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Targeted disruption of pancreatic-derived factor (PANDER, FAM3B) impairs pancreatic beta-cell function
Claudia E Robert-Cooperman1, Jason R Carnegie, Camella G Wilson
1Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.
Objective:
Pancreatic-derived factor (PANDER, FAM3B) is a pancreatic islet-specific cytokine-like protein that is secreted from beta-cells upon glucose stimulation. The biological function of PANDER is unknown, and to address this we generated and characterized a PANDER knockout mouse.
Research Design And Methods:
To generate the PANDER knockout mouse, the PANDER gene was disrupted and its expression was inhibited by homologous recombination via replacement of the first two exons, secretion signal peptide and transcriptional start site, with the neomycin gene. PANDER(-/-) mice were then phenotyped by a number of in vitro and in vivo tests to evaluate potential effects on glucose regulation, insulin sensitivity, and beta-cell morphology and function.
Results:
Glucose tolerance tests demonstrated significantly higher blood glucose levels in PANDER(-/-) versus wild-type male mice. To identify the mechanism of the glucose intolerance, insulin sensitivity and pancreatic beta-cell function were examined. Hyperinsulinemic-euglycemic clamps and insulin tolerance testing showed similar insulin sensitivity for both the PANDER(-/-) and wild-type mice. The in vivo insulin response following intraperitoneal glucose injection surprisingly produced significantly higher insulin levels in the PANDER(-/-) mice, whereas insulin release was blunted with arginine administration. Islet perifusion and calcium imaging studies showed abnormal responses of the PANDER(-/-) islets to glucose stimulation. In contrast, neither islet architecture nor insulin content was impacted by the loss of PANDER. Interestingly, the elevated insulin levels identified in vivo were attributed to decreased hepatic insulin clearance in the PANDER(-/-) islets. Taken together, these results demonstrated decreased pancreatic beta-cell function in the PANDER(-/-) mouse.
Conclusions:
These results support a potential role of PANDER in the pancreatic beta-cell for regulation or facilitation of insulin secretion.
Insights
Pancreatic-derived factor (PANDER) plays a role in pancreatic beta-cell function. PANDER knockout mice show impaired glucose regulation and altered insulin secretion, suggesting PANDER facilitates insulin release.
Area of Science:
- Endocrinology
- Metabolism
- Molecular Biology
Background:
- Pancreatic-derived factor (PANDER, FAM3B) is a protein secreted by pancreatic beta-cells.
- Its biological function remains largely unknown.
- Understanding PANDER's role is crucial for metabolic research.
Purpose of the Study:
- To investigate the biological function of PANDER.
- To characterize the physiological effects of PANDER deficiency.
- To determine PANDER's role in glucose regulation and insulin secretion.
Main Methods:
- Generation of PANDER knockout (PANDER-/-) mice using homologous recombination.
- Phenotyping included glucose tolerance tests, insulin tolerance tests, and hyperinsulinemic-euglycemic clamps.
- In vitro studies involved islet perifusion and calcium imaging.
Main Results:
- PANDER-/- mice exhibited impaired glucose tolerance with higher blood glucose levels.
- Insulin sensitivity remained unchanged between PANDER-/- and wild-type mice.
- PANDER deficiency led to abnormal islet responses to glucose and blunted arginine-stimulated insulin release, alongside decreased hepatic insulin clearance.
Conclusions:
- PANDER plays a significant role in pancreatic beta-cell function.
- PANDER appears to regulate or facilitate insulin secretion.
- Further research into PANDER's mechanisms is warranted.
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