Ketone Body Induction: Insights into Metabolic Disease Management

Abstract

Ketone bodies (KBs), particularly β-hydroxybutyrate, are crucial metabolites that provide clean and efficient energy, especially during periods of low glucose availability. Ketogenesis is a promising therapeutic avenue for conditions such as obesity, metabolic syndrome, and diabetes. This review aims to summarize the current evidence on ketogenesis across different health conditions and therapeutic modalities, highlighting the potential to mitigate metabolic disorders and diabetes-related complications. By reducing inflammation and oxidative stress, increased KB production provides cardiovascular and neuroprotective benefits. Ketogenesis is enhanced under physiological conditions like pregnancy and fasting, as well as in pathophysiological states such as diabetes and heart failure. Various interventions, including the promotion of endogenous ketogenesis through diet and exercise, drug-induced ketogenesis via sodium-glucose cotransporter 2 inhibitors, and exogenous ketone supplementation, have demonstrated favorable effects on metabolic health. However, challenges remain, including risks such as pathological ketoacidosis and dyslipidemia. In specific populations, such as lean mass hyper-responders, laboratory lipid profiles might reflect the metabolic privilege. This review will assist in the future clarification of individual differences and optimized therapeutic approaches leveraging ketogenesis for the personalized management of metabolic disorders.

Keywords: diabetes; ketogenesis; ketone bodies; metabolic diseases; β-hydroxybutyrate.

Figure 1

Strategies to induce ketosis. Endogenous ketogenesis can be induced by physiological conditions, including fasting, aerobic exercise, and a ketogenic diet; pathophysiological states, including diabetes and heart failure; and therapeutic interventions, including treatment with glucose-lowering agents. These strategies to promote ketogenesis, along with exogenous ketone supplementation, can enhance metabolic resilience. GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2.

Figure 2

Spectrum of blood ketone body concentrations (mM) and their associated metabolic states. Physiological ketogenesis (0.5–5.0 mM) is induced by fasting, exercise, or a ketogenic diet. Pathophysiological ketogenesis (0.1–1.5 mM) represents a transitional zone that may reflect either adaptive or dysregulated metabolism. Pathological ketogenesis (3.0–25.0 mM), as observed in diabetic ketoacidosis, indicates a loss of homeostatic regulation and requires clinical intervention.

Figure 3

Metabolic adaptations associated with ketogenesis in lean mass hyper-responders illustrated by the lipid energy model, which describes a physiological transition from carbohydrate-based to fat-based energy metabolism. In individuals with a BMI below 25 kg/m² who follow a ketogenic diet, there is evidence of increased peripheral uptake of TGs carried by VLDL and enhanced microbial-mediated cholesterol transformation in the gut. This contributes to elevated levels of both LDL and HDL. Ketogenesis in this population represents a key energy adaptation mechanism, and its association with a metabolically privileged phenotype, despite apparent dyslipidemia, warrants further investigation. The upward red arrow denotes an increase. BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very-low-density lipoprotein.

Figure 4

Physiological and metabolic effects of β-hydroxybutyrate. β-Hydroxybutyrate exerts multiple beneficial effects, including reductions in inflammation, oxidative stress, and insulin resistance. It serves as an efficient fuel across various organs—enhancing neuroprotection, supporting the energy demands of cardiac and skeletal muscle, and reducing proteolysis and lipolysis. Furthermore, β-hydroxybutyrate offers protective effects in diabetic nephropathy and exerts insulinotropic effects on pancreatic β-cells. While ketogenesis may reduce MASLD, its impact on the lipid profile remains inconclusive. The upward red arrow denotes an increase, and the downward blue arrow denotes a decrease. The dashed arrow indicates a pathway whose effect remains uncertain. MASLD, metabolic dysfunction-associated steatotic liver disease.