Advanced

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

Bizzotto, Roberto ; Jennison, Christopher ; Jones, Angus G. ; Kurbasic, Azra LU ; Tura, Andrea ; Kennedy, Gwen ; Bell, Jimmy D. ; Thomas, E. Louise ; Frost, Gary and Eriksen, Rebeca , et al. (2021) In Diabetes Care 44(2). p.511-518
Abstract

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.... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes Care
volume
44
issue
2
pages
8 pages
publisher
American Diabetes Association
external identifiers
  • scopus:85100280805
  • pmid:33323478
ISSN
1935-5548
DOI
10.2337/dc20-1567
language
English
LU publication?
yes
id
fb4a81a9-f9db-44ad-a405-e2645f837d42
date added to LUP
2021-02-11 11:37:36
date last changed
2021-06-08 03:26:35
@article{fb4a81a9-f9db-44ad-a405-e2645f837d42,
  abstract     = {<p>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.</p>},
  author       = {Bizzotto, Roberto and Jennison, Christopher and Jones, Angus G. and Kurbasic, Azra and Tura, Andrea and Kennedy, Gwen and Bell, Jimmy D. and Thomas, E. Louise and Frost, Gary and Eriksen, Rebeca and Koivula, Robert W. and Brage, Soren and Kaye, Jane and Hattersley, Andrew T. and Heggie, Alison and McEvoy, Donna and 't Hart, Leen M. and Beulens, Joline W. and Elders, Petra and Musholt, Petra B. and Ridderstråle, Martin and Hansen, Tue H. and Allin, Kristine H. and Hansen, Torben and Vestergaard, Henrik and Lundgaard, Agnete T. and Thomsen, Henrik S. and De Masi, Federico and Tsirigos, Konstantinos D. and Brunak, Søren and Viñuela, Ana and Mahajan, Anubha and McDonald, Timothy J. and Kokkola, Tarja and Forgie, Ian M. and Giordano, Giuseppe N. and Pavo, Imre and Ruetten, Hartmut and Dermitzakis, Emmanouil and McCarthy, Mark I. and Pedersen, Oluf and Schwenk, Jochen M. and Adamski, Jerzy and Franks, Paul W. and Walker, Mark and Pearson, Ewan R. and Mari, Andrea},
  issn         = {1935-5548},
  language     = {eng},
  number       = {2},
  pages        = {511--518},
  publisher    = {American Diabetes Association},
  series       = {Diabetes Care},
  title        = {Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study},
  url          = {http://dx.doi.org/10.2337/dc20-1567},
  doi          = {10.2337/dc20-1567},
  volume       = {44},
  year         = {2021},
}