The relationship between ketone body metabolism and insulin resistance eludes discrete definition. Variables obscuring characterization include (i) physiological state in which hormone–fuel relationships are measured (fed, fasted, clamped); (ii) what is measured—for example, static ketone concentrations versus ketone body turnover, and whether acetoacetate is measured along with beta-hydroxybutyrate (βOHB); and (iii) wherein the natural history of insulin resistance progression the model or participant falls. Insulin resistance and ketogenesis are intricately linked metabolic processes that hold critical roles in the regulation of energy within the body.¹ Insulin resistance, defined as diminished responsiveness to insulin regulation in a postprandial state, contrasts with ketogenesis, a natural process by which hepatic mitochondria convert adipocyte-derived fatty acids to produce acetoacetate and its redox partner βOHB, particularly during times of glucose scarcity.² Ketogenesis is hormonally regulated, with glucagon stimulating it, and insulin (in)directly inhibiting it.^{3, 4} Understanding the intricate relationship between ketogenesis and insulin resistance may be crucial for maintaining wellness and is likely to be guided by distinct molecular signals than those driving impaired suppression of glucose production in insulin resistance.⁵

A recent study contributed by Mey et al.⁶ seeks to determine the interplay between ketone bodies and lipid-induced insulin resistance in human participants. Acute insulin resistance was provoked via a 12 h overnight intravenous lipid infusion in a randomized crossover design, and hepatic and peripheral tissue insulin sensitivity were quantified by hyperinsulinemic–euglycemic clamps, focusing on understanding whether the propensity of the liver to generate ketones protects against insulin resistance. Though as expected, controlled lipid infusion resulted in elevated static plasma concentrations of βOHB, ketone body levels related to insulin resistance in a tissue-specific manner: a positive correlation between plasma βOHB levels and insulin-stimulated suppression of hepatic glucose production (HGP), indicative of hepatic insulin sensitization by hepatic ketogenesis, was observed. However, a negative correlation emerged between βOHB levels and peripheral insulin sensitivity, measured as the quantity of glucose disposed per unit of plasma insulin.

Limitations of this study design leave opportunity for the development of additional insights. First, the lipid infusion protocol⁶ did not include heparin, an anticoagulant that also liberates lipoprotein lipase from adipose into the circulation. Lipoprotein lipase is crucial for the lipolysis of fatty acids from circulating lipoproteins, and heparin prevents the uptake of lipids in adipose tissue, ensuring the availability of ketogenic-free fatty acids to the liver.⁷ Additionally, this study⁶ did not quantify ketone body turnover, specifically the rates of hepatic ketogenesis (rate of appearance) and extrahepatic ketolysis (rate of disappearance).² While a static plasma βOHB concentration often reflects hepatic ketogenesis rates, whether hepatic ketogenesis or extrahepatic disposal are dynamically regulated is important to understand in pathophysiological states such as insulin resistance. Furthermore, a direct relationship between βOHB and the inflammatory response to lipid infusion was not present, potentially due to the mild inflammatory response induced by the low-dose lipid infusion. Additional studies are warranted to develop the anti-inflammatory properties of βOHB and its relevance to systemic or tissue-specific inflammation in humans.⁸ It is also important to underscore that the physiological responses to acute lipid overload in healthy, young participants may not entirely mirror the physiology of insulin resistance that develops because of long-term metabolic alterations observed in obese individuals. In a complementary study in mice subjected to a prolonged high-fat diet regimen, alterations in ketone body turnover were observed only in the advanced stages of diet-induced insulin resistance.^{9, 10} In a prior study in clamped obese humans, ketone metabolism was not altered in obese participants, unlike glucose metabolism.⁵ Moreover, ketogenesis is frequently utilized as a proxy for hepatic beta-oxidation, and both processes display a diminished dynamic range in individuals with metabolic inflexibility, particularly those afflicted with insulin resistance. These limitations endure even in the context of hyperinsulinemic–euglycemic clamps conducted during lipid infusion states.¹¹

In conclusion, the results of this study do provide significant insight into the complex relationship between ketone body metabolism and insulin resistance—and underscore the importance of tissue-selective insulin responsiveness. Although these findings challenge existing hypotheses, they reveal the imperative need for further research to study the underlying biological mechanisms governing these intricate relationships. Understanding the role of ketone bodies in insulin resistance could pave the way for effective interventions that address as obesity-related insulin resistance and diabetes.