Gck Gene-Edited Canine Model: Neonatal Diabetes Model

Model Overview

Neonatal diabetes mellitus (NDM) is one of the most unusual and exceptional type of diabetes that occurs in infants before the age of 6 months. Transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM) have been identified clinically. Permanent neonatal diabetes is the main type of neonatal diabetes. Compared with temporary neonatal diabetes, its clinical symptoms are more serious and the onset is often in the state of ketoacidosis. In addition, there is no self-remission process after the onset of permanent neonatal diabetes and lifelong treatment is required. PNDM is an autosomal dominant disorder. PNDM in humans can be caused by the homozygous nullification of glucokinase (GCK), which is a key rate-limiting enzyme in glucose metabolism in pancreatic β cells and hepatocytes and is considered as the “glucose sensor” for the regulation of insulin secretion. Here, for the first time, by utilizing a newly developed base-editing technology named BE3 system, we attempted to generate a dog model of PNDM that contained homozygous GCK point mutations.

Clinical Phenotype

The model dogs exhibit a phenotype of low body weight and high blood sugar. Glycogen staining reveals alterations in glycogen synthesis following a Gck point mutation. Oil Red O staining demonstrates the presence of numerous lipid droplets in the livers of the model dogs, indicating severe abnormalities in lipid metabolism (with no significant differences in TC and TG).

Significance of Model

Neonatal diabetes refers to diabetes that occurs within 6 months of birth. It is a rare and special type of diabetes. According to different clinical manifestations, it is divided into temporary neonatal diabetes and permanent neonatal diabetes. The clinical symptoms of permanent neonatal diabetes are severe, and they are often in a state of ketoacidosis at the onset, and there is no spontaneous remission process after the onset, so lifelong treatment is required.

The disease is mostly inherited in an autosomal dominant manner. The protein encoded by the Gck gene is a member of the hexokinase family. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in supplementing glucose uptake and conversion to glycogen. GCK gene mutation is a common causative gene for neonatal diabetes. A C->T point mutation diabetic disease model dog was obtained through CRISPR/Cas9 technology.

Publications

2021 Oct 12;7(1):92. doi: 10.1038/s41421-021-00304-y.

Generation of permanent neonatal diabetes mellitus dogs with glucokinase point mutations through base editing
https://pubmed.ncbi.nlm.nih.gov/34635647/
2021 Dec 9;7(1):120. doi: 10.1038/s41421-021-00348-0.

Author Correction: Generation of permanent neonatal diabetes mellitus dogs with glucokinase point mutations through base editing
https://pubmed.ncbi.nlm.nih.gov/34887377/

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Gck Gene-Edited Canine Model: Neonatal Diabetes Model

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Significance of Model

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