2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/l) and hyperglycemic (9-11 mmol/l) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 ml/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23-139±25 ml/min/1.73 m 2 , P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). This distal tubular condition is sensed as a low effective circulating volume stimulus at the level of the juxtaglomerular apparatus, causing an afferent renal vasodilatory response ( Figure 1B). The consequence of this altered TGF results in supranormal glomerular filtration rate (GFR) values into the hyperfiltration range. Targeting TGF in renal hyperfiltration has shown promising results in experimental animal models by using phlorizin, a nonspecific inhibitor of the renal tubular glucose transporters SGlT1 and SGlT2. 13,14 The clinical relevance of these findings, however, could not be conclusively studied in humans, because of the poor tolerability of phlorizin resulting from its low selectivity for SGlT2, SGlT1 inhibition-related gastrointestinal side effects and very limited oral bioavailability. Conclusions-In14 Subsequent studies with selective SGlT2 inhibitors in animals have also shown similar significant effects on renal hyperfiltration. 15 More recently, several highly selective SGlT2 inhibitors have been developed for use in clinical trials in patients with type 2 diabetes mellitus (T2D). 16,17 These compounds generally do not affect SGlT1 at clinical doses and have pharmacological features that allow once daily oral dosing. In T2D, this class of drugs is well-tolerated and has consistently improved glycemic control, along with weight loss, and antihypertensive effects. 17,18 Available evidence for SGlT2 inhibitors in T1D is however limited, and is mainly derived from experimental animal models. Only 1 clinical pilot study has been conducted, which demonstrated that a single dose of remogliflozin improved postprandial glucose profiles. 19 Based on previous findings with phlorizin and other SGlT2 inhibitors in animals, the concept of altering renal hyperfiltration by blocking renal glucose absorption with SGlT2 inhibitors is intriguing, because reducing this surrogate marker of intraglomerular pressure is renal protective in experimental models of diabetes mellitus. 13,20,21 However, potential renal hemodynamic effects of these drugs in subjects with diabetes mellitus, including effects on renal hyperfiltration, remain unknown. Accordingly, the p...

BackgroundThe neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males.MethodsWe examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility.ResultsThere was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing.ConclusionOur findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.

Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder -Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (Po0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P FDR )¼1.29Â10 À5 ), the AGRE cohort (P FDR ¼0.0011) and the combined families (P FDR ¼2.34Â10 À9 ). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P FDR ¼8.65Â10 À7 and 6.07Â10 5 , respectively), AGRE cohort (P FDR ¼0.0034 and 0.015, respectively) and the combined families (P FDR ¼2.34Â10 À9 and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P FDR ¼2.63Â10 À11 ) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values o0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.