Changes in the lipidome in type 1 diabetes following low carbohydrate diet: a randomized crossover trial

Aims/hypothesis Lipid metabolism might be compromised in type 1 diabetes and the understanding of their physiology is critically important. This study aimed to compare the change in plasma lipid concentrations during carbohydrate dietary changes in individuals with type 1 diabetes and identify predictive biomarkers and early-stage pathophysiology for dyslipidaemia. We hypothesized that: (1) the lipidomics profiles before and after ingesting low or high carbohydrate diet for 12 weeks would be different; and (2) specific annotated lipid species would have significant associations with metabolic outcomes. Methods Ten adults with type 1 diabetes (mean±SD: age 43.6±13.8 years, diabetes duration 24.5±13.4 years, BMI 24.9±2.1 kg/m 2 , HbA 1c 57.6±2.6 mmol/mol) using insulin pumps participated in a randomized 2-period crossover study with a 12-week intervention period of low carbohydrate diet ( 250 g carbohydrates/day) respectively, separated by a 12-week washout period. A large-scale non-targeted lipidomics was performed with mass spectrometry for fasting plasma samples obtained before and after each diet intervention. Logitudinal lipid levels were analysed using linear mixed-effects models. Results In total, 289 lipid species were identified from 14 major lipid classes (triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, hexosyl-ceramide, sphingomyelins, lyso-phosphatidylcholines, ceramides, lactosyl-ceramide, lyso-phoshatidylethanolamine, free fatty acids, phosphatidylinositols, phosphatidylglycerols, phosphatidylserines and sulfatides). Comparing the two diets, 11 lipid species belonging to sphingomyelins, phosphatidylcholines and LPC(O-16:0) were changed. All the 11 lipid species were significantly elevated during low carbohydrate diet. Two lipid species were most differentiated between diets, namely SM(d36:1) (β±SE: 1.44±0.28, FDR = 0.010) and PC(P-36:4)/PC(O-36:5) (β±SE: 1.34±0.25, FDR = 0.009) species. Poly-unsaturated PC(35:4) was inversely associated with BMI and positively associated with HDL-cholesterol (p < 0.001). Conclusion/interpretation Lipidome-wide outcome analysis of a randomized cross-over trial of individuals with type 1 diabetes following a low carbohydrate diet showed an increase in sphingomyelins and phosphatidylcholines which are thought to reduce dyslipidaemia. The poly-unsaturated phosphatidylcholine 35:4 was inversely associated with BMI and positively associated with HDL-cholesterol (p < 0.001). Results from this study warrant for more investigation on the long-term effect of PC(35:4) lipid-species in lipid homeostasis in type 1 diabetes. Trial registration Clinicaltrials.gov NCT02888691 Research in context What is already known about this subject? Individuals with type 1 diabetes have an increased rate of cardiovascular disease for which dyslipidaemia is a major risk factor. Dysregulated lipid metabolism is recognized as an established risk factor in cardiovascular diseases. What is the key question? Which specific circulating lipid species are changed after 12 weeks of low- and –high carbohydrate diet and do they reflect dyslipidemia risk? What are the new findings? Plasma from individuals with type 1 diabetes showed a significant increase in phosphatidylcholine and sphingomyelin lipid species during low carbohydrate diet (n=11 lipid species). Poly-unsaturated phosphatidylcholine 35:4 was inversely associated with BMI and positively associated with HDL-cholesterol ( p < 0.001). How might this impact on clinical practice in the foreseeable future? This study demonstrates that very-long-chain phosphatidylcholines and sphingomyelins elevates substantially with diet in individuals with type 1 diabetes following low carbohydrate diet. This points to a need for more specific dietary guidelines regarding fat intake to support individuals with type 1 diabetes. Lipidomics could be used to monitoring the lipid intake, thereby guiding the person to consume ‘good’ lipids that could prevent dyslipidemia.