Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

• Published in: Diabetologia 2023-12, Vol.66 (12), p.2307-2319
• Main Authors: Taskinen, Marja-Riitta, Matikainen, Niina, Björnson, Elias, Söderlund, Sanni, Inkeri, Jussi, Hakkarainen, Antti, Parviainen, Helka, Sihlbom, Carina, Thorsell, Annika, Andersson, Linda, Adiels, Martin, Packard, Chris J., Borén, Jan
• Format: Article
• Language: English
• Subjects: Apolipoprotein B-100; Apolipoprotein B-100 - therapeutic use; Apolipoprotein B-48; Apolipoproteins; Apolipoproteins B - metabolism; Apolipoproteins B - therapeutic use; Arteriosclerosis; Cardiovascular diseases; Cardiovascular Diseases - complications; Cardiovascular Diseases - drug therapy; Chylomicrons; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Endocrinology and Diabetes; Endokrinologi och diabetes; Human Physiology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypotheses; Internal Medicine; Lipoproteins; Lipoproteins (very low density); Lipoproteins, IDL; Lipoproteins, VLDL - metabolism; Liver; Low density lipoprotein; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Metformin; Postprandial; Stable isotope; Statins; Triglycerides; VLDL
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-023-06008-0

Aims/hypothesis This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk. Methods To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL. Results The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL 1 and VLDL 2 density ranges (all p  < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p  < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p =0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p  < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation ( p  < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL 2 . Conclusions/interpretation Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in indiv