(ES05-22) Ketogenic Propensity Is Related to the Magnitude of Insulin Resistance After an Overnight Lipid Infusion: A Hyperinsulinemic-Euglycemic Clamp Study

Determine whether fasting ß-hydroxybutryate (ßHB, a surrogate of hepatic ketogenesis) is related to measures of metabolic health in the context of lipid-induced insulin resistance.

Methods:

Nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m²) received a 12 h overnight lipid infusion (20% intralipid at 0.55 mL/kg/h) or saline in a randomized, crossover design. Insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp. A primed (3.28mg/kg) continuous (0.036mg/kg/min) infusion of D-[6,6-²H₂] glucose was used to calculate hepatic glucose production and insulin sensitivity (M/I; M: insulin-stimulated glucose metabolism, mg/kg/min; I: insulin, µU/mL). Indirect calorimetry was used to determine whole-body substrate metabolism. Skeletal muscle biopsies were collected in a subset of individuals to quantify gene and protein expression of ketolytic enzymes. Plasma ßHB was measured in the basal and insulin-stimulated states of the clamp in both the lipid and saline conditions using a commercially available kit (Cayman Chemical).

Results:

By design, lipid infusion induced insulin resistance, reducing clamp-derived insulin sensitivity (M/I) by 28.8% compared to saline (p=0.007). ßHB was increased with the lipid infusion and reduced in the insulin-stimulated state in both the saline and lipid conditions (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal= 0.78 mM, Insulin 0.51 mM; 2-way ANOVA: Lipid p< 0.001, Insulin p< 0.001, Interaction p=0.09). In the saline condition, basal ßHB was related to less insulin resistance as measured by HOMA-IR (r = -0.544, p=0.016) and was unrelated to clamp-derived insulin sensitivity. In contrast, the lipid condition produced the opposite outcome as basal ßHB was related to greater insulin resistance as measured by HOMA-IR (r = 0.610, p=0.006) and less clamp-derived insulin sensitivity (r = -0.639, p=0.003).

Conclusions:

Recent literature has suggested greater circulating ketones may support metabolic health. However, in this report greater ketones are related to worse metabolic health in the context of a metabolic stress induced by an overnight lipid infusion. Additional research is warranted to better understand the role of ketogenesis and circulating ketones in metabolic health.

Funding Sources:

R01 DK108089 (JPK)