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Increased Genetic Risk for b-Cell Failure Is Associated With b-Cell Function Decline in People With Prediabetes

Billings, Liana K. ; Jablonski, Kathleen A. ; Pan, Qing ; Florez, Jose C. ; Franks, Paul W. LU ; Goldberg, Ronald B. ; Hivert, Marie France ; Kahn, Steven E. ; Knowler, William C. and Lee, Christine G. , et al. (2024) In Diabetes 73(8). p.1352-1360
Abstract

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (b-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher b-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline... (More)

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (b-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher b-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD 20.04, P = 9.6 × 1027, and 28.45 lU/mg, P = 5.6 × 1026, respec-tively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD 24.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the b-cell cluster pPS had worsening in measures of b-cell function.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
73
issue
8
pages
9 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:38758294
  • scopus:85199816759
ISSN
0012-1797
DOI
10.2337/db23-0761
language
English
LU publication?
yes
id
9e3ec91a-1e20-45c9-871e-5326aa56b5f7
date added to LUP
2024-09-09 15:02:32
date last changed
2025-07-15 19:23:11
@article{9e3ec91a-1e20-45c9-871e-5326aa56b5f7,
  abstract     = {{<p>Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (b-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher b-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD 20.04, P = 9.6 × 10<sup>27</sup>, and 28.45 lU/mg, P = 5.6 × 10<sup>26</sup>, respec-tively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD 24.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the b-cell cluster pPS had worsening in measures of b-cell function.</p>}},
  author       = {{Billings, Liana K. and Jablonski, Kathleen A. and Pan, Qing and Florez, Jose C. and Franks, Paul W. and Goldberg, Ronald B. and Hivert, Marie France and Kahn, Steven E. and Knowler, William C. and Lee, Christine G. and Merino, Jordi and Huerta-Chagoya, Alicia and Mercader, Josep M. and Raghavan, Sridharan and Shi, Zhuqing and Srinivasan, Shylaja and Xu, Jianfeng and Udler, Miriam S.}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1352--1360}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Increased Genetic Risk for b-Cell Failure Is Associated With b-Cell Function Decline in People With Prediabetes}},
  url          = {{http://dx.doi.org/10.2337/db23-0761}},
  doi          = {{10.2337/db23-0761}},
  volume       = {{73}},
  year         = {{2024}},
}