This randomized, placebo-controlled human trial investigated the effects of exogenous β-hydroxybutyrate monoester (BHB) on iron metabolism in people with newly diagnosed prediabetes. Over a 4-week period, daily BHB supplementation significantly reduced serum ferritin and increased total antioxidant capacity. These shifts suggest that BHB may help regulate iron homeostasis and lower oxidative stress—factors strongly linked to metabolic dysfunction. This adds a new dimension to ketone-based therapies beyond glucose management.

This conceptual framework outlines a “two-engine” system for optimizing cellular energy: the ketone engine for base-load power and the glucose engine for surge capacity. Researchers propose that ketone metabolism serves as a clean-burning fuel, reducing oxidative stress and enhancing mitochondrial efficiency. Meanwhile, glucose operates as a rapid-response booster engine. This model may inform future metabolic therapies that prioritize ketone-based energy for stable, long-term cellular performance while using glucose strategically for acute demands.

3‑Hydroxybutyrate (3HB) is one of the main ketone bodies produced by the liver during fasting or ketogenic diets. In a study using genetically diabetic mice, researchers evaluated whether increasing circulating 3HB could improve glycaemic control. They found that oral supplementation of a 3HB precursor lowered fasting blood glucose, improved glucose tolerance and reduced insulin resistance. Mechanistically, 3HB acted through the hydroxycarboxylic acid receptor 2 (HCAR2) to raise intracellular Ca2+ and cyclic AMP (cAMP) levels, activating protein kinase A and ultimately inhibiting phosphorylation of the nuclear receptor PPARγ at Ser273—a modification linked with insulin resistance. Genes downstream of PPARγ showed improved expression, and treated mice showed lower HOMA‑IR scores and improved metabolic profiles. These findings suggest that elevating circulating 3HB may be a practical strategy for improving insulin sensitivity in type 2 diabetes.