Insulin signaling in astrocytes plays a role in brain-liver axis in the control of glucose production

Insulin plays a central role in glycaemic control, extending its regulatory influence beyond peripheral organs to the brain. Elevated circulating insulin levels, indicative of insulin resistance, are a hallmark of obesity and type 2 diabetes. Traditionally, the brain was thought to be insensitive to insulin, but our findings show that non-neuronal cells, specifically astrocytes located at the interface of neurons and blood vessels, sense and respond to insulin, thereby influencing systemic glucose control. Intrigued by these discoveries and recognising the potential of targeting these cells to regulate glucose control, particularly in the context of obesity and type 2 diabetes, we generated transgenic mice lacking both insulin and insulin growth factor 1 receptors in astrocytes. This comprehensive blockade of insulin signalling in these glial cells resulted in impaired insulin-mediated neuronal activation, conceivably due to reduced insulin and glucose entry into the brain. Surprisingly, these transgenic mice exhibited elevated serum insulin levels to maintain normal circulating glucose levels despite being leaner on an obesogenic diet. Notably, despite their reduced fat mass, these mice displayed a distinct liver disease phenotype characterised by alterations in the gluconeogenic pathway, which resulted in reduced insulin-mediated suppression of glucose production during hyperinsulinemic-euglycemic clamps. As research progresses, it is becoming increasingly clear that insulin signalling in astrocytes plays a fundamental role in the brain-liver axis of glycaemic control. Further studies are needed to unravel the complex interplay between astrocytes, peripheral insulin sensitivity and metabolic health.