A pilot cost-analysis study comparing AI-based EyeArt® and ophthalmologist assessment of diabetic retinopathy in minority women in Oslo, Norway.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of adult blindness in the working age population worldwide, which can be prevented by early detection. Regular eye examinations are recommended and crucial for detecting sight-threatening DR. Use of artificial intelligence (AI) to lessen the burden on the healthcare system is needed. PURPOSE: To perform a pilot cost-analysis study for detecting DR in a cohort of minority women with DM in Oslo, Norway, that have the highest prevalence of diabetes mellitus (DM) in the country, using both manual (ophthalmologist) and autonomous (AI) grading. This is the first study in Norway, as far as we know, that uses AI in DR- grading of retinal images. METHODS: On Minority Women's Day, November 1, 2017, in Oslo, Norway, 33 patients (66 eyes) over 18 years of age diagnosed with DM (T1D and T2D) were screened. The Eidon - True Color Confocal Scanner (CenterVue, United States) was used for retinal imaging and graded for DR after screening had been completed, by an ophthalmologist and automatically, using EyeArt Automated DR Detection System, version 2.1.0 (EyeArt, EyeNuk, CA, USA). The gradings were based on the International Clinical Diabetic Retinopathy (ICDR) severity scale [1] detecting the presence or absence of referable DR. Cost-minimization analyses were performed for both grading methods. RESULTS: 33 women (64 eyes) were eligible for the analysis. A very good inter-rater agreement was found: 0.98 (P < 0.01), between the human and AI-based EyeArt grading system for detecting DR. The prevalence of DR was 18.6% (95% CI: 11.4-25.8%), and the sensitivity and specificity were 100% (95% CI: 100-100% and 95% CI: 100-100%), respectively. The cost difference for AI screening compared to human screening was $143 lower per patient (cost-saving) in favour of AI. CONCLUSION: Our results indicate that The EyeArt AI system is both a reliable, cost-saving, and useful tool for DR grading in clinical practice.

High prevalence of venous thrombotic events in Cushing's syndrome: data from ERCUSYN and details in relation to surgery.

OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.

VHL-deficiency leads to reductive stress in renal cells.

Heritable renal cancer syndromes (RCS) are associated with numerous chromosomal alterations including inactivating mutations in von Hippel-Lindau (VHL) gene. Here we identify a novel aspect of the phenotype in VHL-deficient human renal cells. We call it reductive stress as it is characterised by increased NADH/NAD+ ratio that is associated with impaired cellular respiration, impaired CAC activity, upregulation of reductive carboxylation of glutamine and accumulation of lipid droplets in VHL-deficient cells. Reductive stress was mitigated by glucose depletion and supplementation with pyruvate or resazurin, a redox-reactive agent. This study demonstrates for the first time that reductive stress is a part of the phenotype associated with VHL-deficiency in renal cells and indicates that the reversal of reductive stress can augment respiratory activity and CAC activity, suggesting a strategy for altering the metabolic profile of VHL-deficient tumours.

Automatic Detection of Microaneurysms in Fundus Images Using an Ensemble-Based Segmentation Method.

In this study, a novel method for automatic microaneurysm detection in color fundus images is presented. The proposed method is based on three main steps: (1) image breakdown to smaller image patches, (2) inference to segmentation models, and (3) reconstruction of the predicted segmentation map from output patches. The proposed segmentation method is based on an ensemble of three individual deep networks, such as U-Net, ResNet34-UNet and UNet++. The performance evaluation is based on the calculation of the Dice score and IoU values. The ensemble-based model achieved higher Dice score (0.95) and IoU (0.91) values compared to other network architectures. The proposed ensemble-based model demonstrates the high practical application potential for detection of early-stage diabetic retinopathy in color fundus images.

Effects of Semaglutide and Empagliflozin on Inflammatory Markers in Patients with Type 2 Diabetes.

Low-grade inflammation is associated with complications of type 2 diabetes. Glucagon-like peptide-1 receptor agonists and sodium-glucose transporter-2 inhibitors have shown cardioprotective effects that are independent of their glucose-lowering effects. Cardio-protection could be mediated by the anti-inflammatory effects of these medications, but there is currently limited evidence to support this hypothesis. We conducted a prospective clinical study in patients with type 2 diabetes requiring treatment intensification. Ten patients were assigned to receive empagliflozin 10 mg and 10 patients to receive s/c semaglutide (titrated to 1 mg once a week) in a non-randomised manner. All parameters were measured at baseline and after 3 months. Fasting plasma glucose and glycated haemoglobin improved significantly in both treatment groups, with no between-group differences. Body weight and body mass index reduced significantly more in the semaglutide group, whereas waist circumference decreased only in the empagliflozin group. There was a trend for high-sensitivity CRP reduction in both treatment groups that did not reach statistical significance. Interleukin-6 and the neutrophil-to-lymphocyte ratio did not change in either group. Ferritin and uric acid decreased significantly only in the empagliflozin group, and ceruloplasmin decreased significantly only in the semaglutide group. Though there were clinically meaningful improvements in diabetes control in both treatment arms, we could detect only minor changes in some inflammatory markers.

GLP-1 Receptor Agonists Induce Growth Hormone Secretion in Healthy Volunteers.

INTRODUCTION: Growth hormone (GH) is an essential regulator of growth, body composition and fuel metabolism and, consequently, GH secretion is under the feedback control of numerous nutritional and endocrine mediators. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to exert pleiotropic effects, including stimulation of the activity of the hypothalamic-pituitary-adrenal axis. As GLP-1RAs exert multiple metabolic effects, we hypothesised that they may also affect the secretion of GH and examined the effect of a short-acting and a long-acting GLP-1 RA on GH secretion. METHODS: This is a post hoc analysis of data from clinical trials. Two separate single-group open-label clinical trials were carried out in the ambulatory care setting with a duration of 1 and 21 days, respectively. Healthy adult male and female volunteers with no chronic illnesses or use of daily medicines were recruited for the study. The two interventions were: study 1, single dose of 10 µg exenatide administered subcutaneously (s.c.); study 2, 0.6 mg liraglutide administered s.c. once daily for 21 days. RESULTS: Administration of a single dose of exenatide (study 1) caused a clear increase in GH levels, peaking between 60 and 120 min post-administration. There was also a small but statistically significant decrease in luteinising hormone and testosterone levels 120 min after exenatide dosing. Administration of the long-acting GLP-1RA liraglutide daily for 21 days (study 2) elicited an increase in GH levels with no change in insulin-like growth factor-1 (IGF-1) concentrations after 3 weeks of treatment. CONCLUSIONS: The results show that the administration of GLP-1RAs may elicit an increase in growth hormone levels. GLP-1 signalling may be a novel mechanism of regulation of GH secretion. This finding needs to be replicated in the placebo-controlled trial. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02089256 and NCT03160261.

Systematic review and meta-analysis of head-to-head trials comparing sulfonylureas and low hypoglycaemic risk antidiabetic drugs.

BACKGROUND: Safety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes. METHODS: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs. STUDY SELECTION: Randomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. OUTCOMES: The primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia. SYNTHESIS OF RESULTS: Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780). RESULTS: Our final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07-1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17-2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20-6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules. CONCLUSION: Our meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.

Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury.

Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.

Colorimetric and Electrochemical Screening for Early Detection of Diabetes Mellitus and Diabetic Retinopathy-Application of Sensor Arrays and Machine Learning.

In this review, a selection of works on the sensing of biomarkers related to diabetes mellitus (DM) and diabetic retinopathy (DR) are presented, with the scope of helping and encouraging researchers to design sensor-array machine-learning (ML)-supported devices for robust, fast, and cost-effective early detection of these devastating diseases. First, we highlight the social relevance of developing systematic screening programs for such diseases and how sensor-arrays and ML approaches could ease their early diagnosis. Then, we present diverse works related to the colorimetric and electrochemical sensing of biomarkers related to DM and DR with non-invasive sampling (e.g., urine, saliva, breath, tears, and sweat samples), with a special mention to some already-existing sensor arrays and ML approaches. We finally highlight the great potential of the latter approaches for the fast and reliable early diagnosis of DM and DR.

High-fat diet associated sensitization to metabolic stress in Wfs1 heterozygous mice.

Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in the wolframin ER transmembrane glycoprotein (WFS1) gene and characterized by diabetes mellitus, diabetes insipidus, optic atrophy and deafness. In experimental models the homozygous Wfs1 mutant mice have a full penetrance and clearly expressed phenotype, whereas heterozygous mutants have a less-pronounced phenotype between the wild-type and homozygous mutant mice. Heterozygous WFS1 mutations have been shown to be significant risk factors for diabetes and metabolic disorders in humans. In the present study we analyzed the response of heterozygous Wfs1 mice to high fat diet (HFD) by exploring potential outcomes and molecular changes induced by this challenge. The HFD treatment increased the body weight (BW) similarly both in Wfs1 wild-type (WT) and heterozygous (HZ) mice, and therefore HFD also prevented the impaired BW gain found in Wfs1 mutant mice. In Wfs1HZ mutant mice, HFD impaired the normalized insulin secretion and the expression of ER stress genes in isolated pancreatic islets. These results suggest that Wfs1HZ mice have a decreased insulin response and pronounced cellular stress response due to a higher sensitivity to HFD as hypothesized. In Wfs1HZ mice, HFD increased the expression of Ire1α and Chop in pancreas and decreased that of Ire1α and Atf4 in liver. The present study shows that HFD can disturb insulin function with an increased ER stress in Wfs1HZ mice and only one functional Wfs1 gene copy is not sufficient to compensate this challenge. In conclusion, our study indicates that quantitative Wfs1 gene deficiency is sufficient to predispose the carriers of single functional Wfs1 copy to diabetes and metabolic syndrome and makes them susceptible to the environmental challenges such as HFD.

A GLP-1 Receptor Agonist Inhibits Aldosterone Release in Healthy Volunteers.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are antidiabetic drugs with effects beyond antihyperglycemic action. The aim of the study was to examine whether a single dose of exenatide could be used as a stimulation test for the pituitary-adrenal axis. We carried out a single-group, open-label pilot clinical trial in an ambulatory setting. Ten healthy volunteers of both sexes with body weight>65 kg and age between 18-50 years were recruited. After fasting for 12 hours the subjects received 10 µg of exenatide solution subcutaneously. Blood samples were taken before the administration of exenatide and up to 150 minutes thereafter. The primary outcome was the maximal level of cortisol after the administration of exenatide. Single administration of exenatide 10 µg resulted in a modest increase in ACTH and cortisol levels, as compared to untreated values, and a decrease in blood glucose levels. Remarkably, a robust suppression of both renin and aldosterone levels occurred. We showed that acute administration of exenatide in a full therapeutic dose modestly stimulates the hypothalamic-pituitary-adrenal axis but inhibits the renin-aldosterone system. Further research is warranted to confirm this finding in the placebo-controlled study.

Tolerance develops toward GLP-1 receptor agonists' glucose-lowering effect in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. Animal experiments and human data indicate that tolerance develops toward at least some of their effects, e.g., gastric motility. Whether tolerance develops toward the glucose-lowering effect of GLP-1 receptor agonists in mice has never been formally tested. The hypothesis of tolerance development in mice will be reported in this study. The direct glucose-lowering effect of the GLP-1 receptor agonists was measured in non-fasted mice and with intraperitoneal glucose tolerance test. Exenatide (10 µg/kg) and liraglutide (600 µg/kg) both substantially lost efficacy during the 18-day treatment as compared to the acute effect. We conclude that our results demonstrate development of tolerance toward GLP-1 receptor agonists' glucose-lowering effect in mice.

Once-Weekly Semaglutide Versus Once-Daily Liraglutide for the Treatment of Type 2 Diabetes: A Long-Term Cost-Effectiveness Analysis in Estonia.

INTRODUCTION: Once-weekly semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue for the treatment of type 2 diabetes that was associated with greater reductions in glycated hemoglobin (HbA1c) and body mass index (BMI) versus once-daily GLP-1 analogue liraglutide in a recent network meta-analysis (NMA). The aim of the present study was to assess the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus liraglutide 1.2 mg in Estonia. METHODS: Outcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model (version 9.0), with baseline cohort characteristics sourced from SUSTAIN 3 and changes in HbA1c, systolic blood pressure (SBP), and BMI associated with once-weekly semaglutide and liraglutide derived from the NMA. Patients were assumed to receive once-weekly semaglutide or liraglutide for 5 years before intensifying to basal insulin. Treatment effects were applied for the first 5 years, after which HbA1c increased to 7.0%, SBP followed a natural progression, and BMI reverted to baseline for the remainder of the analysis. Costs were expressed in euros (EUR) and estimated from a healthcare payer perspective. Utilities associated with diabetes and diabetes-related complications were taken from published sources. RESULTS: Once-weekly semaglutide 1 mg was associated with improvements in quality-adjusted life expectancy of 0.13 quality-adjusted life years (QALYs) versus liraglutide 1.2 mg. Direct costs were EUR 67 higher with once-weekly semaglutide, due to the increased acquisition cost, but this was mostly offset by cost savings due to avoidance of diabetes-related complications. Once-weekly semaglutide 1 mg was therefore associated with an incremental cost-effectiveness ratio of EUR 523 per QALY gained versus liraglutide 1.2 mg, which falls well below a willingness-to-pay threshold of EUR 52,390 per QALY gained (three times the Estonian GDP per capita). CONCLUSION: Once-weekly semaglutide was considered highly cost-effective versus liraglutide 1.2 mg for the treatment of patients with type 2 diabetes in Estonia. FUNDING: Novo Nordisk A/S. Plain language summary available for this article.

Profiling of Acylcarnitines in First Episode Psychosis before and after Antipsychotic Treatment.

Acylcarnitines (ACs) have been shown to have a potential to activate pro-inflammatory signaling pathways and to foster the development of insulin resistance. The first task of the current study was to study the full list of ACs (from C2 to C18) in first episode psychosis (FEP) patients before and after antipsychotic treatment. The second task was to relate ACs to inflammatory and metabolic biomarkers established in the same patient cohort as in our previous studies. Serum levels of ACs were determined with the AbsoluteIDQ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria) using the flow injection analysis tandem mass spectrometry ([FIA]-MS/MS) as well as liquid chromatography ([LC]-MS/MS) technique. Identification and quantification of the metabolites was achieved using multiple reactions monitoring along with internal standards. The comparison of ACs in antipsychotic-naïve first-episode psychosis (FEP) patients (N = 38) and control subjects (CSs, N = 37) revealed significantly increased levels of long-chain ACs (LCACs) C14:1 (p = 0.0001), C16 (p = 0.00002), and C18:1 (p = 0.000001) in the patient group. These changes of LCACs were associated with augmented levels of CARN palmitoyltransferase 1 (CPT-1) (p = 0.006). By contrast, the level of short-chain AC (SCAC) C3 was significantly reduced (p = 0.00003) in FEP patients. Seven months of antipsychotic drug treatment ameliorated clinical symptoms in patients (N = 36) but increased significantly their body mass index (BMI, p = 0.001). These changes were accompanied by significantly reduced levels of C18:1 (p = 0.00003) and C18:2 (p = 0.0008) as well as increased level of C3 (p = 0.01). General linear model revealed the relation of LCACs (C16, C16:1, and C18:1) to the inflammatory markers (epidermal growth factor, IL-2, IL-4, IL-6), whereas SCAC C3 was linked to the metabolic markers (leptin, C-peptide) and BMI. FEP was associated with an imbalance of ACs in patients because the levels of several LCACs were significantly higher and the levels of several SCACs were significantly reduced compared with CSs. This imbalance was modified by 7 months of antipsychotic drug treatment, reversing the levels of both LCACs and SCACs to that established for CSs. This study supports the view that ACs have an impact on both inflammatory and metabolic alterations inherent for FEP.

Tolerance Does Not Develop Toward Liraglutide's Glucose-Lowering Effect.

Context: Glucagon-like peptide-1 receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. Animal experiments and human data indicate that tolerance develops toward at least some of their effects (e.g., gastric motility). Whether tolerance develops toward the glucose-lowering effect of glucagon-like peptide-1 receptor agonists has never been formally tested. Objective: The objective of this pilot study was to test the hypothesis whether tolerance develops toward glucagon-like peptide-1 receptor agonists' glucose-lowering effect in chronic use. Design, Setting, Participants, and Intervention: We conducted a single group, open-label clinical trial. Ten healthy volunteers were treated with 0.6 mg liraglutide once daily subcutaneously for 21 days. The drug's effect was quantified by serial graded glucose infusion tests, with glucose and c-peptide measured every 20 minutes and insulin secretion rate calculated. Main Outcome Measure: The primary outcome was a change in the dose-response relationship between calculated insulin secretion rate and blood glucose level after acute and chronic administration of liraglutide. Results: Liraglutide clearly decreased the glucose values during the graded glucose infusion test and robustly enhanced insulin secretion. For all parameters, chronic liraglutide was as effective as acute treatment in human subjects. Conclusions: We conclude that our results largely refute the hypothesis of tolerance development with prolonged liraglutide use in healthy nonobese humans.

Liraglutide Treatment May Affect Renin and Aldosterone Release.

Nowadays, GLP-1 receptor agonists are widely used as effective and safe antidiabetic medications. In addition to glucose-dependent insulin secretion, their effects reach beyond glucose control. Previously, it has been shown that acute administration of GLP-1 receptor agonists increases circulating glucocorticoid and mineralocorticoid levels in both humans and rodents. So far, no studies have reported the effects of chronic administration of GLP-1 receptor agonists on the hypothalamic-pituitary-adrenal axis in humans. The aim of the current study was to examine the effects of acute and chronic treatment with the GLP-1 receptor agonist liraglutide on adrenal function in humans. Ten healthy volunteers were recruited into a single group open-label clinical trial. Each participant was tested for baseline levels, and after acute and chronic treatment with 0.6 mg liraglutide daily. A graded glucose infusion test was performed 3 times. We found that aldosterone tended to be suppressed (albeit not statistically different) after acute administration of liraglutide, and increased after chronic dosing; the difference was statistically significant when compared between acute and chronic dosing. Changes in aldosterone levels followed the changes in renin concentrations and the aldosterone-to-renin ratio remained stable. No statistically significant differences were observed in ACTH or cortisol levels. In conclusion, we have shown that a low dose of GLP-1 receptor agonist may interfere with renin and aldosterone release. Further studies in a larger patient sample and with higher doses of GLP-1 receptor agonists are warranted to corroborate this finding. The study protocol was registered at clinical.trials.gov (NCT02089256) and EU Clinical Trial Register (2014-000238-43).

Variability in the effect of antidepressants upon Wfs1-deficient mice is dependent on the drugs' mechanism of actions.

There is significant comorbidity between mood disorders and diabetes. Wolfram syndrome-related to deficient WFS1 gene function-causes diabetes and mood disorders in humans. Mice lacking the Wfs1 gene display impaired emotional behaviour and glucose metabolism. Various antidepressant drugs are used for alleviating the symptoms of mood disorders. For this study the tail suspension test and locomotor activity test were used to compare the effects of different antidepressants upon homozygous Wfs1-deficient, heterozygous Wfs1-deficient and wild-type mice. Mouse glucose metabolism was concurrently studied using the glucose tolerance test. We showed that ketamine(10mg/kg),NMDA antagonist, escitalopram(2.5-10mg/kg), selective serotonin reuptake inhibitor(SSRI), and amitriptyline(10mg/kg), noradrenaline and serotonin reuptake inhibitor, elicited a stronger antidepressant-like effect in homozygous Wfs1-deficient mice compared to wild-type mice. The effect of noradrenaline and serotonin reuptake inhibitor desipramine(10 and 20mg/kg) did not differ between genotypes. The dopamine and noradrenaline reuptake inhibitor bupropion(5-20mg/kg) had no significant antidepressant-like effect upon any genotype. Amitriptyline and desipramine potentiated a glucose elevation, escitalopram and bupropion did not affect glucose concentrations, and ketamine improved impaired glucose metabolism in homozygous Wfs1-deficient mice. Therefore, the results of this study suggest that SSRIs are the drugs of choice for the treatment of depressive symptoms in diabetic patients. The efficacy of ketamine for these patients remains to be established. Nonetheless, employing the mechanism of action of ketamine that affected glucose metabolism positively, could be an approach for development of improved antidepressants. Wfs1-deficient mice are likely the good animal model to develop new antidepressants more suitable for depressed patients with diabetes.

Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1.

Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 µg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.

Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.

Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour.

GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists are a new group of antidiabetic medications quickly gaining popularity. We aimed to examine behavioural and neuroendocrine changes following chronic treatment with GLP-1 receptor agonists in animal models. METHODS: The effects of chronic treatment with GLP-1 receptor agonists were determined on behavioural parameters [anxiety level in the light-dark compartment test, the motor activity in automated activity cages, immobility in the forced swimming test (FST)] and on corticosterone release in mice. The possible antidepressant effect of chronic liraglutide treatment was also studied in Flinders Sensitive Line (FSL) rats, a genetic model of depression. RESULTS: Two weeks of treatment with exenatide (10 µg/kg twice daily) or liraglutide (1200 µg/kg once daily) did not affect the anxiety level in a light-dark compartment test nor induce an antidepressant-like effect in the FST in mice. Moreover, chronic treatment with liraglutide had no effect on depression-related behaviour in FSL rats. Interestingly, hypolocomotion induced by the drugs in mice disappeared after chronic dosing. Both of the GLP-1 receptor agonists induced robust increases in corticosterone levels in mice under basal conditions as well as in the case of combination with swimming stress. Remarkably, exenatide was as potent a stimulator of corticosterone release after 2 weeks as after acute administration. CONCLUSIONS: The increases in corticosterone release seen after acute exenatide or liraglutide treatment do not abate after 2 weeks of treatment demonstrating that tolerance does not develop towards this particular effect of GLP-1 agonists.