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

Abstract Context High protein diets (HPD), rich in branched-chain amino acids (BCAAs), are proposed to enhance glycemic control. The metabolic implications of elevated BCAAs in insulin resistance (IR) are unclear, but overactivation of ribosomal protein S6 kinase B1 (S6K1)-related signaling pathway may contribute to IR. Objective To investigate the impact of 2 dietary protein interventions on IR and molecular signaling in skeletal muscle (acutely) and adipose tissue (18-week period) in overweight/obese individuals. Methods The acute study included ingestion of 50 g protein (MPD), 100 g protein (HPD), or 50 g of protein with added fat (MPDAF) on 3 different occasions with muscle biopsies before and after. The 18-week analysis used a subset of data with available adipose tissue biopsies from a randomized, controlled, isoenergetic dietary intervention, focusing on the relevant HPD and control diets. Insulin sensitivity was assessed using labeled intravenous glucose tolerance tests acutely, and by euglycemic-hyperinsulinemic clamp in the 18-week intervention. Results Inositol hexakisphosphate kinase 1 (IP6K1) and total AMP-activated protein kinase (AMPK) protein content significantly decreased following the HPD meal (P = .048 and P = .006 respectively), alongside increased P-AktThr308/Akt2 (P = .046), while S6K1 mRNA was lower after 6 weeks of HPD, compared to the control diet group (P = .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 HPD meal (decreased IP6K1 and AMPK, increased pAkt/Akt2 activity), indicating potential enhancement of insulin-mediated glucose signaling at the molecular level. These findings suggest that, while systemic IR was unchanged, high protein intake may have beneficial effects on cellular insulin signaling.