Hypothalamic Prostaglandins Facilitate Recovery From Severe Hypoglycemia but Exacerbate Recurrent Hypoglycemia in Mice

The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counterregulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Imaging mass spectrometry and liquid chromatography/mass spectrometry showed phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were changed after insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug, was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via shRNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH. Article Highlights Insulin decreases arachidonic acid-containing phospholipids and increases prostaglandin production in the hypothalamus. Prostaglandin in the hypothalamus increases glucagon secretion and glucose production during hypoglycemia. Recurrent hypoglycemia decreases glucagon secretion and glucose production during hypoglycemia. Prostaglandin in the hypothalamus during recurrent hypoglycemia decreases glucagon sensitivity and glucose production.