Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity

Anna A. DePaoli-Roach, Dyann M. Segvich, Catalina M. Meyer, Yasmeen Rahimi, Carolyn A. Worby, Matthew S. Gentry, Peter J. Roach

Research output: Contribution to journalArticle

16 Scopus citations

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 Epm2a2/2 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 Epm2a2/2 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, Epm2b2/2 mice also showed no differences in GTTs and ITTs. In the 6-7-month-old Epm2a2/2 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 Epm2a2/2 or Epm2b2/2 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.

Original languageEnglish (US)
Article numberddr598
Pages (from-to)1604-1610
Number of pages7
JournalHuman molecular genetics
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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