High protein ingestion does not affect whole-body insulin sensitivity in individuals with overweight or obesity

Context High-protein diets (HPD), rich in branched-chain amino acids (BCAAs), proposed to enhance glycemic control. The metabolic implications of elevated BCAAs in insulin resistance are unclear, but overactivation of S6K1-related signaling pathway may contribute to insulin resistance. Objective To investigate the impact of two dietary protein interventions on IR and molecular signaling in skeletal muscle (acutely) and adipose tissue (18-weeks period) in overweight/obese individuals. Design The acute study included ingestion of 50g (MPD), 100g (HPD) or 50g of protein with added fat (MPDAF) on three different occasions with muscle biopsies before and after. The analysis performed in the 18-week data set used a subset of data with available adipose tissue biopsies randomized, controlled, isoenergetic dietary intervention, focusing on the relevant HPD and control diets. Insulin sensitivity was assessed using labelled intravenous glucose tolerance tests (IVGTT) acutely, while the euglycemic-hyperinsulinemic clamp (EHC) was used in the 18-week intervention. Results IP6K1 and total AMPK protein content significantly decreased following the high protein meal (p=0.048 and p= 0.006 respectively), alongside increased p-AktThr308/Akt2 (p=0.046) while S6K1 mRNA was lower after 6-weeks of HPD, compared to the Control diet group (p=0.046), but not at 18-weeks. However, neither intervention changed whole-body IR. Conclusion Key proteins implicated in intracellular insulin signaling were altered with an acute HP meal (decreased IP6K1 and AMPK, increased pAkt/Akt2 activity), indicating a potential enhancement of insulin-mediated glucose signaling at the molecular level. These findings suggest that, while systemic insulin resistance was unchanged, high-protein intake may have beneficial effects on cellular insulin signaling.