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Abstract
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.
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1 Lund University Diabetes Centre, Department of Clinical Science/Diabetes and Endocrinology, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361)
2 University of Bergen, Department of Clinical Science, Center for Diabetes Research, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443)
3 Research Unit for General Practice, Danish Aging Research Center, University of Southern Denmark, Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170); Steno Diabetes Center Copenhagen, Gentofte, Denmark (GRID:grid.419658.7) (ISNI:0000 0004 0646 7285)
4 Steno Diabetes Center Copenhagen, Gentofte, Denmark (GRID:grid.419658.7) (ISNI:0000 0004 0646 7285)
5 Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Department of Endocrinology, Metabolism and Diabetes, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705)
6 Karolinska Institute, South Hospital, Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Stockholm, Sweden (GRID:grid.24381.3c)
7 Karolinska Institute, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Department of Endocrinology, Metabolism and Diabetes, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Academica Specialist Centrum, Center for Diabetes, Stockholm, Sweden (GRID:grid.24381.3c)
8 Karolinska Institute, Danderyd University Hospital, Department of Clinical Sciences, Division of Internal Medicine, Stockholm, Sweden (GRID:grid.24381.3c)
9 Technical University of Denmark, Department of Health Technology, Section for Bioinformatics, Lyngby, Denmark (GRID:grid.5170.3) (ISNI:0000 0001 2181 8870)
10 Folkhälsan Research Center, Biomedicum Helsinki, Folkhälsan Institute of Genetics, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Abdominal Center, Nephrology, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); University of Helsinki, Research Programs for Clinical and Molecular Metabolism, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071)
11 Folkhälsan Research Center, Biomedicum Helsinki, Folkhälsan Institute of Genetics, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Abdominal Center, Nephrology, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); University of Helsinki, Research Programs for Clinical and Molecular Metabolism, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Monash University, Department of Diabetes, Central Clinical School, Melbourne, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857)
12 Steno Diabetes Center Copenhagen, Gentofte, Denmark (GRID:grid.419658.7) (ISNI:0000 0004 0646 7285); University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X)
13 Lund University Diabetes Centre, Department of Clinical Science/Diabetes and Endocrinology, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); University of Helsinki, Institute for Molecular Medicine Finland FIMM, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071)
14 Umeå University, Department of Public Health and Clinical Medicine, Sunderby Research Unit, Umeå, Sweden (GRID:grid.12650.30) (ISNI:0000 0001 1034 3451)
15 University of Gothenburg, Department of Medicine, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
16 Karolinska University Hospital, Department of Endocrinology, Metabolism and Diabetes, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Rolf Luft Center for Diabetes Research, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Solna, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705)
17 University of Helsinki, Research Program Unit, Clinical and Molecular Metabolism, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071)
18 Institute of Clinical Physiology, CNR, Pisa, Italy (GRID:grid.418529.3) (ISNI:0000 0004 1756 390X)
19 Lund University, Centre for Analysis and Synthesis, Department of Chemistry, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361)
20 University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Department of Endocrinology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
21 Lund University Diabetes Centre, Department of Clinical Science/Diabetes and Endocrinology, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); University of Bergen, Department of Clinical Science, Center for Diabetes Research, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443)