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