TY - JOUR
T1 - Processes Underlying Glycemic Deterioration in Type 2 Diabetes
T2 - An IMI DIRECT Study
AU - Bizzotto, Roberto
AU - Jennison, Christopher
AU - Jones, Angus G.
AU - Kurbasic, Azra
AU - Tura, Andrea
AU - Kennedy, Gwen
AU - Bell, Jimmy D.
AU - Thomas, E. Louise
AU - Frost, Gary
AU - Eriksen, Rebeca
AU - Koivula, Robert W.
AU - Brage, Soren
AU - Kaye, Jane
AU - Hattersley, Andrew T.
AU - Heggie, Alison
AU - McEvoy, Donna
AU - 't Hart, Leen M.
AU - Beulens, Joline W.
AU - Elders, Petra
AU - Musholt, Petra B.
AU - Ridderstrale, Martin
AU - Hansen, Tue H.
AU - Allin, Kristine H.
AU - Hansen, Torben
AU - Vestergaard, Henrik
AU - Lundgaard, Agnete T.
AU - Thomsen, Henrik S.
AU - De Masi, Federico
AU - Tsirigos, Konstantinos D.
AU - Brunak, Søren
AU - Vinuela, Ana
AU - Mahajan, Anubha
AU - McDonald, Timothy J.
AU - Kokkola, Tarja
AU - Forgie, Ian M.
AU - Giordano, Giuseppe N.
AU - Pavo, Imre
AU - Ruetten, Hartmut
AU - Dermitzakis, Emmanouil
AU - McCarthy, Mark I.
AU - Pedersen, Oluf
AU - Schwenk, Jochen M.
AU - Adamski, Jerzy
AU - Franks, Paul W.
AU - Walker, Mark
AU - Pearson, Ewan R.
AU - Mari, Andrea
AU - IMI-DIRECT consortium
PY - 2021
Y1 - 2021
N2 - OBJECTIVEWe investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSA 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), beta-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 HbA(1c) deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.RESULTSFaster HbA(1c) 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.CONCLUSIONSDeteriorating insulin sensitivity and beta-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, beta-cell function, and insulin clearance may be relevant to prevent progression.
AB - OBJECTIVEWe investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSA 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), beta-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 HbA(1c) deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.RESULTSFaster HbA(1c) 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.CONCLUSIONSDeteriorating insulin sensitivity and beta-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, beta-cell function, and insulin clearance may be relevant to prevent progression.
KW - BETA-CELL FUNCTION
KW - ASSESSING INSULIN SENSITIVITY
KW - RESISTANCE
KW - PROGRESSION
KW - SECRETION
KW - ROSIGLITAZONE
KW - TRIGLYCERIDES
KW - POPULATION
KW - CLEARANCE
KW - GLYBURIDE
U2 - 10.2337/dc20-1567
DO - 10.2337/dc20-1567
M3 - Journal article
C2 - 33323478
VL - 44
SP - 511
EP - 518
JO - Diabetes Care
JF - Diabetes Care
SN - 0149-5992
IS - 2
ER -