Human islet microtissues as an in vitro and an in vivo model system for diabetes

Loss of pancreatic β-cell function is a critical event in the pathophysiology of type 2 diabetes. However, studies of its underlying mechanisms as well as the discovery of novel targets and therapies have been hindered due to limitations in available experimental models. In this study we exploited the stable viability and function of standardized human islet microtissues to develop a disease-relevant, scalable, and reproducible model of β-cell dysfunction by exposing them to long-term glucotoxicity and glucolipotoxicity. Moreover, by establishing a method for highly-efficient and homogeneous viral transduction, we were able to monitor the loss of functional β-cell mass in vivo by transplanting reporter human islet microtissues into the anterior chamber of the eye of immune-deficient mice exposed to a diabetogenic diet for 12 weeks. This newly developed in vitro model as well as the described in vivo methodology represent a new set of tools that will facilitate the study of β-cell failure in type 2 diabetes and would accelerate the discovery of novel therapeutic agents

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

341-P: Effect of Pitolisant on Glucagon in Human Islets and People with Type 1 Diabetes

In 3D human islet microtissues from nondiabetic donors, pitolisant, a histamine 3 receptor antagonist, increased glucagon secretion &amp;gt;3-fold compared to vehicle control. However, the effect of pitolisant on glucagon was diminished in islets treated with cytokines, insulin, and low glucose to mimic T1D hypoglycemia. The purpose of this study was to determine if pitolisant can restore impaired glucagon secretion response to hypoglycemia in people with T1D. The study was a double-blind randomized placebo-controlled study of five adults (3 on pitolisant and 2 on placebo), 4 men, with long-duration T1D. Patients were domiciled overnight, at baseline and after 7 days of once daily oral pitolisant (36 mg) or matching placebo. Blood glucose levels were kept at 100-120 mg/dL overnight with regular insulin infusion and an insulin tolerance test (ITT) was conducted the following morning. Glucagon was measured by the Mercodia ELISA and glucose by a YSI Glucose Analyzer. Glucose was also assessed using a blinded Dexcom G6 CGM during the trial. Safety tolerability was assessed by standard methods. Mean change (95% CI) from baseline in peak glucagon (pg/ml) was 7.5 (-2.07-17.02) for the pitolisant group and 13.1 (2.08-24.09) for the placebo group. One patient on pitolisant and no patients on placebo returned to blood glucose &amp;gt;/=70 mg/dL during the 180-minute ITT. The pitolisant group required significantly less rescue D50 on-drug vs. at baseline (5 vs. 19 grams, p=0.05), while there was no difference in the placebo group (36 vs. 25 grams). In general, patients on pitolisant had numerically higher mean glucose on CGM during the on-drug period. There were no severe hypoglycemic events and no deaths. Pitolisant was well tolerated. We conclude that pitolisant does not increase glucagon secretion during hypoglycemia in people with T1D but may mitigate hypoglycemia by a glucagon-independent mechanism. The T1D islet microtissue model better predicts the clinical effects of pitolisant on glucagon secretion compared to healthy islets. Disclosure C. A. Dehn: None. M. Fein: None. J. Hu: None. B. Yesildag: None. R. Maxwell: Other Relationship; Self; Ferox Therapeutics LLC. J. B. Harp: Other Relationship; Self; Ferox Therapeutics. Funding Ferox Therapeutics; The Leona M. and Harry B. Helmsley Charitable Trust </jats:sec

POLYMORPHISMS OF THE ANGIOTENSIN CONVERTING ENZYME AND ANGIOTENSINOGEN GENE IN PATIENTS WITH ATRIAL FIBRILLATION

WOS: 000289284500039