<i>Objective </i>
<p>We
investigated the processes underlying glycemic deterioration in type 2 diabetes
(T2D). </p>
<p><i>Research Design and Methods </i></p>
<p>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 HbA<sub>1c</sub> deterioration, adjusted for changes in
BMI and in diabetes medications, were assessed via stepwise multivariable
linear and logistic regression. </p>
<p><i>Results</i></p>
<p>Faster HbA<sub>1c</sub>
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 (<i>R</i><sup>2</sup>=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. </p>
<p><i>Conclusions</i></p>
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.
Liver fat reduction after gastric banding and associations with changes in insulin sensitivity and β‐cell function
