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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 to 9 months) were hyperglycemic. Both insulin and glucagon expression were increased, whereas \u03b2 and \u03b1 cell numbers in the main pancreatic islet were similar to those in wild-types. Insulin receptor expression in skeletal muscle was decreased at 6 months, 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 to 24 months) were normoglycemic, and increased insulin and glucagon expression was accompanied by a prominent increase in pancreatic islet size and \u03b2 and \u03b1 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 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\u2013related) hyperglycemia.<\/jats:p>","DOI":"10.1210\/en.2019-00445","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T09:06:42Z","timestamp":1567674402000},"page":"2759-2772","source":"Crossref","is-referenced-by-count":13,"title":["Age-Dependent Changes in Glucose Homeostasis in Male Deiodinase Type 2 Knockout Zebrafish"],"prefix":"10.1210","volume":"160","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8883-1567","authenticated-orcid":false,"given":"Anne M","family":"Houbrechts","sequence":"first","affiliation":[{"name":"Laboratory of Comparative Endocrinology, Division of Animal Physiology and Neurobiology, Department of Biology, KU Leuven, Leuven, 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