Circulating short and medium chain fatty acids are associated with normoalbuminuria in type 1 diabetes of long duration

Adam Smiles,Aleksandar D Kostic,Monika A Niewczas,Zaipul I Md Dom,Heather Lampert,Salina Moon,John J Tsay

doi:10.1038/s41598-021-87585-1

Abstract

A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown. Therefore, our study included 308 Joslin Kidney Study subjects who had T1D of long duration (median: 24 years), maintained normal renal function and had either normoalbuminuria or a broad range of albuminuria within the 2 years preceding the metabolomic determinations. Serum samples were subjected to global metabolomic profiling. 352 metabolites were detected in at least 80% of the study population. In the logistic analyses adjusted for multiple testing (Bonferroni corrected α = 0.000028), we identified 38 metabolites associated with persistent normoalbuminuria independently from clinical covariates. Protective metabolites were enriched in Medium Chain Fatty Acids (MCFAs) and in Short Chain Fatty Acids (SCFAs) and particularly involved odd-numbered and dicarboxylate Fatty Acids. One quartile change of nonanoate, the top protective MCFA, was associated with high odds of having persistent normoalbuminuria (OR (95% CI) 0.14 (0.09, 0.23); p < 10–12). Multivariable Random Forest analysis concordantly indicated to MCFAs as effective classifiers. Associations of the relevant Fatty Acids with albuminuria seemed to parallel associations with tubular biomarkers. Our findings suggest that MCFAs and SCFAs contribute to the metabolic processes underlying protection against albuminuria development in T1D that are independent from mechanisms associated with changes in renal function.

Highlights

A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown
In the multivariable logistic analyses adjusted for clinical covariates and for multiple testing, 100% of Short Chain Fatty Acids (SCFAs), 50% of Medium Chain Fatty Acids (MCFAs), 9% of LCFAs, and 0% of Very Long Chain Fatty Acids (VLCFAs) were significantly associated with protection from albuminuria (Fig. 3, Supplementary Table S1)
Our study was conducted in a study population of 308 subjects with T1D of long duration, normal renal function, and recent, persistent normoalbuminuria or a wide range of recent, persistent albuminuria

Summary

Introduction

A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown. Our findings suggest that MCFAs and SCFAs contribute to the metabolic processes underlying protection against albuminuria development in T1D that are independent from mechanisms associated with changes in renal function. Despite a cumulative exposure to T1D of over two decades, did not develop albuminuria or renal function impairment may be considered protected to some extent from progressive DKD. We can plausibly speculate that studies focusing on protection against diabetic kidney disease development will complement the current understanding of risk determinants, but will offer new and invaluable insights into the disease mechanisms. The vast majority of these metabolomics studies focused on risk factors of diabetic kidney disease progression

Methods

Results

Conclusion