Acid-sensing ion channel 1a (ASIC1a), a proton-gated ion channel that senses alterations in pH, contributes to cellular responses associated with acidosis. Metabolic, tissue, and cellular acidosis are central to various disease processes, which include cardiometabolic disease (CMD). Recently, we found that global ASIC1a deletion (Asic1a-/-) results in age-associated obesity in both male and female mice. However, only aged male Asic1a-/- mice develop hypertension that is driven by elevated corticosterone, aldosterone, and increased sympathetic activity. To further investigate the mechanisms by which ASIC1a may regulate metabolic function, we performed untargeted metabolomics and identified multiple pathway-level disruptions associated with ASIC1a loss, including altered glucose handling. These findings led us to hypothesize that loss of ASIC1a increases fasting blood glucose (FBG) by enhancing gluconeogenesis and impairing insulin signaling. To begin to address this, we measured fasting blood glucose (FBG), plasma insulin and glucagon, and performed glucose, insulin, and pyruvate tolerance tests in 6-month-old, male and female, wildtype (Asic1a+/+) and Asic1a-/- mice. Both male and female Asic1a-/- mice have elevated FBG (males, p=0.002; females, p=0.0019). This elevation was accompanied by decreased insulin (p=0.004) and increased glucagon (p=0.009) in male mice, but not in female mice. Additionally, glucose tolerance was impaired in male (p=0.0377), but not female Asic1a-/- mice (p=0.7389). Moreover, male Asic1a-/- mice exhibit an enhanced gluconeogenic state, as evidenced by maintained elevated glucose following the pyruvate tolerance test (p=0.0275). Interestingly, however, insulin sensitivity was increased in both male and female Asic1a-/- mice (males, p=0.0207; females, p=0.0044). These findings identify a potential mechanistic link between acid-sensing and CMD, and suggest ASIC1a is a key regulator of glucose homeostasis. Funding Source: National Institute of Health T32 GM144834; University of New Mexico School of Medicine Research Allocation Funding This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
DeLeon et al. (Fri,) studied this question.