Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity

AIMS/HYPOTHESIS: Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. MATERIALS AND METHODS: Insulin sensitivity in Pten heterozygous (Pten(+/−)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/−) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting. RESULTS: Following i.p. insulin challenge, blood glucose levels in Pten(+/−) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/−) mice. Enhanced glucose uptake was observed both in Pten(+/−) myocytes and in skeletal muscle of Pten(+/−) mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten(+/−) myocytes. CONCLUSIONS/INTERPRETATION: Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/−) mice

Aggressive retinal astrocytoma associated with tuberous sclerosis

Machiko Tomida,1 Yoshinori Mitamura,1 Takashi Katome,1 Hiroshi Eguchi,1 Takeshi Naito,1 Takayuki Harada21Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 2Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAbstract: We report the case of a patient with an aggressive retinal astrocytoma accompanied with macular edema and neovascular vessels, who was initially treated with intravitreal bevacizumab injections. A 24-year-old male presented to our clinic complaining of visual disturbance in his right eye. At 8 years of age, he had been diagnosed as having tuberous sclerosis complex. Fundus examination demonstrated a retinal tumor accompanied with marked neovascular vessels on the surface, retinal hemorrhage, and macular edema. After six monthly intravitreal bevacizumab injections, fundus examination demonstrated marked regression of the macular edema and neovascular vessels. Two months later, a vitreous hemorrhage developed which necessitated pars plana vitrectomy. After additional intravitreal bevacizumab injection for preventing intraoperative bleeding, vitrectomy with endophotocoagulation for the tumor was performed. The vitreous sample was obtained during vitrectomy, and we measured the vascular endothelial growth factor concentration by enzyme-linked immunosorbent assay. The surgically removed epiretinal neovascular membrane and biopsied retinal tumor expressed vascular endothelial growth factor, although several intravitreal bevacizumab injections led to a vitreous vascular endothelial growth factor concentration of undetectable levels. The clinical course and immunohistochemical analyses indicate that intravitreal bevacizumab monotherapy may have been insufficient to treat the aggressive retinal astrocytoma with macular edema and that laser photocoagulation or photodynamic therapy for the tumor should be considered following intravitreal bevacizumab injection in such cases.Keywords: aggressive retinal astrocytoma, bevacizumab, macular edema, tuberous sclerosis, vitrectomy, vitreous hemorrhage&nbsp

Changes in metamorphopsia in daily life after successful epiretinal membrane surgery and correlation with M-CHARTS score

Takamasa Kinoshita,1,2 Hiroko Imaizumi,1 Hirotomo Miyamoto,1 Utako Okushiba,1 Yuki Hayashi,2 Takashi Katome,2 Yoshinori Mitamura2 1Department of Ophthalmology, Sapporo City General Hospital, Sapporo, Japan; 2Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Purpose: To determine the correlation between the changes in metamorphopsia in daily life environment and the M-CHARTS scores after epiretinal membrane (ERM) removal, and to determine the criterion for determining whether clinically significant changes in the metamorphopsia score have occurred in M-CHARTS. Methods: We studied 65 eyes undergoing vitrectomy for unilateral ERM. Self-administered questionnaires were used to examine the metamorphopsia in their daily life. The degree of metamorphopsia was determined by M-CHARTS. The receiver operating characteristic curve was used to determine the best predictor of the changes in metamorphopsia in daily life. To determine the reproducibility of the M-CHARTS score, another set of 56 eyes with ERM was tested twice on two different days. Results: The postoperative changes in the logarithm of the M-CHARTS score was defined as M2-value. The area under the receiver operating characteristic curve for the M2-value as a predictor of the changes in metamorphopsia in daily life was larger than area under the receiver operating characteristic curve obtained for any other parameter. The optimal cutoff value was -0.4. The 95% limits of agreement between test and retest measurements had a reproducibility of ±0.3 logarithm of the M-CHARTS score. Taking into account not only the reproducibility but also the consistency with the subjective changes, we determined the criterion for clinically significant changes in the M-CHARTS scores as a change of the M2-value by ≥0.4. Conclusion: Evaluating the changes in the M-CHARTS scores in logarithmic form is favorable not only theoretically but also from the perspective of consistency with the subjective changes. Keywords: metamorphopsia score, ERM, criterion, vitrectomy&nbsp