Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

The brain is the primary organ that senses blood glucose levels and initiates a stress response when blood glucose levels are too low: hypoglycemia). Insulin-dependent people with Type 1 diabetes: T1DM) have an impaired ability to sense hypoglycemia and an impaired ability to activate this counterregulatory response: CRR) to hypoglycemia. As a result, T1DM are at a greater risk of experiencing insulin induced severe hypoglycemic episodes, which can result in seizures, brain damage, or even death. Since hypoglycemia is a major barrier that limits intensive blood glucose control, important research initiatives are needed to prevent or reduce the burden of hypoglycemia for people with Type 1 diabetes, specifically by defining the mechanisms and modulators of brain glucose sensing. The experiments in this thesis were designed to investigate the role and mechanism by which insulin may regulate brain glucose sensing. Recent evidence suggests that insulin acts in the brain to regulate glucose homeostasis, central nervous system: CNS) glucose sensing, and the CRR to hypoglycemia, but the site and method of CNS insulin action are still unknown. This study 1) investigated whether insulin acts on hypothalamic neurons to regulate brain glucose sensing and 2) ascertained how insulin regulates glucose sensing by evaluating its effects on key glucose sensors and CNS glucose uptake. Taking advantage of a genetic mouse model that chronically lacks CNS insulin action: the neuronal insulin receptor knockout NIRKO mouse), this report assessed whether CNS insulin signaling regulates the brain\u27s ability to detect and respond to hypoglycemia by analyzing glucose counterregulation and neuronal activation in response to hypoglycemia. Further, to clarify a mechanism of CNS insulin action, this study assessed whether insulin regulates key glucose sensors and/or CNS glucose uptake by examining the expression patterns of key glucose sensing proteins, including glucose transporters: GLUTs) and glucokinase: GK), and measuring regional brain glucose utilization. Understanding how the brain regulates the counterregulatory response to hypoglycemia is critical to devise therapies to combat severe hypoglycemia in diabetic patients. Overall, this thesis provides new insights into insulin\u27s role in the brain to regulate CNS glucose sensing and the counterregulatory response to hypoglycemia