Hypoglycemic detection at the portal-mesenteric vein: examination of sensitivity, mechanism and integration

2018-10-11Glucosensing at the portal-mesenteric vein (PMV) is essential to the detection of systemic hypoglycemia and for a full sympathoadrenal response. Even though PMV glucosensors are now known to be critical for slow-onset hypoglycemic detection, we still know relatively little how PMV afferents sense low glucose and how the derived signals are integrated into the CNS to ultimately result in a counterregulatory response (CRR). The objectives of this dissertation were 1) to ascertain the primacy of PMV glucosensing during slow-onset hypoglycemia, 2) to examine a potential glucosensing mechanism that underlies PMV hypoglycemic detection, and 3) the functional role of the brain upon receiving hypoglycemic input from the PMV. These objectives were achieved through 3 separate rodent studies utilizing selective surgical catheterization and/or deafferentation techniques, systemic hyperinsulinemic-hypoglycemic or selective brain clamp procedure, and immunohistochemical analysis of the brain or PMV tissues. ❧ In the first study, the primacy of PMV glucosensing was investigated through the glycemic threshold at which the sympathoadrenal response to slow-onset hypoglycemia is initiated. Elimination of PMV afferent innervation significantly attenuated the epinephrine and norepinephrine responses. The glycemic threshold for epinephrine was determined to be 3.95 ± 0.09 mM and this value was shifted lower in the absence of PMV glucosensory input, down to 3.65 ± 0.15 mM. Therefore, PMV glucosensors appear to be the determinants for initiation of the sympathetic response to slow-onset hypoglycemia. ❧ In the second study, the sodium glucose co-transporters (SGLT) residing in the PMV was stimulated to examine if it is a potential mechanism mediating PMV hypoglycemic detection. SGLT activation led to a reduction in the sympathoadrenal response to systemic hypoglycemia, but the effect did not appear specific to the action of PMV glucose afferents. Further, SGLT stimulation failed to alter the hindbrain neuronal activation that has been shown to be engaged by PMV derived hypoglycemic signals. Together, these findings do not support the hypothesis of an SGLT-mediated mechanism in the detection of hypoglycemia at the PMV. Definitive functional role of SGLT glucosensing at the PMV during hypoglycemia requires further investigation. ❧ Finally, the functional role of brain glucosensors during slow-onset hypoglycemia was investigated in the last study. Normalizing brain glycemia significantly suppressed the sympathoadrenal response to peripheral hypoglycemia but did not affect hindbrain neuronal activation. Brain glucosensors appear to provide important central glucosensory input based on local glycemic conditions to modulate the hypoglycemic motor output initiated by the PMV derived signal. Thus, the brain integrates peripheral and central glucosensory inputs to mediate the CRR to slow-onset hypoglycemia and this integration appears to take place at a level beyond the hindbrain