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Chronic allopregnanolone treatment enhances glucose tolerance through parasympathetic activity

It is estimated that one and a half million Americans are diagnosed with diabetes each year. A startling statistic given that diabetes is considered the 7th leading cause of death making diabetes a significant health burden to the United States. It is imperative than that we develop new treatments and regulators of glucose metabolism. The ability of the central nervous system to regulate whole body glucose metabolism is one such treatment avenue. We are particularly interested in the role of the parasympathetic nervous system on glucose homeostasis since stimulation of the vagus nerve alters insulin and glucagon release from the pancreas. Previous work demonstrated that GABAergic signaling to parasympathetic motor neurons is critical to normal parasympathetic function, including the regulation of pancreatic secretions. Recent work from other brain regions identified that allopregnanolone (ALLO) is an endogenous ligand to GABAA receptors and can have positive effects on brain related disorders, such as anxiety, depression, and stroke. There is even evidence that it can improve diabetic neuropathic pain. Therefore, we aimed to determine if ALLO could alter glucose metabolism. We hypothesized that ALLO improves glucose tolerance through improved parasympathetic signaling. In initial experiments, female mice were ovariectomized (OVX), to normalize hormone concentrations, and implanted with subcutaneous silastic capsules (20mm) containing either ALLO (20mg) or vehicle (sesame oil; 0.1% alcohol). After 10 days, mice were administrated an intraperitoneal (i.p.) glucose tolerance test (GTT; 2g/kg) and blood glucose was monitored at intervals of 0, 15, 30, 60, and 120 minutes during the GTT. Mice given ALLO for 10–14 days had a significant improvement in glucose tolerance compared to vehicle (213 ± 12 mg/dL vs 325 ± 37 mg/dL). To determine if the parasympathetic nervous system was involved in the improvement in glucose tolerance after chronic ALLO exposure, a GTT was repeated after a pre‐treatment with atropine methyl nitrate (0.5mg/kg; i.p.). After atropine pre‐treatment mice exposed to ALLO did not demonstrate a significant difference in GTT compared to atropine treated mice exposed to vehicle (351 ± 35 mg/dL vs 362 ± 29 mg/dL), indicating that parasympathetic nervous system function is required for ALLO‐induced improvements in GTT. Follow‐up experiments used interventricular cannula (IVC) administration for ALLO. Again, in OVX females, IVC ALLO improved GTT (265 ± 15 mg/dL vs 346 ± 49 mg/dL), further indicating the important role of the brain in regulating the ability of ALLO to modulate glucose tolerance. On‐going studies will probe the end organ mechanism(s) responsible for this improvement. As well as how ALLO works centrally to modulate vagal motor drive. Interestingly, systematic administration of ALLO to males (20mg) did not demonstrate significant improvements in GTT (423 ± 15 mg/dL vs 410 ± 56 mg/dL). Taken together, these data suggest that ALLO is a novel, modulator of glucose metabolism, particularly in females. By understanding the role of ALLO on vagal drive and glucose homeostasis, we hope to development new therapies to treat diabetes and its complications.