Replacing dietary carbohydrate with protein and fat improves lipoprotein subclass profile and liver fat in type 2 diabetes independent of body weight: evidence from 2 randomized controlled trials

Background: Dyslipidemia with elevated concentrations of triacylglycerol-rich lipoproteins (TRLs), small-dense LDL, and reduced HDL is linked to hepatic steatosis and promotes atherogenesis in type 2 diabetes (T2D). Objectives: We aimed to analyze whether moderate carbohydrate restriction reduces liver fat in T2D independent of changes in body weight and whether this is accompanied by parallel improvements in plasma lipoprotein subclasses. Methods: We determined the density profile of circulating lipoproteins in patients with T2D from 2 previous randomized controlled trials. In the isoenergetic study, 30 participants were allocated in a crossover design to 6 + 6 wk of an isocaloric carbohydrate-reduced high-protein (CRHP, C/P/F = 30/30/40 E%) or conventional diabetes (CD, C/P/F = 50/17/33 E%) diet aimed at weight maintenance. In the hypoenergetic study, 72 participants were allocated in a parallel-group design to 6 wk of a hypocaloric CRHP or CD diet aimed at matched ∼6% weight loss. Both studies provided all meals from a metabolic kitchen to maximize adherence. Results: In the isoenergetic study, the CRHP diet reduced TRL (mean: −33%; 95% CI: −48%, −14%) and LDL₅ (mean: −16%; 95% CI: −26%, −4%) and increased HDL₂/HDL₃ (mean: 10%; 95% CI: 0%, 22%) compared with the CD diet. In the hypoenergetic study, weight loss induced by CRHP diet tended to reduce TRL (mean: −16%; 95% CI: −30%, 1%), reduced LDL₅ (mean: −13%; 95% CI: −22%, −3%), and increased HDL₂/HDL₃ (mean: 11%; 95% CI: 1%, 22%) compared with an equivalent weight loss induced by CD diet. The CRHP diet decreased intrahepatic triacylglycerol (IHTG) more than the CD diet (isoenergetic: −55%; 95% CI: −74%, −22%; hypoenergetic: −26%; 95% CI: −45%, 0%), and changes in IHTG correlated directly with changes in TRL and LDL₅ (r = 0.36–0.55; P < 0.01 for all) in both studies. Conclusions: Replacing dietary carbohydrate with protein and fat improves dyslipidemia in T2D independently of changes in body weight, by inducing an atheroprotective shift in the lipoprotein particle profile possibly facilitated by reduced IHTG accumulation. These trials were registered at clinicaltrials.gov as NCT02764021 (https://clinicaltrials.gov/study/NCT02764021?term=NCT02764021&rank=1) and NCT03814694 (https://clinicaltrials.gov/study/NCT03814694?term=NCT03814694&rank=1).