Fig 1: Treatment with FRAX486 rescues the aberrant blood glucose homeostasis displayed by symptomatic Cdkl5-Het mice. (A) Glucose tolerance test (GTT). Blood glucose levels (glycemia) in Cdkl5 heterozygous (Cdkl5-Het) female mice and wild-type (wt) littermates were measured using a commercial glucometer (Menarini diagnostic) from tail vein blood collected at 0 (baseline), 30, 60, 120 and 180 min following intraperitoneal (i.p.) injection with 2 g/kg body weight d-glucose (10% D glucose solution; Sigma Aldrich) after overnight fasting. No significant genotype differences were found in the GTT. (B) Insulin sensitivity test (IST). One week later, mice were i.p. injected with human recombinant insulin solution (0.4 U/kg body weight, Humulin, Eli-Lilly) after being food-deprived for 5 h. Blood was collected from tail vein at 0 (baseline) and 15 min after insulin administration and glycemia was measured as in (a). Cdkl5-Het mice showed fasting-induced hypoglycemia. (C) Cdkl5-Het and wt mice from a separate cohort were treated for 5 consecutive days via s.c. injections of ctrl and, on the 5th day of treatment, glycemia was measured through tail vein incision under both basal conditions and after 5 h of fasting (1° week). The following week (2° week), Cdkl5-Het mice received once daily, for 5 consecutive days, s.c. injections of 20 mg/kg of FRAX486, while wt mice received ctrl solution, and glycemia was measured as in the first week. A 5-day-long treatment with FRAX486 completely rescued the fasting-induced hypoglycemia of Cdkl5-Het mice, restoring wt-like glycemic levels. Statistical significance was assessed using repeated measures ANOVA (setting genotype as between factor and repeated measurements as within factor) followed by Tukey's post hoc test. Data are mean ± SEM. *p < 0.05, **p < 0.01; N = 4–5 per group (A, B) or N = 7–10 per group (C)