Faculty, Staff and Student Publications
Diet-Enhanced LRG1 Expression Promotes Insulin Hypersecretion and Er Stress in Pancreatic Beta Cells
Language
English
Publication Date
3-1-2025
Journal
Diabetologia
DOI
10.1007/s00125-024-06331-0
PMID
39589509
PMCID
PMC12085111
PubMedCentral® Posted Date
5-17-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.
Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects of LRG1 on insulin secretion and intracellular Ca2+ release. Antibodies targeting various LRG1 epitopes were used to neutralise LRG1 stimulation in MIN6 cells, and their effectiveness was tested in vivo to assess their ability to prevent LRG1-induced hyperinsulinaemia.
Results: We observed a significant positive association between human serum LRG1 levels and both age and BMI, with elevated levels observed in individuals with vs without type 2 diabetes. In mice fed a high-fat diet, LRG1 upregulation in serum was associated with hyperinsulinaemia. Lrg1 knockout protected mice from diet-induced islet hyperplasia and the loss of beta cell mass. Furthermore, neutralising LRG1 activity prevented the onset of diet-induced hyperinsulinaemia and preserved glucose tolerance. Mechanistically, LRG1 induces inositol triphosphate (IP3) production and intracellular Ca2+ release from the endoplasmic reticulum (ER) in a phospholipase C (PLC)-dependent manner, leading to excessive insulin secretion and ER stress in MIN6 beta cells.
Conclusions/interpretation: In summary, this study identifies LRG1 as a significant contributor to hyperinsulinaemia and beta cell dysfunction. Targeting LRG1 activity emerges as a promising therapeutic approach for addressing diet-induced beta cell dysfunction and managing type 2 diabetes.
Keywords
Insulin-Secreting Cells, Animals, Humans, Endoplasmic Reticulum Stress, Male, Mice, Diet, High-Fat, Mice, Knockout, Mice, Inbred C57BL, Female, Insulin, Glycoproteins, Insulin Secretion, Hyperinsulinism, Obesity, Diabetes Mellitus, Type 2, Adult, Adipokine, Beta cell failure, Beta cells, Ca2+ signalling, ER stress, Hyperinsulinaemia, Insulin secretion, LRG1, Type 2 diabetes
Published Open-Access
yes
Recommended Citation
Morales, Desirae D; Ryu, Jiyoon; Wei, Cong; et al., "Diet-Enhanced LRG1 Expression Promotes Insulin Hypersecretion and Er Stress in Pancreatic Beta Cells" (2025). Faculty, Staff and Student Publications. 5322.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5322
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