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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction
1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Abstract:
Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARγ and CIS expression. FGF21 treatment also reversed GH-induced insulin expression, beta-cell proliferation and GH-impaired glucose-stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21-KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction.
Insights
Fibroblast growth factor (FGF) 21 regulates pancreatic islet function by modulating growth hormone (GH) signaling. FGF21 deficiency impairs islet morphology and glucose-stimulated insulin secretion, contributing to insulin resistance.
Area of Science:
- Endocrinology
- Metabolism
- Molecular Biology
Background:
- Fibroblast growth factor (FGF) 21 is an endocrine factor known to regulate glucose homeostasis and insulin sensitivity.
- The pancreas, particularly pancreatic islets, is a target organ for FGF21, but its precise role within islets is not fully understood.
- Understanding FGF21's function in pancreatic islets is crucial for elucidating its role in metabolic diseases like diabetes.
Purpose of the Study:
- To investigate the physiological role of FGF21 in pancreatic islets.
- To elucidate the mechanisms by which FGF21 influences beta-cell function and insulin secretion.
- To examine the impact of FGF21 deficiency on islet morphology and glucose metabolism.
Main Methods:
- Utilized fibroblast growth factor 21-knockout (FGF21-KO) mice to study the effects of FGF21 deficiency.
- Assessed glucose and insulin tolerance in FGF21-KO and control mice.
- Analyzed gene and protein expression related to islet function, including growth hormone (GH) signaling, PPARγ, and CIS.
- Evaluated islet morphology and insulin-secreting capacity (GSIS) in vitro and in vivo.
Main Results:
- FGF21-KO mice exhibited insulin resistance with compensatory increases in beta-cell proliferation and insulin synthesis, linked to enhanced GH sensitivity.
- Exogenous FGF21 treatment in normal islets reduced GH signaling, upregulated PPARγ and CIS, and normalized GH-induced insulin expression and GSIS.
- FGF21-KO islets showed reduced PPARγ and CIS expression, distorted morphology, and impaired GSIS, which could be reversed by blocking GH signaling.
Conclusions:
- FGF21 plays a critical role in regulating beta-cell proliferation and insulin synthesis within pancreatic islets, likely through modulation of GH signaling.
- FGF21 acts as an obligatory metabolic regulator in pancreatic islets, influencing islet function and contributing to the pathogenesis of insulin resistance.
- These findings highlight FGF21 as a potential therapeutic target for managing insulin resistance and islet dysfunction.
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