GLP-1-directed NMDA receptor antagonism for obesity treatment.

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.

Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig.

The alpha7 nicotinic acetylcholine receptor (α7-nAChR) has has long been considered a promising therapeutic target for addressing cognitive impairments associated with a spectrum of neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, despite this potential, clinical trials employing α7-nAChR (partial) agonists such as TC-5619 and encenicline (EVP-6124) have fallen short in demonstrating sufficient efficacy. We here investigate the target engagement of TC-5619 and encenicline in the pig brain by use of the α7-nAChR radioligand 11C-NS14492 to characterize binding both with in vitro autoradiography and in vivo occupancy using positron emission tomography (PET). In vitro autoradiography demonstrates significant concentration-dependent binding of 11C-NS14492, and both TC-5619 and encenicline can block this binding. Of particular significance, our in vivo investigations demonstrate that TC-5619 achieves substantial α7-nAChR occupancy, effectively blocking approximately 40% of α7-nAChR binding, whereas encenicline exhibits more limited α7-nAChR occupancy. This study underscores the importance of preclinical PET imaging and target engagement analysis in informing clinical trial strategies, including dosing decisions.

Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome.

BACKGROUND AND PURPOSE: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS. EXPERIMENTAL APPROACH: Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos. KEY RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals. CONCLUSION AND IMPLICATIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.

Preload dependence in an animal model of mild heart failure with preserved ejection fraction (HFpEF).

AIM: Heart Failure with preserved Ejection Fraction (HFpEF) is characterized by diastolic dysfunction and reduced cardiac output, but its pathophysiology remains poorly understood. Animal models of HFpEF are challenging due to difficulties in assessing the degree of heart failure in small animals. This study aimed at inducing HFpEF in a mouse model to probe preload-dependency. METHODS: Increased body mass and arterial hypertension were induced in mice using a Western diet and NO synthase inhibition. Preload dependence was tested ex vivo. RESULTS: Mice with obesity and hypertension exhibited reduced cardiac output, indicating a failing heart. Increased left ventricular filling pressure during diastole suggested reduced compliance. Notably, the ejection fraction was preserved, suggesting the development of HFpEF. Spontaneous physical activity at night was reduced in HFpEF mice, indicating exercise intolerance; however, the cardiac connective tissue content was comparable between HFpEF and control mice. The HFpEF mice showed increased vulnerability to reduced preload ex vivo, indicating that elevated left ventricular filling pressure compensated for the rigid left ventricle, preventing a critical decrease in cardiac output. CONCLUSION: This animal model successfully developed mild HFpEF with a reduced pump function that was dependent on a high preload. A model of mild HFpEF may serve as a valuable tool for studying disease progression and interventions aimed at delaying or reversing symptom advancement, considering the slow development of HFpEF in patients.

Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology.

Circadian clocks temporally orchestrate biological processes critical for cellular/organ function. For example, the cardiomyocyte circadian clock modulates cardiac metabolism, signaling, and electrophysiology over the course of the day, such that, disruption of the clock leads to age-onset cardiomyopathy (through unknown mechanisms). Here, we report that genetic disruption of the cardiomyocyte clock results in chronic induction of the transcriptional repressor E4BP4. Importantly, E4BP4 deletion prevents age-onset cardiomyopathy following clock disruption. These studies also indicate that E4BP4 regulates both cardiac metabolism (eg, fatty acid oxidation) and electrophysiology (eg, QT interval). Collectively, these studies reveal that E4BP4 is a novel regulator of both cardiac physiology and pathophysiology.

Situation Analysis of Suicide and Self-Harm in the WHO Eastern Mediterranean Region.

OBJECTIVE: An estimated 41,000 lives are lost to suicide each year in World Health Organization Eastern Mediterranean Region Office (WHO EMRO) countries. The objective of this study was to conduct a situation analysis for suicide and self-harm in the WHO EMRO region. METHODS: Data on suicide were obtained from the WHO Global Health Estimates for the years 2000-2019. Information on risk groups efforts to prevent self-harm and suicide in the EMRO region were retrieved through scientific studies, grey literature, and public websites. RESULTS: During 2000-2019, the age-standardized suicide rate was 6.7 per 100,000 inhabitants, albeit there are concerns regarding data quality. Self-harm and suicide remain criminal acts in more than half of the countries. Few countries have a national plan for prevention of suicide. Toxic agents, such as pesticides and black henna, are easily available and frequently used for suicide in some areas, as are firearms and self-immolation. Successful prevention measures include means restriction and psychosocial interventions after self-harm. CONCLUSION: Many WHO EMRO countries remain underserved in terms of mental health care. Decriminalization of suicide and means restriction might be further promoted. Online-based tools for mental health literacy and psychosocial therapy are other options to explore.

Suicidal behavior remains a criminal act in more than half of the WHO EMRO countries.Easily available toxic agents, such as pesticides and black henna, and firearms are common methods used for suicidal behavior in the WHO EMRO countries.Access to mental health care is limited in many of the WHO EMRO countries.Online-based psychoeducation and psychosocial intervention programs might be further explored as preventive efforts.

Biomechanical comparison of tension band suture fixation and tension band wiring in olecranon fractures.

PURPOSE: Traditional tension band wire fixation (TBWF) of olecranon fractures is associated with high revision rates due to implant-related complications. The purpose of the study was to compare the strength of fixation in olecranon fractures between TBWF and an all-suture based technique. METHODS: A transverse fracture was created in 20 paired fresh-frozen human cadaveric elbows. Fractures were randomly (alternating right-left) assigned for fixation with either tension band suture fixation (TBSF) or TBWF. The elbow was fixed in 90° of flexion and underwent cycling loading by pulling the triceps tendon to 300 N for 200 cycles. Fracture displacement was optically recorded using digital image correlation (DIC). Finally, load-to-failure was assessed by a monotonic pull to 1000 N and failure mechanism was recorded. RESULTS: Two specimens in the TBSF group were excluded from the cycling loading analysis due to technical difficulties with the DIC. After cyclic loading, median (min-max) fracture displacement was 0.28 mm (0.10-0.44) in the TBSF group and 0.18 mm (0.00-1.48) in the TBWF group (p = 0.315). No difference was found between the two groups in the repeated measures analysis of variance (p = 0.329). In the load-to-failure test, 6/10 specimens failed in the TBSF group (median load-to-failure 791 N) vs. 8/10 in the TBWF group (median load-to-failure 747 N). The TBSF constructs failed due to fracture of the dorsal cortex, suture breakage or triceps failure. The TBWF constructs failed due to breakage of the wire. CONCLUSION: There was no difference in fixation strength between the TBWF and TBSF constructs. Our findings suggest TBSF to be a feasible alternative to TBWF and we hypothesize that a non-metallic implant may have fewer implant-related complications. LEVEL OF EVIDENCE: Basic science study.

The transport function of the human lymphatic system-A systematic review.

Physiological properties and function of the lymphatic system is still somewhat of a mystery. We report the current knowledge about human lymphatic vessel contractility and capability of adaptation. A literature search in PubMed identified studies published January 2000-September 2022. Inclusion criteria were studies investigating parameters related to contraction frequency, fluid velocity, and lymphatic pressure in vivo and ex vivo in human lymphatic vessels. The search returned 2885 papers of which 28 met the inclusion criteria. In vivo vessels revealed baseline contraction frequencies between 0.2 ± 0.2 and 1.8 ± 0.1 min1 , velocities between 0.008 ± 0.002 and 2.3 ± 0.3 cm/s, and pressures between 4.5 (range 0.5-9.2) and 60.3 ± 2.8 mm Hg. Gravitational forces, hyperthermia, and treatment with nifedipine caused increases in contraction frequency. Ex vivo lymphatic vessels displayed contraction frequencies between 1.2 ± 0.1 and 5.5 ± 1.2 min-1 . Exposure to agents affecting cation and anion channels, adrenoceptors, HCN channels, and changes in diameter-tension properties all resulted in changes in functional parameters as known from the blood vascular system. We find that the lymphatic system is dynamic and adaptable. Different investigative methods yields alternating results. Systematic approaches, consensus on investigative methods, and larger studies are needed to fully understand lymphatic transport and apply this in a clinical context.

Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na+,K+-ATPase α2-Isoform.

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.

Daytime and scheduled surgery for major dysvascular lower extremity amputation.

INTRODUCTION: Patients undergoing a major dysvascular lower extremity amputation (LEA) often have a poor outcome with a high risk of complications and mortality despite improvements in care and perioperative programmes. We evaluated whether scheduled surgery would reduce the failure rate in patients with a major LEA. METHODS: A total of 328 consecutive patients undergoing a major LEA from 2016 to 2019 were enrolled at a single centre. Early failure was defined as re-amputation or revision within 30 days of the index amputation. In 2018, a new regime comprising two scheduled surgery days was implemented. The risk of failure comparing the two cohorts (2016-2017, n = 165 versus 2018-2019, n = 163) was calculated for amputation on scheduled versus non-scheduled days and for other potentially influencing factors. RESULTS: The median (25-75% quartiles) age of all patients was 74 (66-83) years, 91% had an American Society of Anesthesiologists (ASA) grade ≥ 3 and 92% had atherosclerosis or diabetes mellitus. The index amputee levels were 36% below-knee, 60% transfemoral and 4% bilateral transfemoral. In the intervention cohort, 59% were amputated on the scheduled days versus 36% in the control group (p less-than 0.001). Correspondingly, more patients (72.4% versus 57.6%, p = 0.005) were amputated during daytime and the 30-day failure rate was reduced to 11.0% (n = 18) versus 16.4% (n = 27) (p = 0.2). Risk of failure on scheduled days in the intervention group was 8.3% versus 14.9% on any other day (p = 0.2). Correspondingly, daytime surgery reduced the risk of failure (6.8% versus 22.2%, p = 0.005). CONCLUSION: Daytime and scheduled surgery for major LEA may possibly reduce early risk of failure. FUNDING: none. TRIAL REGISTRATION: not relevant.

Augmented Ouabain-Induced Vascular Response Reduces Cardiac Efficiency in Mice with Migraine-Associated Mutation in the Na+, K+-ATPase α2-Isoform.

Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α2-isoform-specific inhibition of the Na+,K+-ATPase by ouabain is augmented in α2+/G301R mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α2-isoform to in vivo cardiovascular function of wild-type (WT) and α2+/G301R mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α2+/G301R mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α2+/G301R mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α2+/G301R mice. In conclusion, the ouabain-induced vascular response was augmented in α2+/G301R mice with consequent suppression of cardiac function.

Intramural Purkinje fibers facilitate rapid ventricular activation in the equine heart.

BACKGROUND: The Purkinje fibers convey the electrical impulses at much higher speed than the working myocardial cells. Thus, the distribution of the Purkinje network is of paramount importance for the timing and coordination of ventricular activation. The Purkinje fibers are found in the subendocardium of all species of mammals, but some mammals also possess an intramural Purkinje fiber network that provides for relatively instantaneous, burst-like activation of the entire ventricular wall, and gives rise to an rS configuration in lead II of the ECG. AIM: To relate the topography of the horse heart and the distribution and histology of the conduction system to the pattern of ventricular activation as a mechanism for the unique electrical axis of the equine heart. METHODS: The morphology and distribution of the cardiac conduction system was determined by histochemistry. The electrical activity was measured using ECG in the Einthoven and orthogonal configuration. RESULTS: The long axis of the equine heart is close to vertical. Outside the nodal regions the conduction system consisted of Purkinje fibers connected by connexin 43 and long, slender parallel running transitional cells. The Purkinje fiber network extended deep into the ventricular walls. ECGs recorded in an orthogonal configuration revealed a mean electrical axis pointing in a cranial-to-left direction indicating ventricular activation in an apex-to-base direction. CONCLUSION: The direction of the mean electrical axis in the equine heart is determined by the architecture of the intramural Purkinje network, rather than being a reflection of ventricular mass.

Suture tension band fixation vs. metallic tension band wiring for patella fractures - A biomechanical study on 19 human cadaveric patellae.

PURPOSE: Traditional tension band fixation of patella fracture is associated with high reoperation rates. The purpose of the study was to assess strength of fixation in patella fractures treated with either a non-metallic all suture-based technique or traditional metallic tension band wiring. METHODS: Ten paired human cadaveric specimens were included. A transverse fracture was created, reduced and fixated with a non-metallic or metallic approach. Non-metallic fixation was done according to a previously published technique, metallic fixation was done according to AO description. Specimens were fixed in 90° of flexion and underwent 200 cycles of loading by pulling the Quadriceps tendon to 300 Newton. Fracture displacement was optically monitored. Primary outcome was fracture displacement after 200 cycles compared to the first cycle. Subsequently, load-to-failure was assessed by a monotonic pull to 1000 N. RESULTS: For cyclic loading analysis, one specimen from each group was excluded due to machine synchronization, resulting in a total population of 18 specimens. Median (min-max) fracture displacement was 0.65 mm (0.06-1.3) in the non-metallic group and 0.68 mm (0-1.23), (p=0.931) in the metallic group. No difference in displacement was found between the two groups in the repeated measures analysis of variance (p=0.5524). For load-to-failure analysis one specimen was excluded due to machine synchronization, resulting a total population of 19 specimens. 2/9 specimens failed in the non-metallic group (at 979 and 635 N) and 2/10 failed in the metallic group (745 and 654 N). CONCLUSION: Non-metallic technique is a biomechanically viable alternative to traditional tension band fixation and it can hopefully lead to fewer implant-related complications.

Phenylephrine-Induced Cardiovascular Changes in the Anesthetized Mouse: An Integrated Assessment of in vivo Hemodynamics Under Conditions of Controlled Heart Rate.

OBJECTIVE: Investigating the cardiovascular system is challenging due to its complex regulation by humoral and neuronal factors. Despite this complexity, many existing research methods are limited to the assessment of a few parameters leading to an incomplete characterization of cardiovascular function. Thus, we aim to establish a murine in vivo model for integrated assessment of the cardiovascular system under conditions of controlled heart rate. Utilizing this model, we assessed blood pressure, cardiac output, stroke volume, total peripheral resistance, and electrocardiogram (ECG). HYPOTHESIS: We hypothesize that (i) our in vivo model can be utilized to investigate cardiac and vascular responses to pharmacological intervention with the α1-agonist phenylephrine, and (ii) we can study cardiovascular function during artificial pacing of the heart, modulating cardiac function without a direct vascular effect. METHODS: We included 12 mice that were randomly assigned to either vehicle or phenylephrine intervention through intraperitoneal administration. Mice were anesthetized with isoflurane and intubated endotracheally for mechanical ventilation. We measured blood pressure via a solid-state catheter in the aortic arch, blood flow via a probe on the ascending aorta, and ECG from needle electrodes on the extremities. Right atrium was electrically paced at a frequency ranging from 10 to 11.3 Hz before and after either vehicle or phenylephrine administration. RESULTS: Phenylephrine significantly increased blood pressure, stroke volume, and total peripheral resistance compared to the vehicle group. Moreover, heart rate was significantly decreased following phenylephrine administration. Pacing significantly decreased stroke volume and cardiac output both prior to and after drug administration. However, phenylephrine-induced changes in blood pressure and total peripheral resistance were maintained with increasing pacing frequencies compared to the vehicle group. Total peripheral resistance was not significantly altered with increasing pacing frequencies suggesting that the effect of phenylephrine is primarily of vascular origin. CONCLUSION: In conclusion, this in vivo murine model is capable of distinguishing between changes in peripheral vascular and cardiac functions. This study underlines the primary effect of phenylephrine on vascular function with secondary changes to cardiac function. Hence, this in vivo model is useful for the integrated assessment of the cardiovascular system.

Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts.

Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and ß-adrenergic receptor blockers (ß-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and ß-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of ß-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of ß-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.

PROTOCOL: Testing frequency and student achievement: A systematic review.

This is the protocol for a Campbell review. Our primary research question is: What are the effects of different testing frequencies on student achievement? Our secondary research question is: What are the effects of different testing frequencies on measures of students' testing anxiety? Our third research question is: How are the effects of different testing frequencies on student achievement and testing anxiety moderated by subject, grade, type of test, duration of the intervention, and gender?

PROTOCOL: School-based language, math, and reading interventions for executive functions in children and adolescents: A systematic review.

This is the protocol for a Campbell systematic review. Our primary objective for this systematic review is to examine if preschool and school-based interventions aimed at improving language, literacy, and/or mathematical skills increase children's and adolescents' executive functions. As a secondary objective, we will examine how the effects of language, literacy, and mathematics interventions on executive functions are moderated by the subject of the intervention, child age or grade, the type of EF measured, and the at-risk status of participants. We will also explore how the effects are moderated by other study characteristics, and estimate the effects of the included interventions on language, literacy, and mathematical skills.

Prolonged QT intervals in mice with cardiomyocyte-specific deficiency of the molecular clock.

AIM: Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte-specific disruption of the molecular clock genes have lower heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted. METHODS: We implanted radio transmitters in male mice with cardiomyocyte-specific Bmal1 knockout (CBK) and in control mice and recorded 24-h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo. RESULTS: Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P < .05; and QT: 53 ± 4 vs 48 ± 2 ms, P < .05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P < .05). CONCLUSION: The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24-h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted.

Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V.

Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12-14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8-10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.