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Activation of Central Lactate Metabolism lowers Glucose Production in Uncontrolled Diabetes and Diet-induced Insulin Resistance

¹Departments of Physiology and
²Medicine, University of Toronto, Toronto, M5S 1A8, Canada
³Toronto General Hospital Research Institute, University Health Network, Toronto, M5G 1L7, Canada

Objective: Hypothalamic lactate metabolism lowers hepatic glucose production (GP) and plasma glucose levels in normal rodents. However, it remains unknown whether activation of hypothalamic lactate metabolism lowers GP and plasma glucose levels in rodents with diabetes and obesity.

Research Design And Methods: We performed intracerebroventricular (i.c.v.) administration of lactate to enhance central lactate metabolism in (A) the early-onset of streptozotocin (STZ)-induced uncontrolled diabetic rodents, (B) experimentally induced-hypoinsulinemic normal rodents, and (C) the early-onset of diet-induced insulin resistant rodents. Tracer-dilution methodology was used to assess the impact of i.c.v. lactate on the rate of GP in all three models.

Results: We first report that in the absence of insulin treatment, i.c.v. lactate administration lowered GP and glucose levels in rodents with uncontrolled diabetes. Second, i.c.v. lactate administration lowered GP and glucose levels in normal rodents with experimentally-induced hypoinsulinemia. Finally, i.c.v. lactate administration lowered GP in normal rodents with diet-induced insulin resistance.

Conclusions: Central lactate metabolism lowered GP in uncontrolled diabetic and normal rodents with hypoinsulinemia, and in diet-induced insulin resistant rodents. These data suggest that insulin signaling is not required for central lactate to lower GP, and the activation of hypothalamic lactate metabolism could consequently bypass insulin resistance and lower glucose levels in the early-onset of diabetes and obesity.

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