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

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.

Six-Month Periodic Fasting in Patients With Type 2 Diabetes and Diabetic Nephropathy: A Proof-of-Concept Study

“…While the specific increase in acetylcarnitine levels results most likely from pronounced activation of lipolysis during prolonged fasting periods, it is yet unclear whether acetylcarnitine is just a marker of high compliance to FMD or serves as a substrate for renal metabolism and thereby affects the response of microalbuminuria to FMD ( 48 ). This finding is also in line with a previous report associating circulating short-chain fatty acids with normoalbuminuria in diabetes ( 49 ). The nephroprotective effects of fatty acid oxidation and ketogenesis are probably explained by the fact that kidney metabolism relies highly on lipolysis and ketone bodies.…”

Traditional Chinese medicine improved diabetic kidney disease through targeting gut microbiota

“…Moon et al. ( 2021 ) proposed that circulating SCFAs contribute to metabolic processes that mitigate the development of albuminuria in T1DM. Generally, alternative therapy with SCFAs enhances kidney function by activating GPR43 and GPR109A.…”

Cohort profile: the ‘Biomarkers of heterogeneity in type 1 diabetes’ study—a national prospective cohort study of clinical and metabolic phenotyping of individuals with long-standing type 1 diabetes in the Netherlands

“…For example, certain medium-chain fatty acids and short-chain fatty acids have been suggested to be protective against albuminuria development in T1D. 28 Omics approaches, also applied in this Biomarker study, are very promising for biomarker development, but so far they have not been able to deliver validated biomarkers for clinical use, probably because of the fragmented nature of the information obtained through the single omics approach. 29 30 Novel computational approaches to data processing may help overcome challenges associated with the relatively small number of subjects in studies.…”