Roberto Bizzotto1, Christopher Jennison2, Angus G Jones3,4, Azra Kurbasic5, Andrea Tura6, Gwen Kennedy7, Jimmy D Bell8, E Louise Thomas8, Gary Frost9, Rebeca Eriksen9, Robert W Koivula5,10, Soren Brage11, Jane Kaye12,13, Andrew T Hattersley3,4, Alison Heggie14, Donna McEvoy15, Leen M 't Hart16,17,18, Joline W Beulens16, Petra Elders19, Petra B Musholt20, Martin Ridderstråle21, Tue H Hansen22, Kristine H Allin22, Torben Hansen22, Henrik Vestergaard22,23, Agnete T Lundgaard24,25, Henrik S Thomsen26, Federico De Masi27, Konstantinos D Tsirigos24,25, Søren Brunak24,25, Ana Viñuela28,29, Anubha Mahajan30, Timothy J McDonald3,31, Tarja Kokkola32, Ian M Forgie33, Giuseppe N Giordano5, Imre Pavo34, Hartmut Ruetten20, Emmanouil Dermitzakis28, Mark I McCarthy10,30,35, Oluf Pedersen22, Jochen M Schwenk36, Jerzy Adamski37,38,39, Paul W Franks5, Mark Walker40, Ewan R Pearson33, Andrea Mari. 1. CNR Institute of Neuroscience, Padova, Italy roberto.bizzotto@cnr.it. 2. Department of Mathematical Sciences, University of Bath, Bath, U.K. 3. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. 4. Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. 5. Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Malmö, Sweden. 6. CNR Institute of Neuroscience, Padova, Italy. 7. Immunoassay Biomarker Core Laboratory, School of Medicine, Ninewells Hospital, Dundee, U.K. 8. School of Life Sciences, Research Centre for Optimal Health, University of Westminster, London, U.K. 9. Section for Nutrition Research, Faculty of Medicine, Hammersmith Campus, Imperial College London, London, U.K. 10. Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. 11. MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K. 12. Faculty of Law, Centre for Health, Law and Emerging Technologies, University of Oxford, Oxford, U.K. 13. Melbourne Law School, Centre for Health, Law and Emerging Technologies, University of Melbourne, Carlton, Victoria, Australia. 14. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K. 15. Diabetes Research Network, Royal Victoria Infirmary, Newcastle upon Tyne, U.K. 16. Department of Epidemiology and Data Science, Amsterdam UMC-Location VUmc, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands. 17. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. 18. Department of Biomedical Data Sciences, Molecular Epidemiology Section, Leiden University Medical Center, Leiden, the Netherlands. 19. Department of General Practice, Amsterdam UMC-Location VUmc, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands. 20. R&D Global Development, Translational Medicine & Clinical Pharmacology, Sanofi Deutschland GmbH, Frankfurt, Germany. 21. Clinical Pharmacology and Translational Medicine, Novo Nordisk A/S, Søborg, Denmark. 22. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 23. Bornholms Hospital, Rønne, Denmark. 24. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark. 25. Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark. 26. Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark. 27. Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. 28. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. 29. Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle, U.K. 30. Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K. 31. Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. 32. Department of Medicine, University of Eastern Finland, Kuopio, Finland. 33. Population Health and Genomics, School of Medicine, University of Dundee, Dundee, U.K. 34. Eli Lilly Regional Operations GmbH, Vienna, Austria. 35. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, U.K. 36. Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden. 37. Research Unit of Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, Neuherberg, Germany. 38. Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany. 39. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 40. Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle, U.K.
Abstract
OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R 2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R 2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
Authors: Ludovica Ilari; Agnese Piersanti; Christian Göbl; Laura Burattini; Alexandra Kautzky-Willer; Andrea Tura; Micaela Morettini Journal: Front Physiol Date: 2022-02-17 Impact factor: 4.566
Authors: Alexis C Wood; Elizabeth T Jensen; Alain G Bertoni; Gautam Ramesh; Stephen S Rich; Jerome I Rotter; Yii-Der I Chen; Mark O Goodarzi Journal: Metabolites Date: 2021-06-26