Hypothalamic prostaglandins facilitate recovery from severe hypoglycemia but exacerbate recurrent hypoglycemia in mice

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The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counter-regulatory 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. Using imaging mass spectrometry and liquid chromatography/mass spectrometry, phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were increased following insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), 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 short-hairpin RNA 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.

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