Introduction and Objective: Despite advances in the development of new insulin formulations and the use of diabetes technologies, severe hypoglycemia remains a major problem for people with type 1 diabetes on intensive insulin therapy due in part to defective counterregulatory hormone responses and a lack of symptomatic awareness of hypoglycemia. Elevated brain lactate levels in the ventromedial hypothalamus (VMH), play a significant role in impairing the counterregulatory responses to hypoglycemia and contribute to the development of impaired hypoglycemia awareness in poorly controlled type 1 diabetes. However, the mechanism underlying the rise in central lactate remains unclear. The current study investigated whether pharmacological treatment with sodium oxamate, a lactate dehydrogenase inhibitor, can restore the counterregulatory responses to hypoglycemia in rats with type 1 diabetes.Methods: Poorly controlled streptozotocin-induced type 1 diabetic rats (N=6) were treated daily with intraperitoneal injections of sodium oxamate (550mg/kg) for a period of one week to inhibit lactate production prior to undergoing a hypoglycemic clamp study with microdialysis study to evaluate the effect of this treatment on VMH lactate levels and the counterregulatory hormone responses. These results were compared to those from a control group that received intraperitoneal injections of saline (N=6).Results: Although oxamate treatment reduced brain lactate concentrations by ~50% (P<0.05), plasma lactate levels were not affected. We documented that oxamate treatment improved both the glucagon and epinephrine responses to hypoglycemia by 2.2 to 3.8-fold (P<0.03 vs saline), respectively, in diabetic animals.Conclusion: Our results suggest that inhibiting lactate production with oxamate may be a suitable treatment strategy to improve glucose counterregulatory responses to hypoglycemia and potentially, hypoglycemia awareness, in people with type 1 diabetes.
D. Appadurai: Employee; Current; Vira Regen Inc. Stock/Shareholder; Current; Vira Regen Inc. A. Sundar: None. O. Chan: None.
Utah Center for Metabolic Health
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