Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 β-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive β-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced β-cell death.DOI: http://dx.doi.org/10.7554/eLife.12977.001

e Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and ␤ cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased ␤ cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in ␤ cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and ␤ cell survival in adult mice.

INTRODUCTION: Hospital and ambulatory care systems are rapidly building their virtual care capacity in response to the novel coronavirus (COVID-19) pandemic. The use of resident trainees in telemedicine is one area of potential development and expansion. To date, however, training opportunities in this field have been limited, and residents may not be adequately prepared to provide high-quality telemedicine care. AIM: This study evaluates the impact of an adapted telemedicine Objective Structured Clinical Examination (OSCE) on telemedicine-specific training competencies of residents. SETTING: Primary Care Internal Medicine residents at a large urban academic hospital. PROGRAM DESCRIPTION: In March 2020, the New York University Grossman School of Medicine Primary Care program adapted its annual comprehensive OSCE to a telemedicine-based platform, to comply with distance learning and social distancing policies during the COVID-19 pandemic. A previously deployed in-person OSCE on the subject of a medical error was adapted to a telemedicine environment and deployed to 23 primary care residents. Both case-specific and core learning competencies were assessed, and additional observations were conducted on the impact of the telemedicine context on the encounter. PROGRAM EVALUATION: Three areas of telemedicine competency need were identified in the OSCE case: technical proficiency; virtual information gathering, including history, collateral information collection, and physical exam; and interpersonal communication skills, both verbal and nonverbal. Residents expressed enthusiasm for telemedicine training, but had concerns about their preparedness for telemedicine practice and the need for further competency and curricular development. DISCUSSION: Programs interested in building capacity among residents to perform telemedicine, particularly during the COVID-19 pandemic, can make significant impact in their trainees' comfort and preparedness by addressing key issues in technical proficiency, history and exam skills, and communication. Further research and curricular development in digital professionalism and digital empathy for trainees may also be beneficial.