area-to-mass ratio in obese individuals.(143) Specifically, an obese person has a smaller body surface area-to-body mass ratio for effective sweat evaporation than a leaner person of the same height since his/her gre…”

“Importantly, a diagnosis of any chronic health condition has a negative impact on the productivity of the worker almost immediately with a noticeable reduction in work output within 1 year.(191) To date, there have been few studies in the area of chronic health conditions and the older worker; however, based on the av…”

“, HbA1c); however, it has been suggested that the presence/severity of neuropathy is more closely explained by an inverse relationship with high-density lipoprotein-cholesterol.(97) Collectively, individuals with type 2 diabetes are a particularly vulnerable population group due to their tendency to have relatively po…”

“Aerobic fitness is an important determinant of health status for any individual and higher aerobic fitness is associated with lower all-cause mortality.(183) In the context of thermoregulatory control, higher levels of aerobic fitness and or physically activity have been suggested to improve the capacity to dissipate…”

“7).(188) Altogether, aerobic fitness in healthy adults likely plays an important role in the capacity for heat loss and explains some of the attenuated heat 134 G.”

“function]) mechanisms.(32,33) In the context of wholebody heat loss under heat stress conditions which are compensable (i.”

“Taken together, it appears that mild cold exposuremay be useful for themanagement of type 2 diabetes as a third lifestyle factor (along with diet and exercise) to optimize health.(24,159) However, further examination is required to determine the long-term effects of cold exposure and the optimal exposure level that is…”

“The mechanisms for these improvements remain unclear; however, it has been postulated that increases in muscle blood flow associated with heating(164) and/or activation of heat shock protein 70.(165)”

“In addition, individuals with type 2 diabetes exhibit a decline in baroreflex sensitivity(125) which is closely associated with the level of insulin resistance.(126) Consequently, it would be expected that individuals with type 2 diabetes are less able to maintain blood pressure and cardiovascular stability during an…”

“However, other findings indicate that maximal cutaneous vasodilation elicited pharmacologically and/or via local heating can be reduced in individuals with type 1 diabetes.(45) On the other hand, it remains uncertain whether the impaired maximal cutaneous vasodilation is paralleled by reduced submaximal skin blood flo…”

“Changes in body composition occur with age such that older adults tend to have greater body fat and less muscle mass with this pattern of response being more pronounced in individuals with type 2 diabetes.(132,142)”

“Importantly, it was noted in this study that the productivity losses were not reflected in a higher productivity cost since individuals with type 2 diabetes had lower salaries on average.(192) Thus, the area of type 2 diabetes in the older worker is becoming an important area of focus with the development of exposure…”

“cardiac output during exercise due to left ventricular diastolic dysfunction.(119,120) Moreover, a recent study has noted a ~20% reduction in exercise capacity in their participants with uncomplicated type 2 diabetes relative to their healthy counterparts.”

“These agerelated changes in cardiovascular function to heat stress is further impaired in individuals with pre-existing cardiac dysfunction(127) such that increases in skin blood flow and therefore heat exchange is severely compromised.(130,133) Heart failure and peripheral arterial disease are the most common initial…”

“Based on the observations that individuals with type 1 diabetes demonstrate greater skin blood flow under baseline resting conditions which enhances dry heat loss (this is thought to be associated with the hyperinsulinemic state(44)) combined with the evidence of hypoglycemia-mediated blunting of shivering thermogenes…”

“In addition, improved diabetes management and care strategies have led to markedly increased life expectancy along with reduced incidence of associated complications.(40,41) However, longer life expectancy has also caused a rapidly increasing number of older adults living with type 1 diabetes.”

“In addition, improved diabetes management and care strategies have led to markedly increased life expectancy along with reduced incidence of associated complications.(40,41) However, longer life expectancy has also caused a rapidly increasing number of older adults living with type 1 diabetes.”

“induced sweating during exercise has been recently well established.(113,114)”

“In fact, one study reported that the relative nitric oxide-dependent vasodilation during whole-body passive heating was similar between healthy controls and those with type 2 diabetes; however, absolute skin blood flow was lower in the latter group.(109) Moreover, there is evidence to support an endothelium-independen…”

“increased formation of advanced glycosylated end products(69) which can suppress nitric oxide bioavailability and augment basal oxidative stress which affects skin blood flow control.(70,71)”

“While little information is available regarding the central versus peripheral mechanisms underlying diabetes-related skin blood flow responses, one study implicated a lower onset threshold for vasodilation as the primary factor to explain a lower skin blood flow; an indication that the modulation of skin blood flow is…”

“With respect to individuals with diabetes, none of the exercise studies have considered fitness as a potential factor as the healthy controls were all matched for maximal aerobic capacity along with age and physical characteristics.(57-59,108)”

“, vasodilation) and sweating, both of which are modulated by sympathetic nerves.(28,29) The action of vasodilation opens the skin’s blood vessels to allow greater blood flow to the skin which increases skin temperature, and thereby increasing the gradient for dry heat exchange between the skin and the external environ…”

“While there are a limited number of studies examining the effects of heat stress in older obese individuals during exercise, it has been shown that obesity is associated with reductions in heat tolerance and impairments in the activation of heat loss responses of skin blood flow and sweating.(134,141) This is exacerba…”

“Importantly, these effects appear to depend on fitness such that those with type 2 diabetes who engage in physical activity have reduced impairments in skin vasodilation, albeit individuals with type 2 diabetes exhibit reduced maximal skin blood flow irrespective of fitness.(103) On the other hand, studies of local sw…”

“Diabetes care plans must consider adjustments for the age-related changes in functional status and incorporate appropriate accommodations for individuals who may be less able to manage their glycemia.(42) Furthermore, the earlyonset of type 1 diabetes results in a longer burden of disease, and therefore increased diab…”

“5 times more likely to experience a heat-related fatality compared to lean age-matched individuals.(129)”

“Others have noted impairments in endothelium-dependent and endothelium–independent vasodilation 62 along with reduced nitric oxide bioavailability due primarily to diminished nitric oxide synthase activity.(63).”

“However, individuals with type 2 diabetes appear to have lower skin blood flow relative to their age-matched controls.(18) Although this may be perceived as beneficial in the context of minimizing heat dissipation during cold exposure, type 2 diabetes is also associated with marked impairments in vascular responsivene…”

“Of particular importance, these diabetes-related changes in skin blood flow appear to be closely associated with the duration of diabetes and/or the presence of related complications.(98,99) While little information is available regarding the central versus peripheral mechanisms underlying diabetes-related skin blood…”

“, an indicator of the level of physical activity) during the autumn/winter compared to the spring/summer months.(172) The mechanism underlying these divergent responses in glycemia between those with type 1 and type 2 diabetes in response to environmental factors is unknown and deserves further scrutiny.”

“For example, the absence of C-peptide (produced in pancreatic islet b cells) is known to have an important role in microvascular blood flow in a manner which is nitric oxide-dependent.(60) In fact, infusion of C-peptide in those with type 1 diabetes was successful in reversing the group’s impairment in skin blood flow…”

“However, the effects on skin blood flow have yielded mixed results when assessed under passive heating conditions(128,131,136) whereas consistent reductions in skin blood flow have been measured during exercise in the heat.(137,138) To the best of our knowledge, the effects on sweating have not been studied although m…”

“In the context of eccrine sweating, the general pattern in individuals with type 1 diabetes is relative lower body anhidrosis along with upper body eu- or hyperhidrosis(49,50) which can lead to global anhidrosis.(51) Importantly, these reductions in skin blood flow and sweating in those with type 1 diabetes have been…”

“While there are a limited number of studies examining the effects of heat stress in older obese individuals during exercise, it has been shown that obesity is associated with reductions in heat tolerance and impairments in the activation of heat loss responses of skin blood flow and sweating.(134,141) This is exacerba…”

“For instance, the sweat glands from individuals with type 2 diabetes with poor glycemic control exhibit exacerbated reductions in peri-glandular nerve terminals and in the innervation index.(111,112) On the other TEMPERATURE 129”

“Given the reduced thermosensitivity of the sweating response in those with type 1 diabetes, Carter et al.(58) surmised that the diabetes-related changes in sweating were due to peripherally-mediated changes such as reduced acetylcholine sensitivity, altered physical properties of the actual sweat glands and/or interru…”

“This was linked to a marked decrease in cerebral perfusion during exercise as a consequence of lower cardiac output.(121) Impor-”

“, vasodilation) and sweating, both of which are modulated by sympathetic nerves.(28,29) The action of vasodilation opens the skin’s blood vessels to allow greater blood flow to the skin which increases skin temperature, and thereby increasing the gradient for dry heat exchange between the skin and the external environ…”

“Hot ambient conditions can also independently modulate glycemia by increasing insulin absorption and are reported to have additive effects to exercise in decreasing blood glucose levels.(56) These findings were supported during exercise wherein 75% of participants with type 1 diabetes required glucose supplementation…”

“Along these lines, older adults are known to have a reduced ability to defend core temperature during cold exposure, even that which is relatively mild.(148,149)”

“For instance, the sweat glands from individuals with type 2 diabetes with poor glycemic control exhibit exacerbated reductions in peri-glandular nerve terminals and in the innervation index.(111,112) On the other TEMPERATURE 129”

“However, the effects on skin blood flow have yielded mixed results when assessed under passive heating conditions(128,131,136) whereas consistent reductions in skin blood flow have been measured during exercise in the heat.(137,138) To the best of our knowledge, the effects on sweating have not been studied although m…”

“Although the causes of type 1 diabetes remain to be elucidated, it is probably caused by a combination of genetic predisposition (with >40 loci known to affect susceptibility)(3) and various environmental factors including stress and viruses.(4) On the other hand, type 2 diabetes is most often diagnosed in adults and…”

“Recently, a few studies demonstrated that the combination of hyperosmolality and hypovolemia presented augmented effects to further exacerbate the impairments of heat loss in healthy individuals.(27,174) In contrast, a different study demonstrated that an acute episode of hyperglycemia (as induced by hyperinsulinemich…”

“In addition, a recent study observed that even after accounting for any differences in cardiac function, otherwise healthy individuals with type 1 diabetes had reduced peak blood flow to the active muscles.(74)”

“Consistent with these findings during heat stress, seasonal variations in glycemia have been reported such that HbA1c levels for type 1 diabetes are clinically lower during the spring/summer relative to the autumn/winter months(166,167) with differences recently noted to be as high as 3%.(168) Moreover, Tsujimoto et a…”

“Furthermore, type 1 diabetes has been closely associated with reductions in blood volume which reduces the total amount of fluid available for circulation.(74,80) Therefore, while any impairments in resting cardiovascular function are minimal or non-detectable, individuals with type 1 diabetes may be at increased risk…”

“reported similar increases in skin blood flow between non-neuropathic individuals with type 1 diabetes and their healthy counterparts (albeit responses were blunted in neuropathic individuals) whereas other work has shown clear diabetesrelated impairments in skin blood flow.(47,48) In the context of eccrine sweating,…”

“While this may result in a decrease in core temperature during resting conditions, the associated dysfunction of the autonomic nervous system may eliminate any potential benefits during whole-body heat stress.(59,76) Similarly, episodes of hyperglycemia can also have an important negative impact on core temperature re…”

“Importantly, these reductions in skin blood flow and sweating in those with type 1 diabetes have been related to longer disease duration,(47,52) poorer glycemic control as assessed by higher hemoglobin A1c (HbA1c) levels, 45,50-52 greater degrees of neuropathy, and/or lower aerobic fitness.(53) Despite the fact that t…”

“Individuals with type 1 diabetes are typically diagnosed during childhood or early adulthood (incidence peaks between ages 10-14 years(39)), are leaner and typically have minimal or no comorbidities at diagnosis.(17) In addition, improved diabetes management and care strategies have led to markedly increased life expe…”

“induced sweating during exercise has been recently well established.(113,114)”

“reported a lower magnitude of postexercise hypotension for individuals with type 1 diabetes as early as 20 minutes after exercise which is consistent with prior observations of reduced postexercise muscle blood flow reported in individuals with diabetes.(86) Interestingly, in the study by McGinn et al.”

“In fact, some studies suggest that the use of antihypertensive medications (diuretics, vasodilators, b-blockers) can reduce heat tolerance during exercise in the heat.(144,145)”

“, engaged in physical activity 3 times per week for 20 min) with type 1 diabetes during dynamic exercise was only published in 2013.(57) Specifically, Stapleton et al.”

“In fact, some evidence indicates that heart rate variability can be a predictor for any diabetes-related complications.(117) Importantly, these effects are strongly dependent upon glycemic control, albeit it has been postulated that episodes of acute hyperglycemia exert more damage than chronically poor management of…”

“In line with this, individuals with type 2 diabetes show impairments relative to age-matched controls in heart rate variability (an indicator of autonomic nervous system function) at rest and during postural manipulation.(116) In fact, some evidence indicates that heart rate variability can be a predictor for any diab…”

“increased formation of advanced glycosylated end products(69) which can suppress nitric oxide bioavailability and augment basal oxidative stress which affects skin blood flow control.(70,71)”

“, the same participants) examining the postexercise response in thermal (and cardiovascular responses), McGinn et al.(59) showed that despite these differences in core temperature that persisted throughout the 60 min recovery period, local heat loss responses were similar”

“Based on the observations that individuals with type 1 diabetes demonstrate greater skin blood flow under baseline resting conditions which enhances dry heat loss (this is thought to be associated with the hyperinsulinemic state44) combined with the evidence of hypoglycemia-mediated blunting of shivering thermogenesis…”

“Specifically, the latter was evidenced by reduced redistribution of peripheral blood toward the central circulation and is consistent in males and females.(89,90)”

“Specifically, the latter was evidenced by reduced redistribution of peripheral blood toward the central circulation and is consistent in males and females.(89,90)”

“From a thermoregulatory perspective, hypoglycemia is known to induce sympathetic activation as evidenced by marked increases in sweating, limb blood flow, heart rate, and blood pressure.(173) While this may result in a decrease in core temperature during resting conditions, the associated dysfunction of the autonomic…”

“5% (indicating chronically elevated blood glucose levels) are strongly associated with reductions in skin blood flow,(66,67) and one study has linked even acute hyperglycemic episodes to irreversible vascular changes which could impair heat loss.(68) Finally, type 1 diabetes is associated with Figure 5.”

“Even local heating of the insulin injection site can lower post-prandial glycemia through increasing insulin absorption and activity,(162,163) and has been suggested as a potential avenue to improve long-term glycemic control.(162) The mechanisms for these improvements remain unclear; however, it has been postulated t…”

“is commonly regarded as a measure of autonomic nervous system function, baroreflex sensitivity is a vital cardiovascular reflex with important implications for blood pressure and possibly thermoregulatory control.(27,79) Furthermore, type 1 diabetes has been closely associated with reductions in blood volume which red…”

“While no studies have yet assessed the direct impact of acute or chronic glycemia management on thermoregulatory responses to cold exposure, one study has indicated that short-term changes in HbA1c levels are closely and inversely correlated with the cardiovascular response to a cold pressor test.(171)”