1111-OR: AgRP Neuron Activity Is Both Predictive of and Shaped by the Glycemic Response to Oral Glucose

Introduction and Objective: Hypothalamic AgRP neurons play important roles in both glucose and energy homeostasis, and they are uniquely responsive to nutritional cues. The objective of this study is to investigate how the activity of these neurons is coupled to the glycemic response to an oral glucose load. Methods: We continuously monitored both AgRP neuron activity (by fiber photometry in AgRP-IRES-cre mice) and the arterial glucose level both prior to and after oral gavage (OG) of either water or one of four doses of glucose (0.5-2.5 g/kg). Results: We report that AgRP neuron activity can be subdivided into two functionally distinct phases. The ‘first phase’ of AgRP neuron inhibition begins prior to oral glucose delivery and appears to be anticipatory in nature, as it becomes more robust after the first OG glucose session and once established, is detected regardless of whether glucose or water is administered. This first phase activity is also predictive of subsequent changes in glycemia, suggesting a role in the handling of an oral glucose load. The ‘second phase’ of AgRP neuron activity extends from peak inhibition to its subsequent return towards baseline. Analysis of the relationship between this second phase and changes of glycemia was facilitated by a model that allows residual activity to be removed subsequent to the ‘first phase’ component. We report that the degree of residual inhibition tracks the glycemic response and is more temporally aligned with the BG rate of change (which is predictive of future BG levels) than with the absolute BG concentration, with AgRP neurons lagging BG rate of change by ~ 5 minutes. Conclusion: We conclude that the AgRP neuron response to an oral glucose challenge can be subdivided into distinct phases, each with its own determinants and metabolic implications: an initial anticipatory component that is predictive of the subsequent glycemic response, and a second phase that is shaped by the rate of BG change. Disclosure M. Glat: None. A. Bowen: None. Y. Gou: None. J. Scarlett: None. G. Morton: None. M.W. Schwartz: Consultant; Current; Eli Lilly and Company.