New studies show that a carbohydrate-reduced, high-protein diet reduces liver fat and promotes heart-friendly lipoprotein changes, independent of weight loss.

Study: Replacing dietary carbohydrate with protein and fat improves lipoprotein subclass profile and liver fat in type 2 diabetes independent of body weight: evidence from two randomized controlled trials. Image Credit: Elena Veselova/Shutterstock.com

In a recent study published in The American Journal of Clinical Nutrition, a group of researchers evaluated whether reducing dietary carbohydrates and increasing protein and fat improves lipoprotein subclass profiles in type 2 diabetes (T2D), independent of body weight changes.

Background

Adopting a healthier lifestyle is fundamental in managing T2D, with weight loss often emphasized. Traditional dietary recommendations focus on low-fat, high-carbohydrate diets, but emerging evidence suggests reducing carbohydrate intake may improve glycemic control and diabetic dyslipidemia.

Carbohydrate restriction can normalize triacylglycerol (TAG) and High-density lipoprotein (HDL) cholesterol but has variable effects on Low-density lipoprotein (LDL) cholesterol.

It may also reduce metabolic dysfunction-associated steatotic liver disease (MASLD), though findings remain inconclusive due to challenges like poor adherence and confounding factors like weight loss or exercise. Further research is needed to clarify the independent effects of carbohydrate restriction on lipid metabolism.

About the study

The two studies were conducted as open-label, prospective, randomized controlled trials (RCTs) at Copenhagen University Hospital Bispebjerg to evaluate the effects of a carbohydrate-reduced high-protein (CRHP) diet compared with a conventional diabetes (CD) diet over six weeks.

The Iso study involved a cross-over design with 30 participants maintaining stable weight, while the Hypo study utilized a parallel-group design with 72 participants aiming for a 6% weight loss. Both trials were approved by the local ethics committee and adhered to strict eligibility criteria.

Participants with T2D were included based on Hemoglobin A1c (HbA1c), levels between 48 and 97 mmol/mol (6.5–11%), while exclusions were made for conditions such as severe renal disease, anemia, critical illness, and certain medications.

The dietary intervention provided CRHP meals comprising 30% of energy (E%) from carbohydrates, 30 E% from protein, and 40 E% from fat, compared to 50 E%, 17 E%, and 33 E% in the CD diet.

All meals were prepared and distributed by research staff to ensure adherence, with participants instructed to consume only the provided foods. Weight maintenance or loss was managed according to the study design, with physical activity maintained at habitual levels.

Blood samples and lipoprotein profiling were performed pre- and post-intervention, analyzing parameters such as HbA1c, lipid concentrations, and insulin resistance. Intrahepatic triglyceride (IHTG) content was assessed via magnetic resonance spectroscopy.

Statistical analyses, including linear mixed models, evaluated diet effects and accounted for body weight fluctuations. Correlations between changes in IHTG and lipid profiles were assessed using Pearson’s analysis.

Study results

In both studies, participant retention was high, with only 7% withdrawing after randomization for reasons unrelated to trial outcomes or adverse events. The baseline characteristics of participants in the Iso and Hypo studies were generally comparable.

However, participants in the Hypo study were more obese, had higher fasting insulin concentrations, and were more insulin resistant than those in the Iso study. In the Hypo study, baseline characteristics between dietary groups were balanced except for a higher proportion of men and participants using dipeptidyl peptidase-4 (DPP-4) inhibitors in the CRHP group.

Most participants had well-managed dyslipidemia, with group mean concentrations of TAG, LDL cholesterol, and HDL cholesterol within normal ranges.

In the Iso study, body weight was effectively maintained across both diet groups. However, the CRHP diet significantly improved lipoprotein profiles compared to the CD diet, reducing atherogenic subfractions of TAG-rich lipoproteins (TRL) and LDL5 while increasing the HDL2/HDL3 ratio.

These changes reflected a shift toward a less atherogenic lipoprotein profile. In the Hypo study, where both groups achieved similar weight loss, the CRHP diet showed a tendency to reduce TRL. It significantly reduced LDL5, increased the HDL2/HDL3 ratio, and demonstrated a greater improvement in IHTG compared to the CD diet.

Glucometabolic improvements were observed in both studies. In the Iso study, the CRHP diet reduced HbA1c, fasting TAG, and IHTG significantly more than the CD diet.

In the Hypo study, weight loss alone improved these markers, but the CRHP diet further enhanced the benefits, reducing HbA1c and circulating TAG more effectively than the CD diet. Both studies demonstrated superior reductions in IHTG with the CRHP diet compared to the CD diet.

Correlations between changes in IHTG and lipid parameters revealed consistent relationships. In the Iso study, reductions in IHTG were significantly associated with improvements in TAG, TRL, LDL5, and the HDL2/HDL3 ratio. Similar trends were observed in the Hypo study, where changes in IHTG correlated with reductions in TAG, TRL, and LDL5.

Conclusions

To summarize, the study demonstrated that a CRHP diet improved plasma lipoprotein density profiles in patients with T2D over six weeks. Key changes included reductions in fasting TAG and small-dense LDL5 particles, as well as an increased HDL2/HDL3 ratio compared to a CD diet. These effects were observed during both weight maintenance and weight loss.

Additionally, the CRHP diet lowered total cholesterol, non-HDL cholesterol, and Apolipoprotein B (ApoB) levels in the weight-maintenance setting. Improvements were strongly associated with reductions in IHTG, suggesting that liver fat depletion played a critical role.

While weight loss in both diet groups enhanced lipid profiles, the CRHP diet provided additional atheroprotective benefits, supporting its potential as a targeted dietary intervention for T2D-associated dyslipidemia and metabolic dysfunction.