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

IMI DIRECT Consortium, Roberto Bizzotto (Lead / Corresponding author), 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 EldersPetra 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

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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.

Original languageEnglish
Pages (from-to)511-518
Number of pages8
JournalDiabetes Care
Issue number2
Early online date15 Dec 2020
Publication statusPublished - Feb 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing


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