Mairead L Bermingham1, Marco Colombo2, Stuart J McGurnaghan3, Luke A K Blackbourn3, Frano Vučković4, Maja Pučić Baković4, Irena Trbojević-Akmačić4, Gordan Lauc4, Felix Agakov5, Anna S Agakova5, Caroline Hayward6, Lucija Klarić2,6, Colin N A Palmer7, John R Petrie8, John Chalmers9, Andrew Collier10, Fiona Green11, Robert S Lindsay8, Sandra Macrury12, John A McKnight13, Alan W Patrick14, Sandeep Thekkepat15, Olga Gornik16, Paul M McKeigue2,5, Helen M Colhoun3,17. 1. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K. mairead.bermingham@igmm.ed.ac.uk. 2. Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, U.K. 3. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K. 4. Genos Glycoscience Research Laboratory, Zagreb, Croatia. 5. Pharmatics, Ltd., Edinburgh, U.K. 6. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, U.K. 7. Cardiovascular and Diabetes Medicine, University of Dundee, Dundee, U.K. 8. Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, U.K. 9. Diabetes Centre, Victoria Hospital, Kirkcaldy, U.K. 10. Diabetic Day Centre University Hospital, Ayr, U.K. 11. Research & Development Support Unit, Dumfries & Galloway Royal Infirmary, Dumfries, U.K. 12. Highland Diabetes Institute, Raigmore Hospital, NHS Highland, Inverness, U.K. 13. Western General Hospital, NHS Lothian, Edinburgh, U.K. 14. Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, U.K. 15. David Matthews Diabetes Centre, Monklands Hospital, Airdrie, U.K. 16. Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia. 17. Department of Public Health, NHS Fife, Kirkcaldy, U.K.
Abstract
OBJECTIVE: Poorer glycemic control in type 1 diabetes may alter N-glycosylation patterns on circulating glycoproteins, and these alterations may be linked with diabetic kidney disease (DKD). We investigated associations between N-glycans and glycemic control and renal function in type 1 diabetes. RESEARCH DESIGN AND METHODS: Using serum samples from 818 adults who were considered to have extreme annual loss in estimated glomerular filtration rate (eGFR; i.e., slope) based on retrospective clinical records, from among 6,127 adults in the Scottish Diabetes Research Network Type 1 Bioresource Study, we measured total and IgG-specific N-glycan profiles. This yielded a relative abundance of 39 total (GP) and 24 IgG (IGP) N-glycans. Linear regression models were used to investigate associations between N-glycan structures and HbA1c, albumin-to-creatinine ratio (ACR), and eGFR slope. Models were adjusted for age, sex, duration of type 1 diabetes, and total serum IgG. RESULTS: Higher HbA1c was associated with a lower relative abundance of simple biantennary N-glycans and a higher relative abundance of more complex structures with more branching, galactosylation, and sialylation (GP12, 26, 31, 32, and 34, and IGP19 and 23; all P < 3.79 × 10-4). Similar patterns were seen for ACR and greater mean annual loss of eGFR, which were also associated with fewer of the simpler N-glycans (all P < 3.79 × 10-4). CONCLUSIONS: Higher HbA1c in type 1 diabetes is associated with changes in the serum N-glycome that have elsewhere been shown to regulate the epidermal growth factor receptor and transforming growth factor-β pathways that are implicated in DKD. Furthermore, N-glycans are associated with ACR and eGFR slope. These data suggest that the role of altered N-glycans in DKD warrants further investigation.
OBJECTIVE: Poorer glycemic control in type 1 diabetes may alter N-glycosylation patterns on circulating glycoproteins, and these alterations may be linked with diabetic kidney disease (DKD). We investigated associations between N-glycans and glycemic control and renal function in type 1 diabetes. RESEARCH DESIGN AND METHODS: Using serum samples from 818 adults who were considered to have extreme annual loss in estimated glomerular filtration rate (eGFR; i.e., slope) based on retrospective clinical records, from among 6,127 adults in the Scottish Diabetes Research Network Type 1 Bioresource Study, we measured total and IgG-specific N-glycan profiles. This yielded a relative abundance of 39 total (GP) and 24 IgG (IGP) N-glycans. Linear regression models were used to investigate associations between N-glycan structures and HbA1c, albumin-to-creatinine ratio (ACR), and eGFR slope. Models were adjusted for age, sex, duration of type 1 diabetes, and total serum IgG. RESULTS: Higher HbA1c was associated with a lower relative abundance of simple biantennary N-glycans and a higher relative abundance of more complex structures with more branching, galactosylation, and sialylation (GP12, 26, 31, 32, and 34, and IGP19 and 23; all P < 3.79 × 10-4). Similar patterns were seen for ACR and greater mean annual loss of eGFR, which were also associated with fewer of the simpler N-glycans (all P < 3.79 × 10-4). CONCLUSIONS: Higher HbA1c in type 1 diabetes is associated with changes in the serum N-glycome that have elsewhere been shown to regulate the epidermal growth factor receptor and transforming growth factor-β pathways that are implicated in DKD. Furthermore, N-glycans are associated with ACR and eGFR slope. These data suggest that the role of altered N-glycans in DKD warrants further investigation.
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