Abstract
Aims/hypothesisEmerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes.MethodsWe analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic–euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years.ResultsIn participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = −0.242 to r = −0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered.Conclusions/interpretationHigher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes.Graphical abstract
Highlights
Cardiovascular autonomic neuropathy (CAN), with its hallmark reduced heart rate variability (HRV), affects approximately 20% of people with diabetes and predicts an increased risk of major cardiac events and mortality [1]
We recently demonstrated that lower HRV, indicating diminished cardiovagal tone, in recent-onset type 2 diabetes is associated with insulin resistance, hepatic steatosis and blunted cardiorespiratory fitness, suggesting that these components could play an important role in the early development of CAN, apart from well-known risk factors such as higher age, obesity, hypertension or poor glycaemic control [2]
After Bonferroni correction and following adjustment for sex, age, BMI, smoking status, HbA1c, fasting blood glucose, M value, triacylglycerols, cholesterol, HDL-cholesterol, LDL-cholesterol, creatinine, proteinuria, insulin therapy, oral glucose-lowering drugs, antihypertensive drugs and lipid-lowering drugs, the following associations were noted among the time-domain HRV indices: SD of all NN intervals (SDNN) was inversely associated with higher levels of diacylphosphatidylcholine (PCaa) C32:0 and PCaa C34:1, and acylalkyl-phosphatidylcholine (PCae) C36:0, as well as SM C16:0 and SM C16:1; SD for differences between adjacent NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2 and PCae C36:0, as well as SM C16:1 and root mean square of successive differences (RMSSD) was inversely associated with PCae C36:0
Summary
Cardiovascular autonomic neuropathy (CAN), with its hallmark reduced heart rate variability (HRV), affects approximately 20% of people with diabetes and predicts an increased risk of major cardiac events and mortality [1]. There is accumulating evidence suggesting that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to neuropathy, for type 2 diabetes. Since both hyperglycaemia and dyslipidaemia affect multiple cells in the peripheral nervous system, including neuronal axons, Schwann cells and dorsal root ganglia, deciphering the mechanisms by which perturbed glucose and lipid metabolism converge to result in nerve damage could foster the development of novel lipid-based diseasemodifying treatments for diabetic neuropathy [4]. The Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study showed that hypertriacylglycerolaemia was associated with prevalent CAN [6], while low HDL-cholesterol levels were predictors of incident polyneuropathy over 13 years [7]
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