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

Abstract

<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.

Quantification of beta cell carrying capacity in prediabetes

“…Slow changes in insulin sensitivity in prediabetes, on the scale of a year, are consistent with findings from recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI-DIRECT) study (41). Insulin sensitivity decreased by a factor of about 2 over 36 months in a subpopulation of fast progressors, and showed no change on average in the remainder 90% of the population.…”

Insulin resistance and beta‐cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

“…In a paper by Zaharia et al 30 data generated by hyperinsulinemic euglycemic clamp and C‐peptide response to intravenous glucose were included in a similar cluster analysis, confirming with more sophisticated techniques the existence of the subgroups described by Ahlqvist et al 29 . The same clusters were observed by Dennis et al, 31 who used the HOMA for investigating insulin secretion and sensitivity, and by Bizzotto et al 32 who used mathematical models applied to mixed meal tests for the assessment of both insulin secretion and sensitivity.…”

Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals

“…Among other lipid species, elevated plasma triglycerides have been traditionally considered a mere consequence of obesity and insulin resistance, their negative effects being supposedly mediated by their circulating metabolites FFA. Nevertheless, large population-based studies demonstrated that high plasma triglycerides are predictive of glucose intolerance and type 2 diabetes in a dose-dependent fashion, regardless of insulin resistance and FFA [4][5][6][7][8]. Studies using a Mendelian randomization approach found associations between genetically determined hypertriglyceridemia and risk of diabetes [9,10].…”