Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes

Abstract

Aims/hypothesis Emerging 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. Methods We 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. Results In 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/interpretation Higher 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.

Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes

“… 33 Several phosphatidylcholines and sphingomyelins correlated inversely with cardiac autonomic neuropathy in participants with type 2, but not type 1, diabetes, concluding this may arise from dyslipidemia as a major driver of nerve damage secondary to type 2 diabetes. 33 …”

“…33 Several phosphatidylcholines and sphingomyelins correlated inversely with cardiac autonomic neuropathy in participants with type 2, but not type 1, diabetes, concluding this may arise from dyslipidemia as a major driver of nerve damage secondary to type 2 diabetes. 33 We have also reported lipidomic analyses of other diabetic complications in the Pimas, including nephropathy 13 and retinopathy. 34 The neuropathy lipidomic signatures from the current study were distinct to both the DKD and the retinopathy signatures, although signatures in all three diabetic complications centered around impaired boxidation.…”

The Effects of Consuming White Button Mushroom Agaricus bisporus on the Brain and Liver Metabolome Using a Targeted Metabolomic Analysis

“…Glycerophospholipid, and sphingolipid accumulation in cerebrospinal fluid (CSF) [36] and plasma [37] have shown an increased lipid turnover in subjects with Alzheimer's disease (AD) consistent with the formation of inflammatory lipids [38][39][40][41][42]. Similar changes in inflammatory lipid species have also been found in Parkinson's disease [43] and Multiple sclerosis [44], as well as metabolic diseases such as type 2 diabetes [45], non-alcoholic steatohepatitis [46] and non-alcoholic fatty liver [47] where liver biopsies and high serum levels of sphingomyelins have been used as biomarkers of visceral adipose tissue and hepatic triglyceride content [47,48]. A protective association between metabolites reflecting the consumption of mushroom and brain health have been proposed in a prospective cognitive decline study with humans [18] and after oral administration of the mushroom derived antioxidant ergothioneine in a recognition memory study in rodents [17].…”

Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Is Associated With Disturbances in TCA, Lipid, and Glucose Metabolism

“…In crude analyses we found CAN to be associated with lower levels of phosphatidylcholine 38:6 and 32:0 and the E/I ratio the proportionally associated with phosphatidylcholine 34:3. Recently, opposite associations were found in persons with recent onset type 2 diabetes ( 36 ), where more pathological measures of autonomic dysfunction by HRV were associated with higher levels of several phosphatidylcholines including 32:0. The same study examined persons with recent onset type 1 diabetes and found no associations between CAN and lipid compounds.…”