Insulin signaling in the central nervous system influences satiety, counterregulation, and peripheral insulin sensitivity. Neurons expressing the Glut4 glucose transporter influence peripheral insulin sensitivity. Here, we analyzed the effects of insulin receptor (IR) signaling in hypothalamic Glut4 neurons on glucose sensing as well as leptin and amino acid signaling. By measuring electrophysiological responses to low glucose conditions, we found that the majority of Glut4 neurons in the ventromedial hypothalamus (VMH) were glucose excitatory neurons. GIRKO mice with a combined ablation of IR in Glut4-expressing tissues showed increased counterregulatory response to either 2-deoxyglucose-induced neuroglycopenia or systemic insulin-induced hypoglycemia. The latter response was recapitulated in mice with decreased VMH IR expression, suggesting that the effects on the counterregulatory response are likely mediated through the deletion of IRs on Glut4 neurons in the VMH. Using immunohistochemistry in fluorescently labelled hypothalamic Glut4 neurons, we show that IR signaling promotes hypothalamic cellular signaling responses to the rise of insulin, leptin, and amino acids associated with feeding. We conclude that hypothalamic Glut4 neurons modulate the glucagon counterregulatory response, and that IR signaling in Glut4 neurons is required to integrate hormonal and nutritional cues for the regulation of glucose metabolism.

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