Acute hyper- and hypoglycemia uncouples the metabolic cooperation between glucose and lactate to disrupt sleep

• Published in: bioRxiv
• Main Authors: Carroll, Caitlin M, Stanley, Molly, Raut, Ryan V, Constantino, Nicholas J, Irmen, Riley E, Mitra, Anish, Snipes, J Andy, Raichle, Marcus E, Holtzman, David M, Gould, Robert W, Kishida, Kenneth T, Macauley, Shannon L
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.09.2022
• Subjects: Alzheimer's disease; Alzheimers disease; Biosensors; Blood glucose; Cooperation; Diabetes mellitus; Diurnal; EEG; Glucose; Hippocampus; Homeostasis; Hypoglycemia; Lactic acid; Metabolism; Nervous system; Neurodegenerative diseases; Oscillations; Sleep; Sleep and wakefulness
• DOI: 10.1101/2022.09.15.507967

The sleep-wake cycle is a master regulator of metabolic and neuronal activity and when altered, can have profound effects on metabolic health and disease. Although consideration is given to how fluctuations in blood glucose affect peripheral physiology and metabolism, less is known about how glucose dysregulation impacts the intrinsic cooperation between brain metabolism and neuronal activity to regulate sleep. To understand the effect of peripheral hyper- and hypoglycemia on these relationships, we paired biosensors measuring hippocampal interstitial fluid (ISF) levels of glucose and lactate with cortical EEG/EMG recordings to produce simultaneous sub second recordings of ISF glucose, lactate, and sleep-wake states. First, we describe a conserved temporal relationships between ISF glucose and lactate based on their intrinsic oscillations, diurnal rhythms, and sleep/wake cycles. ISF glucose and lactate oscillations are largely anti-correlated but the frequency of their oscillations dictate their power, coherence, and phase. While ISF glucose and lactate both have diurnal fluctuations, only ISF lactate is consistently elevated during wake. During wake, fluctuations in ISF lactate are associated with changes in the EEG power spectrum, suggesting wake-related activity is more closely associated with ISF lactate. Modulation of glucose availability via both hyper- or hypoglycemia disrupts the relationship between peripheral metabolism, brain metabolism, and sleep. Hyper- and hypo-glycemia increase ISF lactate, decrease NREM, and alter EEG spectral activity, again demonstrating ISF lactate drives wake-associated behaviors and disrupts sleep. Taken together, these studies demonstrate that peripheral glucose homeostasis is necessary for maintaining the relationships between brain metabolism, neuronal activity, and sleep-wake patterns and deviations in blood glucose levels are sufficient to disrupt the metabolic signature of sleep-wake states, putting the brain at risk in diseases like type-2-diabetes and Alzheimer's disease. Competing Interest Statement DMH co-founded and is on the scientific advisory board of C2N Diagnostics. DMH is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Alector.