Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study
Authors: Roberto Bizzotto, Christopher Jennison, Angus G. Jones, Azra Kurbasic, Andrea Tura, Gwen Kennedy, Jimmy D. Bell, E. Louise Thomas, Gary Frost, Rebeca Eriksen, Robert W. Koivula, Soren Brage, Jane Kaye, Andrew T. Hattersley, Alison Heggie, Donna McEvoy, Leen M. ’t Hart, Joline W. Beulens, Petra Elders, Petra B. Musholt, Martin Ridderstråle, Tue H. Hansen, Kristine H. Allin, Torben Hansen, Henrik Vestergaard, Agnete T. Lundgaard, Henrik S. Thomsen, Federico De Masi, Konstantinos D. Tsirigos, Søren Brunak, Ana Viñuela, Anubha Mahajan, Timothy J. McDonald, Tarja Kokkola, Ian M. Forgie, Giuseppe N. Giordano, Imre Pavo, Hartmut Ruetten, Emmanouil Dermitzakis, Mark I. McCarthy, Oluf Pedersen, Jochen M. Schwenk, Jerzy Adamski, Paul W. Franks, Mark Walker, Ewan R. Pearson, Andrea Mari, Moustafa Abdalla, Jonathan Adam, Jerzy Adamski, Kofi Adragni, Rosa L. Allesøe, Kristine H. Allin, Manimozhiyan Arumugam, Naeimeh Atabaki Pasdar, Tania Baltauss, Karina Banasik, Patrick Baum, Jimmy D. Bell, Margit Bergstrom, Joline W. Beulens, Susanna Bianzano, Roberto Bizzotto, Amelie Bonneford, Caroline A. Brorsson, Andrew A. Brown, Søren Brunak, Louise Cabrelli, Robert Caiazzo, Mickaël Canouil, Matilda Dale, David Davtian, Adem Y. Dawed, Federico De Masi, Nathalie de Preville, Koen F. Dekkers, Emmanouil T. Dermitzakis, Harshal A. Deshmukh, Christiane Dings, Louise Donnelly, Avirup Dutta, Beate Ehrhardt, Petra Elders, Line Engelbrechtsen, Rebeca Eriksen, Juan Fernandez, Jorge Ferrer, Hugo Fitipaldi, Ian M. Forgie, Annemette Forman, Paul W. Franks, Francesca Frau, Andreas Fritsche, Philippe Froguel, Gary Frost, Johann Gassenhuber, Nick N. Giordano, Toni Giorgino, Stephen Gough, Ulrike U. Graefe-Mody, Harald Grallert, Rolf Grempler, Lenka Groeneveld, Leif Groop, Valborg Gudmundsdóttir, Mark Haid, Torben Hansen, Tue H. Hansen, Andrew T. Hattersley, Ragna Haussler, Alison J. Heggie, Anita M. Hennige, Anita V. Hill, Reinhard W. Holl, Mun-Gwan Hong, Michelle Hudson, Bernd Jablonka, Christopher Jennison, Yunlong Jiao, Joachim Johansen, Angus G. Jones, Anna Jonsson, Tugce Karaderi, Jane Kaye, Maria Klintenberg, Robert W. Koivula, Tarja Kokkola, Anitra D. Koopman, Azra Kurbasic, Teemu Kuulasmaa, Markku Laakso, Thorsten Lehr, Heather Loftus, Agnete T. Lundgaard, Anubha Mahajan, Andrea Mari, Gianluca Mazzoni, Mark I. McCarthy, Timothy J. McDonald, Donna McEvoy, Nicky McRobert, Ian McVittie, Miranda Mourby, Petra B. Musholt, Pascal Mutie, Rachel Nice, Claudia Nicolay, Agnes M. Nielsen, Birgitte Nilsson, Colin N. Palmer, Francois Pattou, Imre Pavo, Ewan R. Pearson, Helle K. Pedersen, Oluf Pedersen, Mandy H. Perry, Hugo Pomares-Millan, Simon Rasmussen, Violeta Raverdy, Martin Ridderstrale, Neil Robertson, Slieker C. Roderick, Marianne Rodriquez, Hartmut Ruetten, Femke Rutters, Peter W. Sackett, Nina Scherer, Jochen M. Schwenk, Nisha Shah, Sapna Sharma, Iryna Sihinevich, Nadja B. Sondertoft, Hans-Henrik Staerfeldt, Birgit Steckel-Hamann, Leen M. t Hart, Harriet Teare, Cecilia E. Thomas, Melissa K. Thomas, Elizabeth L. Thomas, Henrik S. Thomsen, Barbara Thorand, Claire E. Thorne, Joachim Tillner, Martina Troll, Konstantinos D. Tsirigos, Andrea Tura, Mathias Uhlen, Nienke van Leeuwen, Helene Verkindt, Henrik Vestergaard, Ana Viñuela, Josef K. Vogt, Dianne Wake, Mark Walker, Agata Wesolowska-Andersen, Brandon Whitcher, Han Wu
Journal: Diabetes Care (2020)

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 (R2 = 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.