ObjectiveIt has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization, or Gcgr antagonist can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. However, the models used in these studies were rendered diabetic by chemical- or immune-mediated β-cell destruction, in which insulin depletion is incomplete. Therefore, it is unclear whether glucagon suppression could overcome the consequence of the complete lack of insulin.MethodsTo directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO).ResultsIn both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls.ConclusionTherefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.
ObjectiveHyperglucagonemia is present in many forms of diabetes and contributes to hyperglycemia, and glucagon suppression can ameliorate diabetes in mice. Leptin, a glucagon suppressor, can also reverse diabetes in rodents. Lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) effectively targets the liver and is in clinical trials for the treatment of various diseases. We compared the effectiveness of glucagon receptor (Gcgr)-siRNA delivered via LNPs to leptin in two mouse models of diabetes.MethodsGcgr siRNA encapsulated into LNPs or leptin was administered to mice with diabetes due to injection of the β-cell toxin streptozotocin (STZ) alone or combined with high fat diet (HFD/STZ).ResultsIn STZ-diabetic mice, a single injection of Gcgr siRNA lowered blood glucose levels for 3 weeks, improved glucose tolerance, and normalized plasma ketones levels, while leptin therapy normalized blood glucose levels, oral glucose tolerance, and plasma ketones, and suppressed lipid metabolism. In contrast, in HFD/STZ-diabetic mice, Gcgr siRNA lowered blood glucose levels for 2 months, improved oral glucose tolerance, and reduced HbA1c, while leptin had no beneficial effects.ConclusionsWhile leptin may be more effective than Gcgr siRNA at normalizing both glucose and lipid metabolism in STZ diabetes, Gcgr siRNA is more effective at reducing blood glucose levels in HFD/STZ diabetes.
Background: The COVID-19 pandemic resulted in a rapid shift from in-person to virtual care delivery for many medical specialties across Canada. The purpose of this study was to explore the lived experiences of resident physicians and faculty related to teaching, learning and assessment during ambulatory virtual care encounters within the competency-based medical education model. Methods: In this qualitative phenomenological study, we recruited resident physicians (postgraduate year [PGY] 1–5 trainees) and faculty from the Departments of Surgery and Medicine at Queen’s University, Ontario, via purposive sampling. Participants were not required to have exposure to virtual care. Interviews were conducted from September 2020 to March 2021 by 1 researcher, and 2 researchers conducted focus groups via Zoom to explore participants’ experiences with the transition to virtual care. These were audio-recorded and transcribed verbatim; qualitative data were analyzed thematically. Results: There were 18 male and 19 female participants; 20 were resident physicians and 17 were faculty; 19 were from the Department of Surgery and 18 from the Department of Medicine. All faculty participants had participated in virtual care during ambulatory care; 2 PGY-1 residents in surgery had not actively participated in virtual care, although they had participated in clinics where faculty were using virtual care. The mean age of faculty participants was 38 (standard deviation [SD] 8.6) years, and the mean age of resident physicians was 29 (SD 5.4) years. Overall, 28 interviews and 4 focus groups (range 2–3 participants per group) were conducted, and 4 themes emerged: teaching and learning, assessment, logistical considerations, and suggestions. Barriers to teaching included the lack of direct observations and teaching time, and barriers to assessment included an absence of specific Entrustable Professional Activities (EPAs) and feedback focused on virtual care–related competencies. Logistical challenges included lack of technological infrastructure, insufficient private office space and administrative burdens. Both resident physicians and faculty did not foresee virtual care limiting resident physicians’ ability to progress within competency-based medical education. Benefits of virtual care included increased accessibility to patients for follow-up visits, for disclosing patients’ results and for out-of-town visits. Suggestions included faculty development, improved access to technology and space, educational guidelines for conducting virtual care encounters, and development of virtual care–specific competencies and EPAs. Interpretation: In the postgraduate program we studied, virtual care imposed substantial barriers on teaching, learning and assessment during the first year of the COVID-19 pandemic. Adapting to new circumstances such as virtual care with suggestions from resident physicians and faculty may help to ensure the continuity of...
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