title: Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity.
abstract: Lafora disease is a fatal, progressive myoclonus epilepsy caused in ~90% of cases by mutations in the EPM2A or EPM2B genes. Characteristic of the disease is the formation of Lafora bodies, insoluble deposits containing abnormal glycogen-like material in many tissues, including neurons, muscle, heart and liver. Because glycogen is important for glucose homeostasis, the aberrant glycogen metabolism in Lafora disease might disturb whole-body glucose handling. Indeed, Vernia et al. [Vernia, S., Heredia, M., Criado, O., Rodriguez de Cordoba, S., Garcia-Roves, P.M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P. et al. (2011) Laforin, a dual-specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice. Hum. Mol. Genet., 20, 2571-2584] reported that Epm2a-/- mice had enhanced glucose disposal and insulin sensitivity, leading them to suggest that laforin, the Epm2a gene product, is involved in insulin signaling. We analyzed 3-month- and 6-7-month-old Epm2a-/- mice and observed no differences in glucose tolerance tests (GTTs) or insulin tolerance tests (ITTs) compared with wild-type mice of matched genetic background. At 3 months, Epm2b-/- mice also showed no differences in GTTs and ITTs. In the 6-7-month-old Epm2a-/- mice, there was no evidence for increased insulin stimulation of the phosphorylation of Akt, GSK-3 or S6 in skeletal muscle, liver and heart. From metabolic analyses, these animals were normal with regard to food intake, oxygen consumption, energy expenditure and respiratory exchange ratio. By dual-energy X-ray absorptiometry scan, body composition was unaltered at 3 or 6-7 months of age. Echocardiography showed no defects of cardiac function in Epm2a-/- or Epm2b-/- mice. We conclude that laforin and malin have no effect on whole-body glucose metabolism and insulin sensitivity, and that laforin is not involved in insulin signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: DePaoli-Roach
authors.forename: Dyann M
authors.initials: DM
authors.lastname: Segvich
authors.forename: Catalina M
authors.initials: CM
authors.lastname: Meyer
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Worby
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Gentry
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roach
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D006321:Heart / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor