Haplotype-tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance task (CPT). Three hundred sixty four individuals were sampled from 152 families ascertained on the basis of at least 1 child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Generalized obesity, regional adiposity, hyperinsulinemia and hypertriglyceridemia are all potential indicators of equine metabolic syndrome (EMS). This study aimed to assess the relationship between morphometric measurements of body condition and metabolic hormone concentrations in ponies, with and without a neck crest or generalised obesity. Twenty-six ponies were assigned a body condition score (BCS) and cresty neck score (CNS). Height, girth, and neck measurements were taken. An oral glucose test (OGT; 0.75g dextrose/kg BW) was performed and blood samples collected prior to and 2 hours post dosing. Basal blood samples were analysed for blood glucose, serum insulin, triglyceride and leptin, and plasma HMW adiponectin concentrations. Post-prandial samples were analysed for serum insulin concentration. The ponies were grouped as having a) a normal to fleshy body status (BCS ≤7 and CNS ≤2; n = 10); b) having a high CNS, but without generalised obesity (BCS ≤7 and CNS ≥3; n = 11), or c) being obese (BCS ≥8 and CNS ≥1; n = 5). Responses to the OGT indicated that both normal and insulin-dysregulated ponies were included in the cohort. Post-prandial serum insulin was positively associated with CNS (P<0.035) and ponies with a CNS ≥ 3 had 5 times greater odds of being insulin-dysregulated. The high CNS group had a greater insulin response to the OGT than those in the normal/fleshy group (P = 0.006), whereas obese ponies did not differ from the other two groups. Basal HMW adiponectin was negatively correlated with post-prandial insulin concentrations (r = -0.5, P = 0.009), as well as being decreased in the group with a high CNS, compared to the obese group (P = 0.05). Cresty neck score was more predictive of insulin dysregulation than BCS, and this may be relevant to the diagnosis of EMS. Adiponectin may also be a measure of insulin dysregulation that is independent of body condition.

Background A previous six-week (wk) study demonstrated the potential of the sodium-glucose linked transport inhibitor velagliflozin as a novel treatment for equine insulin dysregulation. The present study examined the safety and efficacy of velagliflozin over 16 wk. of treatment, and over 4 wk. of withdrawal. Twenty-four insulin dysregulated ponies were selected, based on their hyper-responsiveness to a diet challenge meal containing 3.8 g non-structural carbohydrates (NSC)/kg bodyweight (BW). Ponies with serum insulin > 90 μIU/mL either 2 or 4 h after feeding were enrolled, and randomly allocated to receive either velagliflozin (0.3 mg/kg BW orally once daily, n = 12), or a placebo ( n = 10–12) for 16 wk. The subjects were fed 7.5 g NSC/kg BW/day to maintain a fat body condition. Safety was assessed through daily monitoring, veterinary examination, and the measurement of fasting blood glucose, biochemistry and haematology. Efficacy at reducing post-prandial hyperinsulinemia was assessed using a diet challenge every 8 wk. during treatment and 4 wk. after withdrawal. Results Velagliflozin was well accepted by all subjects and caused no adverse effects or hypoglycaemia. Post-prandial serum insulin (insulin C max ) did not change significantly in the control animals over the entire study period ( P = 0.101). In contrast, insulin C max (mean ± SE) concentrations fell over time in the velagliflozin-treated group from 205 ± 25 μIU/mL in wk. 0, to 119 ± 19 μIU/mL ( P = 0.015) and 117 ± 15 μIU/ml ( P = 0.029) after 8 and 16 wk. of treatment, respectively. Although the insulin C max in this group was not significantly lower than in controls at wk-8 ( P = 0.061), it was lower at wk-16 ( P = 0.003), and all 12 treated ponies were below the previously-determined risk threshold for laminitis at this time. After 4 wk. withdrawal, the insulin C max returned to 199 ± 36 μIU/mL in the treated group, with no rebound effect. Conclusions Velagliflozin appears to be a promising and safe treatment for equine insulin dysregulation, bringing post-prandial insulin concentrations below the laminitis risk threshold, albeit without normalising them. Electronic supplementary material The online version of this article (10.1186/s12917-019-1811-2) contains supplementary material, which is available to authorized users.

BackgroundSupraphysiological insulin and incretin responses to a cereal‐based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described.ObjectivesTo determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin‐dysregulated and healthy ponies.AnimalsA cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID).MethodsIn this case‐control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose‐dependent insulinotropic peptide (GIP) and active glucagon‐like peptide‐1 (aGLP‐1), and compared among pony groups and day of pasture access.ResultsThe area under the insulin curve when grazing increased with ID severity (P < .03). The median (range) maximal insulin concentration was greater in the MID (72.5 [129] μIU/mL) and SID (255 [338.5] μIU/mL) groups, compared to the NIR (11.7 [24.9] μIU/mL) group (P < .03) and occurred within 2‐4 hours of grazing. Postprandial OGT insulin concentration was positively correlated with 2 hours post‐grazing insulin across all 3 grazing days (P ≤ .03). The aGLP‐1 and GIP concentrations increased in response to grazing but did not differ among groups.Conclusions and Clinical ImportanceGrazing pasture provoked an increased insulin and incretin response in insulin‐dysregulated ponies within 4 hours of grazing. The pasture and OGT insulin concentrations were correlated.

This study has demonstrated that GLP-2 may be important in the pathogenesis of equine ID and suggests that the eGLP-2R may be a novel therapeutic target for the treatment of equine ID.