Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes

• Published in: Scientific reports Vol. 10; no. 1; p. 11561
• Main Authors: Jain, Ruchi, Özgümüş, Türküler, Jensen, Troels Mygind, du Plessis, Elsa, Keindl, Magdalena, Møller, Cathrine Laustrup, Falhammar, Henrik, Nyström, Thomas, Catrina, Sergiu-Bogdan, Jörneskog, Gun, Jessen, Leon Eyrich, Forsblom, Carol, Haukka, Jani K., Groop, Per-Henrik, Rossing, Peter, Groop, Leif, Eliasson, Mats, Eliasson, Björn, Brismar, Kerstin, Al-Majdoub, Mahmoud, Nilsson, Peter M., Taskinen, Marja-Riitta, Ferrannini, Ele, Spégel, Peter, Berg, Tore Julsrud, Lyssenko, Valeriya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2020; Nature Publishing Group
• Subjects: 631/1647/320; 692/53; 692/699/2743/137/138; 692/699/2743/137/1418; Aged; Apolipoprotein C-III; Biomarkers - blood; Biosynthesis; Blood Glucose; C-Peptide - blood; Clinical Medicine; Diabetes; Diabetes Complications - blood; Diabetes Complications - genetics; Diabetes Complications - pathology; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - pathology; Endocrinology and Diabetes; Endokrinologi och diabetes; Erythritol; Fatty liver; Female; Genetic Predisposition to Disease; Glycine; Glycolysis; Humanities and Social Sciences; Humans; Insulin; Insulin Resistance - genetics; Klinisk medicin; Liquid chromatography; Liver; Liver - metabolism; Male; Mass spectrometry; Mass spectroscopy; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolites; Metabolomics; Microvasculature; Middle Aged; multidisciplinary; Nucleotides - biosynthesis; Nucleotides - blood; Pentose phosphate pathway; Phenylalanine; Picolinic acid; Pyruvic acid; Science; Science (multidisciplinary); Serine; Thiamine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-68130-y

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.