PUBLICATION
Age-dependent changes in glucose homeostasis in male deiodinase type 2 knockout zebrafish
- Authors
- Houbrechts, A.M., Beckers, A., Vancamp, P., Sergeys, J., Gysemans, C., Mathieu, C., Darras, V.M.
- ID
- ZDB-PUB-190911-10
- Date
- 2019
- Source
- Endocrinology 160(11): 2759-2772 (Journal)
- Registered Authors
- Darras, Veerle
- Keywords
- none
- MeSH Terms
-
- Aging/metabolism
- Animals
- Animals, Genetically Modified
- Glucose/metabolism*
- Glucose Transport Proteins, Facilitative/metabolism
- Homeostasis
- Hyperglycemia/genetics
- Iodide Peroxidase/deficiency*
- Iodide Peroxidase/genetics
- Islets of Langerhans/cytology
- Islets of Langerhans/physiology
- Male
- Proglucagon/metabolism
- Proinsulin/metabolism
- Receptor, Insulin/metabolism
- Receptors, Glucagon/metabolism
- Zebrafish
- PubMed
- 31504428 Full text @ Endocrinology
Citation
Houbrechts, A.M., Beckers, A., Vancamp, P., Sergeys, J., Gysemans, C., Mathieu, C., Darras, V.M. (2019) Age-dependent changes in glucose homeostasis in male deiodinase type 2 knockout zebrafish. Endocrinology. 160(11):2759-2772.
Abstract
Thyroid hormones (THs) are crucial regulators of glucose metabolism and insulin sensitivity. Moreover, inactivating mutations in type 2 deiodinase (DIO2), the major TH-activating enzyme, have been associated with type 2 diabetes mellitus (T2D) in both humans and mice. We studied the link between Dio2 deficiency and glucose homeostasis in fasted males of two different Dio2-knockout (KO) zebrafish lines. Young adult Dio2KO zebrafish (6-9 months (M)) were hyperglycemic. Both insulin and glucagon expression were increased, while β and α cell numbers in the main pancreatic islet were similar to wild-types. Insulin receptor expression in skeletal muscle was decreased at 6M, accompanied by a strong downregulation of hexokinase and pyruvate kinase expression. Blood glucose levels in Dio2KO zebrafish however normalized around 1 year of age. Older mutants (18-24M) were normoglycemic and increased insulin and glucagon expression was accompanied by a prominent increase in pancreatic islet size and β and α cell numbers. Older Dio2KO zebrafish also showed strongly decreased expression of glucagon receptors in the gastrointestinal system as well as decreased expression of glucose transporters GLUT2 and GLUT12, glucose-6-phosphatase and glycogen synthase 2. This study shows that Dio2KO zebrafish suffer from a transient hyperglycemia, which is counteracted with increasing age by a prominent hyperplasia of the endocrine pancreas together with decreases in hepatic glucagon sensitivity and intestinal glucose uptake. Further research on the mechanisms allowing compensation in older Dio2KO zebrafish may help to identify new therapeutic targets for (TH deficiency related) hyperglycemia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping