A 3-Week Ketogenic Diet Increases Skeletal Muscle Insulin Sensitivity in Individuals With Obesity: A Randomized Controlled Crossover Trial

Abstract

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of type 2 diabetes development. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two 3-week interventions: 1) a KD and 2) a standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2-kg weight loss and increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.

Graphical abstract

Figure 1

Study day design.

Figure 2

Substrate and hormone concentrations during the study day taken at t = 360 and 540 min. A: Plasma $\beta$-hydroxybutyrate concentrations were higher in the basal period after the KD compared with the SDD. B: Plasma lactate concentrations were similar. C: Plasma FFA concentrations were similar during both periods. In A–C, data are presented as median with interquartile range. D: Plasma insulin concentrations were similar during the basal period with a slightly lower concentration after the KD during the clamp. Data are presented as mean with SD. All data were analyzed using linear mixed-model analysis.

Figure 3

Measurements of organ-specific insulin sensitivity. A: The KD increased glucose disposal during hyperinsulinemia ($\mathrm{\Delta }$R_d) compared with the SDD. Data were analyzed with a Wilcoxon test. B: R_d was similar in the basal period with a higher increase in R_d during insulin infusion after the KD. Data are presented as median with interquartile range. C: The KD did not change the relative suppression of EGP ($\mathrm{\Delta }$EGP%) during hyperinsulinemia compared with the SDD. Data were analyzed with a paired t test. D: EGP was lower in the basal period and decreased less during the clamp after the KD, compared with the SDD. Data are presented as mean with SD. E: The KD lowered the relative suppression of palmitate flux ($\mathrm{\Delta }$ palmitate flux%) compared with the SDD. Data were analyzed with a paired t test. F: The KD induced a slightly lower suppression of palmitate flux from the basal to the clamp period. Data are presented as mean with SD. Abbreviation: TBW, total body weight.

Figure 4

Measurements with indirect calorimetry. A: EE values were similar after both diets and periods. B: RER was consistently lower during the KD compared with the SDD. C: Protein oxidation (ox) was higher in the basal period after the KD but similar during the clamp. All data are presented as mean with SD.