Metabolite Signature of Albuminuria Involves Amino Acid Pathways in 8661 Finnish Men Without Diabetes

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2020 Sep 29

PMID 32992327

Citations 6

Authors

Lilian Fernandes Silva

Jagadish Vangipurapu

Ulf Smith

Markku Laakso

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the metabolite signature of albuminuria in individuals without diabetes or chronic kidney disease to identify possible mechanisms that result in increased albuminuria and elevated risk of type 2 diabetes (T2D).

Research Design And Methods: The study cohort was a population-based Metabolic Syndrome In Men (METSIM) study including 8861 middle-aged and elderly Finnish men without diabetes or chronic kidney disease at baseline. A total of 5504 men participated in a 7.5-year follow-up study, and 5181 of them had metabolomics data measured by Metabolon's ultrahigh performance liquid chromatography-tandem mass spectroscopy.

Results: We found 32 metabolites significantly (P < 5.8 × 10-5) and positively associated with the urinary albumin excretion (UAE) rate. These metabolites were especially downstream metabolites in the amino acid metabolism pathways (threonine, phenylalanine, leucine, arginine). In our 7.5-year follow-up study, UAE was significantly associated with a 19% increase (hazard ratio 1.19; 95% confidence interval, 1.13-1.25) in the risk of T2D after the adjustment for confounding factors. Conversion to diabetes was more strongly associated with a decrease in insulin secretion than a decrease in insulin sensitivity.

Conclusions: Metabolic signature of UAE included multiple metabolites, especially from the amino acid metabolism pathways known to be associated with low-grade inflammation, and accumulation of reactive oxygen species that play an important role in the pathogenesis of UAE. These metabolites were primarily associated with an increase in UAE and were secondarily associated with a decrease in insulin secretion and insulin sensitivity, resulting in an increased risk of incident T2D.

Citing Articles

Metabolomics-Based Machine Learning for Predicting Mortality: Unveiling Multisystem Impacts on Health.

Oravilahti A, Vangipurapu J, Laakso M, Fernandes Silva L Int J Mol Sci. 2024; 25(21).

PMID: 39519188 PMC: 11546733. DOI: 10.3390/ijms252111636.

Metabolomics in diabetic nephropathy: Unveiling novel biomarkers for diagnosis (Review).

Luo Y, Zhang W, Qin G Mol Med Rep. 2024; 30(3).

PMID: 38963028 PMC: 11258608. DOI: 10.3892/mmr.2024.13280.

Metabolomic profiling reveals key metabolites associated with hypertension progression.

Al Ashmar S, Anwardeen N, Anlar G, Pedersen S, Elrayess M, Zeidan A Front Cardiovasc Med. 2024; 11:1284114.

PMID: 38390445 PMC: 10881871. DOI: 10.3389/fcvm.2024.1284114.

H NMR metabolomics insights into comparative diabesity in male and female zebrafish and the antidiabetic activity of DL-limonene.

Benchoula K, Serpell C, Mediani A, Albogami A, Mohmad Misnan N, Ismail N Sci Rep. 2024; 14(1):3823.

PMID: 38360784 PMC: 10869695. DOI: 10.1038/s41598-023-45608-z.

Circulating Metabolites Associated with Albuminuria in a Hispanic/Latino Population.

Reynolds K, Lin B, Armstrong N, Ottosson F, Zhang Y, Williams A Clin J Am Soc Nephrol. 2022; 18(2):204-212.

PMID: 36517247 PMC: 10103280. DOI: 10.2215/CJN.09070822.

References

Bakris G, Molitch M . Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014; 37(3):867-75. DOI: 10.2337/dc13-1870. View

Oxenkrug G . Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol. 2013; 48(2):294-301. PMC: 3779535. DOI: 10.1007/s12035-013-8497-4. View

Pilz S, Rutters F, Nijpels G, Stehouwer C, Hojlund K, Nolan J . Insulin sensitivity and albuminuria: the RISC study. Diabetes Care. 2014; 37(6):1597-603. DOI: 10.2337/dc13-2573. View

Song Y, Yeung E, Liu A, VanderWeele T, Chen L, Lu C . Pancreatic beta-cell function and type 2 diabetes risk: quantify the causal effect using a Mendelian randomization approach based on meta-analyses. Hum Mol Genet. 2012; 21(22):5010-8. PMC: 3607483. DOI: 10.1093/hmg/dds339. View

Hennermann J, Roloff S, Gellermann J, Vollmer I, Windt E, Vetter B . Chronic kidney disease in adolescent and adult patients with phenylketonuria. J Inherit Metab Dis. 2012; 36(5):747-56. DOI: 10.1007/s10545-012-9548-0. View

Mogensen C . Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984; 310(6):356-60. DOI: 10.1056/NEJM198402093100605. View

Mykkanen L, Haffner S, Kuusisto J, Pyorala K, Laakso M . Microalbuminuria precedes the development of NIDDM. Diabetes. 1994; 43(4):552-7. DOI: 10.2337/diab.43.4.552. View

Solini A, Manca M, Penno G, Pugliese G, Cobb J, Ferrannini E . Prediction of Declining Renal Function and Albuminuria in Patients With Type 2 Diabetes by Metabolomics. J Clin Endocrinol Metab. 2015; 101(2):696-704. DOI: 10.1210/jc.2015-3345. View

Laakso M, Kuusisto J . Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol. 2014; 10(5):293-302. DOI: 10.1038/nrendo.2014.29. View

10.

Casanova F, Wood A, Yaghootkar H, Beaumont R, Jones S, Gooding K . A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function. Diabetes. 2020; 69(5):1072-1082. PMC: 7611011. DOI: 10.2337/db19-0862. View

11.

Hocher B, Adamski J . Metabolomics for clinical use and research in chronic kidney disease. Nat Rev Nephrol. 2017; 13(5):269-284. DOI: 10.1038/nrneph.2017.30. View

12.

Fernandes Silva L, Vangipurapu J, Kuulasmaa T, Laakso M . An intronic variant in the GCKR gene is associated with multiple lipids. Sci Rep. 2019; 9(1):10240. PMC: 6629684. DOI: 10.1038/s41598-019-46750-3. View

13.

Karu N, McKercher C, Nichols D, Davies N, Shellie R, Hilder E . Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study. BMC Nephrol. 2016; 17(1):171. PMC: 5103367. DOI: 10.1186/s12882-016-0387-3. View

14.

ROGERS K, Evangelista S . 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-stimulated insulin release from rat pancreatic islets. Proc Soc Exp Biol Med. 1985; 178(2):275-8. DOI: 10.3181/00379727-178-42010. View

15.

Luo S, Coresh J, Tin A, Rebholz C, Appel L, Chen J . Serum Metabolomic Alterations Associated with Proteinuria in CKD. Clin J Am Soc Nephrol. 2019; 14(3):342-353. PMC: 6419293. DOI: 10.2215/CJN.10010818. View

16.

Fernandes Silva L, Vangipurapu J, Smith U, Laakso M . Metabolite Signature of Albuminuria Involves Amino Acid Pathways in 8661 Finnish Men Without Diabetes. J Clin Endocrinol Metab. 2020; 106(1):143-152. PMC: 7765644. DOI: 10.1210/clinem/dgaa661. View

17.

Tofte N, Vogelzangs N, Mook-Kanamori D, Brahimaj A, Nano J, Ahmadizar F . Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes. J Clin Endocrinol Metab. 2020; 105(7). DOI: 10.1210/clinem/dgaa173. View

18.

Pawlak D, Tankiewicz A, Matys T, Buczko W . Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure. J Physiol Pharmacol. 2003; 54(2):175-89. View

19.

Cerasola G, Cottone S, Mule G . The progressive pathway of microalbuminuria: from early marker of renal damage to strong cardiovascular risk predictor. J Hypertens. 2010; 28(12):2357-69. DOI: 10.1097/HJH.0b013e32833ec377. View

20.

Wang Z, Hoy W . Albuminuria as a marker of the risk of developing type 2 diabetes in non-diabetic Aboriginal Australians. Int J Epidemiol. 2006; 35(5):1331-5. DOI: 10.1093/ije/dyl115. View