Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study.
Diabetes care 2020 ; 44: 511-518.
Bizzotto R, Jennison C, Jones AG, Kurbasic A, Tura A, Kennedy G, Bell JD, Thomas EL, Frost G, Eriksen R, Koivula RW, Brage S, Kaye J, Hattersley AT, Heggie A, McEvoy D, 't Hart LM, Beulens JW, Elders P, Musholt PB, Ridderstråle M, Hansen TH, Allin KH, Hansen T, Vestergaard H, Lundgaard AT, Thomsen HS, De Masi F, Tsirigos KD, Brunak S, Viñuela A, Mahajan A, McDonald TJ, Kokkola T, Forgie IM, Giordano GN, Pavo I, Ruetten H, Dermitzakis E, McCarthy MI, Pedersen O, Schwenk JM, Adamski J, Franks PW, Walker M, Pearson ER, Mari A, and IMI DIRECT Consortium
DOI : 10.2337/dc20-1567
PubMed ID : 33323478
We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).
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 HbA deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.
Faster HbA 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 ( = 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.
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.