Recent Developments in Islet Biology: A Review With Patient Perspectives.

Navigating the coronavirus disease-2019 (COVID-19, now COVID) pandemic has required resilience and creativity worldwide. Despite early challenges to productivity, more than 2,000 peer-reviewed articles on islet biology were published in 2021. Herein, we highlight noteworthy advances in islet research between January 2021 and April 2022, focussing on 5 areas. First, we discuss new insights into the role of glucokinase, mitogen-activated protein kinase-kinase/extracellular signal-regulated kinase and mitochondrial function on insulin secretion from the pancreatic ß cell, provided by new genetically modified mouse models and live imaging. We then discuss a new connection between lipid handling and improved insulin secretion in the context of glucotoxicity, focussing on fatty acid-binding protein 4 and fetuin-A. Advances in high-throughput "omic" analysis evolved to where one can generate more finely tuned genetic and molecular profiles within broad classifications of type 1 diabetes and type 2 diabetes. Next, we highlight breakthroughs in diabetes treatment using stem cell-derived ß cells and innovative strategies to improve islet survival posttransplantation. Last, we update our understanding of the impact of severe acute respiratory syndrome-coronavirus-2 infection on pancreatic islet function and discuss current evidence regarding proposed links between COVID and new-onset diabetes. We address these breakthroughs in 2 settings: one for a scientific audience and the other for the public, particularly those living with or affected by diabetes. Bridging biomedical research in diabetes to the community living with or affected by diabetes, our partners living with type 1 diabetes or type 2 diabetes also provide their perspectives on these latest advances in islet biology.

The evaluation of pancreas ß-cell autoantibodies in non-diabetic COVID-19 patients.

Objective: This study aims to evaluate potential pancreas endocrine damage due to SARS-CoV-2 by measuring ß-cell autoantibodies in COVID-19 patients. Subjects and methods: Between June and July 2020, 95 inpatients with a positive COVID-19 test result after polymerase-chain-reaction (PCR) and who met the inclusion criteria were enrolled in our study. Laboratory parameters that belong to glucose metabolism and ß-cell autoantibodies, including anti-islet, anti-glutamic acid decarboxylase, and anti-insulin autoantibodies, were measured. ß-cell autoantibodies levels of the patients were measured during COVID-19 diagnosis. Positive results were reevaluated in the 3rd month of control. Results: In the initial evaluation, 4 (4.2%) patients were positive for anti-islet autoantibody. Only one (1.1%) patient was positive for anti-glutamic acid decarboxylase autoantibody. No patient had positive results for anti-insulin autoantibody. FPG, HbA1c, and C-peptide levels were similar in patients who were split into groups regarding the initial positive or negative status of anti-islet and anti-GAD autoantibodies (p>0.05). In the 3rd month after the initial measurements, anti-islet autoantibody positivity of 2 (50%) of 4 patients and anti-glutamic acid decarboxylase positivity of 1 (100%) patient were persistent. Finally, 3 (3.1%) patients in the whole group were positive for anti-islet autoantibody in the 3rd month of control. No difference was determined between the initial and the 3rd month of parameters of glucose metabolism. Conclusion: Following an ongoing autoantibody positivity in the present study brings the mind that SARS-CoV-2 may be responsible for the diabetogenic effect. Clinicians should be aware of autoantibody-positive DM as a potential autoimmune complication in patients with SARS-CoV-2.

Islet Biology During COVID-19: Progress and Perspectives.

The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020, more than 2,500 peer-reviewed articles have been published on pancreatic islet biology. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase and incretin hormones in insulin secretion, as well as the discovery of inceptor and signalling by circulating RNAs. The year 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing beta-cell proliferation, a "pancreas-on-a-chip" to study glucose-stimulated insulin secretion and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem-cell-derived islet-like cells coated with semipermeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation after transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2. Herein, we highlight novel functional insights, technologies and therapeutic approaches that emerged between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend a broader perspective to developments and challenges in islet research.

Respiratory infections and type 1 diabetes: Potential roles in pathogenesis.

Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non-viral) as potential risk factors for IA/T1D.

Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets.

Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1ß (IL-1ß), anti-IL-6, and anti-tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of ß-cell-altered proinsulin processing, as well as ß-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflammatory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.

Post-acute sequelae of COVID-19: A metabolic perspective.

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.

Impacts of the COVID-19 pandemic on a human research islet program.

Designated a pandemic in March 2020, the spread of severe acute respiratory syndrome virus 2 (SARS-CoV2), the virus responsible for coronavirus disease 2019 (COVID-19), led to new guidelines and restrictions being implemented for individuals, businesses, and societies in efforts to limit the impacts of COVID-19 on personal health and healthcare systems. Here we report the impacts of the COVID-19 pandemic on pancreas processing and islet isolation/distribution outcomes at the Alberta Diabetes Institute IsletCore, a facility specializing in the processing and distribution of human pancreatic islets for research. While the number of organs processed was significantly reduced, organ quality and the function of cellular outputs were minimally impacted during the pandemic when compared to an equivalent period immediately prior. Despite the maintained quality of isolated islets, feedback from recipient groups was more negative. Our findings suggest this is likely due to disrupted distribution which led to increased transit times to recipient labs, particularly those overseas. Thus, to improve overall outcomes in a climate of limited research islet supply, prioritization of tissue recipients based on likely tissue transit times may be needed.

The Prevalence of Islet Autoantibodies in Children and Adolescents With Type 1 Diabetes Mellitus: A Global Scoping Review.

Background and Purpose: Pancreatic islet autoantibodies (iAb) are the hallmark of autoimmunity in type 1 diabetes. A more comprehensive understanding of the global iAb prevalence could help reduce avertible morbidity and mortality among children and adolescents and contribute to the understanding in the observed differences in the incidence, prevalence and health outcomes of children and adolescents with type 1 diabetes across and within countries. We present the first scoping review that provides a global synthesis of the prevalence of iAb in children and adolescents with type 1 diabetes. Research Design and Methods: We searched Ovid MEDLINE® with Daily Update, Embase (Elsevier, embase.com) and PubMed (National Library of Medicine -NCBI), for studies pertaining to prevalence in children and adolescents (0-19) with type 1 diabetes published between 1 Jan 1990 and 18 June 2021. Results were synthesized using Covidence systematic review software and meta-analysis was completed using R v3·6·1. Two reviewers independently screened abstracts with a third reviewer resolving conflicts (k= 0·92). Results: The review revealed 125 studies from 48 different countries, with 92 from high-income countries. Globally, in new-onset type 1 diabetes, IA-2A was the most prevalent iAb 0·714 [95% CI (0·71, 0·72)], followed by ICA 0·681 [95% CI (0·67, 0·69)], ZnT8A was 0·654 [95% CI (0·64, 0·66)], GADA 0·636 [95% CI (0·63, 0·66)] and then IAA 0·424 [95% CI (0·42, 0·43)], with substantial variation across world regions. The weighted mean prevalence of IA-2A was more variable, highest in Europe at 0·749 [95% CI (0·74, 0·76)] followed by Northern America 0·662 [95% CI (0·64, 0·69)], Latin America and the Caribbean 0·632 [95% CI (0·54, 0·72)], Oceania 0·603 [95% CI (0·54, 0·67)], Asia 0·466 [95% CI (0·44, 0·50)] and Africa 0·311 [95% CI (0·23, 0·40)]. In established cases of type 1 diabetes, GADA was the most prevalent iAb 0·407 [95% CI (0·39, 0·42)] followed by ZnT8A 0·322 [95% CI (0·29, 0·36)], IA-2A 0·302 [95% CI (0·29, 0·32)], IAA 0·258 [95% CI (0·24, 0·26)] and ICA 0·145 [95% CI (0·13, 0·16)], again with substantial variation across world regions. Conclusion: Understanding the global prevalence of iAb in children and adolescents with type 1 diabetes could help with earlier identification of those at-risk of developing type 1 diabetes and inform clinical practice, health policies, resource allocation, and targeted healthcare interventions to better screen, diagnose and manage children and adolescents with type 1 diabetes.

Role of the SARS-CoV-2 virus in the appearance of new onset type 1 diabetes mellitus in children in Gran Canaria, Spain.

OBJECTIVES: It has been hypothesized that SARS-CoV-2 may play a role in the development of different forms of diabetes mellitus (DM). The Canary Islands have the highest incidence of type 1 DM (T1DM) reported in Spain (30-35/100,000 children under 14 years/year). In 2020-2021 we observed the highest incidence so far on the island of Gran Canaria, as a result of which we decided to evaluate the possible role of COVID-19 in the increased number of onsets. METHODS: We examined the presence of IgG antibodies against SARS-CoV-2 in children with new onset T1DM between October 2020 and August 2021. We compared recent T1DM incidence with that of the previous 10 years. RESULTS: Forty-two patients were diagnosed with T1DM (48.1/100,000 patients/year), representing a nonsignificant 25.7% increase from the expected incidence. Of the 33 patients who consented to the study, 32 presented negative IgG values, with only one patient reflecting undiagnosed past infection. Forty-four percent of patients presented with ketoacidosis at onset, which was similar to previous years. CONCLUSIONS: We conclude that there is no direct relationship between the increased incidence of T1DM and SARS-CoV-2 in the region. The COVID-19 pandemic did not result in an increased severity of T1DM presentation.

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes.

Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.

Islet organoid as a promising model for diabetes.

Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development in vitro and provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an in vitro human organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.

SARS-CoV-2 and pancreas: a potential pathological interaction?

The widespread extrapulmonary complications of coronavirus disease 2019 (COVID-19) have gained momentum; the pancreas is another major target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we take a closer look into potential pathological interactions. We provide an overview of the current knowledge and understanding of SARS-CoV-2 infection of the pancreas with a special focus on pancreatic islets and propose direct, indirect, and systemic mechanisms for pancreas injury as result of the COVID-19-diabetes fatal bidirectional relationship.

Severe acute respiratory syndrome coronavirus 2 as a potential cause of type 1 diabetes facilitated by spike protein receptor binding domain attachment to human islet cells: An illustrative case study and experimental data.

AIMS: Aim of this study is to report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, responsible for coronavirus disease 2019 (COVID-19), as a possible cause for type 1 diabetes by providing an illustrative clinical case of a man aged 45 years presenting with antibody-negative diabetic ketoacidosis post-recovery from COVID-19 pneumonia and to explore the potential for SARS-CoV-2 to adhere to human islet cells. METHODS: Explanted human islet cells from three independent solid organ donors were incubated with the SARS-CoV-2 spike protein receptor biding domain (RBD) fused to a green fluorescent protein (GFP) or a control-GFP, with differential adherence established by flow cytometry. RESULTS: Flow cytometry revealed dose-dependent specific binding of RBD-GFP to islet cells when compared to control-GFP. CONCLUSIONS: Although a causal basis remains to be established, our case and in vitro data highlight a potential mechanism by which SARS-CoV-2 infection may result in antibody-negative type 1 diabetes.

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas.

Infection-related diabetes can arise as a result of virus-associated ß-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human ß-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in ß-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the ß-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that ß-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.

Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report.

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l-1, blood glucose concentration of 30.6 mmol l-1 (552 mg dl-1) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic ß-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on ß-cells.