American Diabetes Association
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study

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posted on 2020-12-15, 19:50 authored by Roberto Bizzotto, Christopher Jennison, Angus G Jones, Azra Kurbasic, Andrea Tura, Gwen Kennedy, Jimmy D Bell, Elizabeth L 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, the IMI DIRECT consortium

We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).

Research Design and Methods

732 recently diagnosed T2D patients from the IMI-DIRECT study were extensively phenotyped over three 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.


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 AUROC=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 to 0.09). T2D polygenic risk score and baseline pancreatic fat, GLP-1, glucagon, diet, and physical activity did not show an independent role.


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 T2D patients 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.


The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Information on the project can be found at