3030-LB: Cold–Heat Alternation Impairs Glucose Tolerance through B-Cell Suppression and Tissue-Specific Metabolic Reprogramming

Introduction and Objective: Environmental temperature fluctuations are emerging as metabolic stressors, yet little is known about how repeated transitions between cold and warm environments affect energy balance, glucose homeostasis, and diabetes risk. We examined the systemic and tissue-specific effects of 21 days of controlled cold-heat alternation in mice. Methods: Mice were exposed to temperature cycling for three weeks. Indirect calorimetry assessed VO2, VCO2, energy expenditure (EE). On day 21, intraperitoneal glucose tolerance tests (ipGTT) and insulin/glucagon ELISAs were performed. Liver, skeletal muscle, and adipose tissues underwent RNA profiling and Western blotting to evaluate glucose and lipid metabolism, insulin signaling, inflammation, macrophage polarization, oxidative stress, and ER stress. Results: Temperature cycling induced a persistent hypermetabolic state, with VO2, VCO2, and EE rising by days 20-21 relative to days 2-3. Early in exposure, VO2, VCO2, and EE were nearly two-fold higher between high- and low-temperature periods, a difference that attenuated later. Despite increased metabolic activity, mice displayed glucose intolerance and reduced insulin levels reflecting inadequate β-cell compensation. Liver showed dysregulated gluconeogenic and lipid pathways and reduced insulin receptor expression. Skeletal muscle exhibited altered insulin signaling and extracellular matrix remodeling, while adipose tissue displayed thermogenic activation, M2 macrophage signatures, ER and oxidative stress, and pro-inflammatory pathways. Conclusion: Cold-heat alternation triggers a hypermetabolic yet glucose-intolerant phenotype, driven by β-cell suppression and tissue-specific metabolic reprogramming. For humans routinely transitioning between extreme outdoor temperatures and air-conditioned spaces, repeated exposure to such fluctuations may represent an underrecognized environmental contributor to metabolic instability and diabetes susceptibility. Disclosure A. Al Madhoun: None. P. George: None. M. Bourashed: None. G. Boualayan: None. N. Abukhalaf: None. R. Ahmad: None. F. Al-Mulla: None. Funding ACEC-2023-002