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Updated: Jun 11, 2026
A Protocol for Multiple Gene Knockout in Mouse Small Intestinal Organoids Using a CRISPR-concatemer
Published on: July 12, 2017
Knockouts of SOD1 and GPX1 exert different impacts on murine islet function and pancreatic integrity
Xiaodan Wang1, Marko Z Vatamaniuk, Carol A Roneker
1Department of Animal Science, Cornell University, Ithaca, New York 14853, USA.
Abstract:
Metabolic subtlety and clinical relevance of different forms of reactive oxygen species in diabetes remain unclear. Using single knockout of Cu,Zn-superoxide dismutase (SOD1(-/-)) or Se-glutathione peroxidase-1 (GPX1(-/-)) and their double-knockout (DKO) mouse models, we determined if elevating endogenously-derived superoxide and hydroperoxide exerted distinct impacts and mechanisms on body glucose homeostasis. Whereas the three knockout groups displayed decreased plasma insulin concentrations and islet β-cells mass, only SOD1(-/-) showed decreased body weight, increased blood glucose, and blocked glucose-stimulated insulin secretion. Null of SOD1 and GPX1 elevated respective islet superoxide and hydroperoxide production, and upregulated p53 phosphorylation. Knockout of SOD1 downregulated the foxhead box A2/pancreatic and duodenal homeobox 1 pathway in a superoxide-dependent fashion at epigenetic, mRNA, and protein levels in islets, but improved insulin signaling in liver and muscle. The SOD1(-/-) mice showed more apparent pancreatitis than the GPX1(-/-) mice that were more susceptible to the cerulein-induced amylase increase. Knockout of SOD1 impaired islet function, pancreas integrity, and body glucose homeostasis more than that of GPX1. Simultaneous ablation of both enzymes did not result in additive or aggravated metabolic outcomes.
Insights
Mice lacking Cu,Zn-superoxide dismutase (SOD1) showed worse diabetes symptoms than those lacking Se-glutathione peroxidase-1 (GPX1). Neither enzyme deficiency worsened outcomes when both were absent, suggesting distinct roles in metabolic health.
Area of Science:
- Biochemistry
- Metabolism
- Endocrinology
Background:
- Reactive oxygen species (ROS) play a role in diabetes, but the specific functions of different ROS forms are not fully understood.
- Superoxide and hydroperoxide are key ROS, but their distinct impacts on glucose homeostasis and pancreatic function require further investigation.
Purpose of the Study:
- To investigate the distinct roles of superoxide and hydroperoxide in glucose homeostasis and pancreatic integrity using knockout mouse models.
- To elucidate the molecular mechanisms underlying the effects of these ROS on islet function and insulin signaling.
Main Methods:
- Generation and analysis of single knockout (SOD1(-/-), GPX1(-/-)) and double knockout (DKO) mouse models.
- Assessment of body weight, blood glucose, plasma insulin, islet beta-cell mass, and glucose-stimulated insulin secretion.
- Evaluation of pancreatic histology, pancreatitis markers, and molecular pathways including p53 phosphorylation and the FOXA2/PDX1 pathway.
Main Results:
- SOD1(-/-) mice exhibited decreased body weight, elevated blood glucose, and impaired glucose-stimulated insulin secretion compared to GPX1(-/-) mice.
- Both SOD1 and GPX1 deficiency led to reduced plasma insulin and islet beta-cell mass.
- SOD1 knockout impaired islet function and pancreas integrity more severely than GPX1 knockout, with distinct effects on pancreatitis.
- Simultaneous ablation of SOD1 and GPX1 did not result in additive or aggravated metabolic dysfunction.
Conclusions:
- Cu,Zn-superoxide dismutase (SOD1) plays a more critical role than Se-glutathione peroxidase-1 (GPX1) in maintaining islet function, pancreas integrity, and overall glucose homeostasis.
- Distinct ROS, superoxide and hydroperoxide, exert differential impacts on metabolic regulation and pancreatic health.
- Targeting SOD1 may be a more promising therapeutic strategy for managing diabetes-related metabolic dysfunction and pancreatic complications.
