Ketones and Insulin: A Paradoxical Interplay With Implications for Glucose Metabolism

Abstract Ketone bodies have emerged as critical metabolic regulators with apparent hormone-like signaling properties. Exogenous ketone supplements allow for immediate induction of ketosis, providing a valuable tool to investigate ketone signaling. Particularly the glucose-lowering effect of exogenously administered β-hydroxybutyrate has attracted attention; yet the mechanisms underlying this effect remain elusive. This review synthesizes historical and contemporary studies investigating the interplay between ketone bodies and insulin, which appears to at least partly mediate the hypoglycemic effect of ketones. Early studies suggested that chronic exposure to ketones led to initial stimulation of insulin secretion but ultimately resulted in exhaustion of β cells and subsequent hyperglycemia. More recent investigations confirm an insulin stimulatory effect of ketones in isolated islets, rodent models, and human participants—though the effect appears dependent on the metabolic context including availability of glucose and duration of exposure. These insulinogenic properties of ketone bodies themselves are particularly intriguing given a state of ketosis—when induced endogenously, either via fasting or a diet very low in carbohydrates—is commonly associated with very low concentrations of insulin and holds promise for clinical utility of diabetes reversal or treatment. Similarly, exogenous ketones are now suggested to hold therapeutic potential in the context of dysregulated glucose metabolism. Collectively, these findings underscore the nuanced and complex metabolic role of ketones that warrant further studies aimed at disentangling the effect of ketones both as alternative fuel source and signaling metabolite.