Mesenchymal Stem/Stromal Cells: DEVELOPMENT OF A GMP BANKING PROCESS FOR UMBILICAL CORD MESENCHYMAL STROMAL CELLS (UC-MSCS) AND USE OF UC-MSC IN CHARACTERISATION ASSAYS, FUNCTIONAL ASSAYS AND GENE EDITING STUDIES

Background & Aim: The pro-angiogenic, immunoregulatory and anti- inflammatory properties of MSCs are being exploited for the development of cellular therapies, including the treatment of graft versus host disease (GvHD), inflammatory bowel disease and COVID-19. SNBTS have developed a GMP process to bank umbilical cord MSCs (UC-MSCs) whereby we can reliably bank 100 vials of 10 million P2 UC-MSCs per cord. Each of these vials can be extensively expanded and stored for specific applications. The ultimate aim of the bank is for off-the-shelf clinical use, e.g., in GvHD or as an adjuvant therapy in Islet transplantations. Methods, Results & Conclusion(s): During process development, different basal media and supplements were screened for proliferation and MSC marker expression. Cells grown in promising media combinations were then tested for tri-lineage differentiation (identity), their chemokine/cytokine expression and T-cell inhibition (function) assessed. Medium selected for further GMP development and scale up was ultimately determined by all round performance and regulatory compliance. GMP-like UC-MSCs were shown to have immune-modulatory activity in T-cell proliferation assays at 4:1 or 16:1 ratios. Co-culture of UC-MSCs and freshly isolated leukocytes, +/- the immune activating agent LPS, show a dose dependent survival effect on leukocytes. In particular, neutrophils, which are normally very short lived in vitro demonstrated increased viability when co-cultured with UCMSCs. The survival effect was partially reproduced when UC-MSC were replaced with conditioned medium or cell lysate indicating the involvement of soluble factors. This improved neutrophil survival also correlates with results from leukocyte migration studies that demonstrate neutrophils to be the main cell type attracted to MSCs in in vitro and in vivo. Genetic modification of UC-MSC may improve their therapeutic potential. We have tested gene editing by CRISPR/Cas9 technology in primary UC-MSCS. The CXCL8 gene, highly expressed in UC-MSC, was targeted in isolates from several different donors with editing efficiencies of 78-96% observed. This translated to significant knockdown of CXCL8 protein levels in resting cells, however after stimulation levels of CXCL8 were found to be very similar in edited and non-edited UC-MSCs. This observation requires further study, but overall the results show the potential to generate future banks of primary UC-MSCS with genetically enhanced pro-angiogenic, immunoregulatory and/or anti-inflammatory activities.Copyright © 2023 International Society for Cell & Gene Therapy

SARS-CoV-2 Positive Serology and Islet Autoantibodies in Newly Diagnosed Pediatric Cases of Type 1 Diabetes Mellitus: A Single-Center Cohort Study.

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although presenting less severe forms of the disease in children, seems to play a role in the development of other conditions, including type 1 diabetes mellitus (T1DM). After the beginning of the pandemic, an increase in the number of T1DM pediatric patients was observed in several countries, thus leading to many questions about the complex relationship between SARS-CoV-2 infection and T1DM. Our study aimed to highlight possible correlations between SARS-CoV-2 serology and T1DM onset. Therefore, we performed an observational retrospective cohort study that included 158 children diagnosed with T1DM in the period April 2021-April 2022. The presence or absence of SARS-CoV-2 and T1DM-specific antibodies and other laboratory findings were assessed. In the group of patients with positive SARS-CoV-2 serology, a higher percentage had detectable IA-2A antibodies, more children were positive for all three islet autoantibodies determined (GADA, ICA, and IA-2A), and a higher mean HbA1c value was found. No difference existed between the two groups regarding DKA presence and severity. A lower C-peptide level was found in the patients presenting diabetic ketoacidosis (DKA) at T1DM onset. When compared to a group of patients diagnosed before the pandemic, an increased incidence of both DKA and severe DKA, as well as a higher age at diagnosis and higher levels of HbA1c were present in our study group. These findings have important implications for the ongoing monitoring and management of children with T1DM after the COVID-19 pandemic and highlight the need for further research to better understand the complex relationship between SARS-CoV-2 infection and T1DM.

SARS-CoV-2 VARIANTS-DEPENDENT INFLAMMASOME ACTIVATION

Background: Innate immunity is the first line of defense in response to pathogens, which acts locally and also leads the stimulation of adaptive immunity through at least with IL-1beta secretion. It has been shown that SARSCoV- 2 infection triggered the NLRP-3 inflammasome activation and the IL-1beta secretion. The aim of this study was to analyze and compare the level of IL-1beta secretion that is one of the most important innate immunity cytokines, in monocyte-like cells infected with 6 different variants of the SARS-CoV-2. Method(s): Six SARS-CoV-2 variants (historical (B.1, D614G), Alpha, Beta, Gamma, Delta and Omicron BA.1) were isolated from COVID-19 hospitalized patients. Viral stocks were obtained by inoculation in Vero and Vero-TRMPSS2 cells. THP-1 monocyte-like cells were cultured with RPMI-hepes 10% FBS-0.05 mM 2-mercaptoethanol. A total of 5 x 104 of THP-1 cells was plated per well in 96-wells plate and differentiated with 10nM of PMA for 24h. Differenciated- THP-1 were first primed with LPS 1mug/ml for 2h and infected with different SARS-CoV-2 variants with a MOI 0.1. IL-1beta was measured by luminescence in the supernatant after 24 h of infection. Result(s): We analyzed and compared IL-1beta secretion between SARS-CoV-2 virus 6 sublineages after infection of monocytes like THP-1. We observed that THP-1 cells infected with SARS-CoV-2 variants presented a significantly higher IL-1beta secretion than non-infected cells. Moreover, some SARS-CoV-2 variants led to a stronger IL-1beta secretion, and particularly we observed a significantly higher level of IL-1beta cells infected with Omicron BA.1 sublineage compared to other variants. Indeed, Omicron BA.1 infected cells presented the higher IL-1beta secretion (median 385.7 pg/ml IQR[302.6-426.3]) follows by the Delta variants and the historical variants (median 303.6 [266.3-391.9] and 281.9 [207.2-410], respectively). Alpha, Beta and Gamma variants presented the lowest IL-1beta secretion (median 228.1 [192.5-276.4], 219.1 [185.1-354.2] and 211 [149.8- 228.8]). Conclusion(s): We observed the inflammasome activation for the 6 SARS-CoV-2 sublineages with a variation in level of IL-1beta secretion. Indeed, our results suggested that Omicron BA.1 was more recognized by the innate immune cells than other SARS-CoV-2, which could in part, with its upper respiratory tract tropism, possibly explain its less clinical virulence. Taking together, these results suggest that the innate immunity response and precisely, IL-1beta secretion pathways were activated in a SARS-CoV-2 variants-dependent manner.

The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023

Nonhuman Primate Model of Long Covid: Immune Insights of Glycometabolic Dysfunctions

Background: A major consequence of COVID-19 is long-term metabolic complications (metabolic PASC or Long COVID) following acute disease resolution leading to hyperglycemia, increased risk of diabetes or defects in glucose metabolism. However, the mechanisms underlying the links between COVID-19 and glycometabolic disruptions remain unclear. Method(s): 15 African green monkeys (AGM;Chlorocebus aethiops) were infected with SARS-CoV-2 (Wuhan stain) and divided into two groups: unvaccinated (n=10) and vaccinated (BNT162b2 (Pfizer) 4-days post infection;n=5). Subgenomic SARS-CoV-2 mRNA (sgRNA) reflecting active replication was quantified in nasal and pharyngeal swabs, and blood chemistry analysis was performed longitudinally up to 18 weeks post-infection. We quantified liver glycogen at necropsy using Periodic acid-Schiff staining. Finally, we longitudinally analyzed 96 plasma proteins using a proximity extension assay (Olink). STRING was used to identify enriched protein networks. Comparisons between the two groups over time were performed using PERMANOVA. Result(s): All animals had detectable sgRNA ( >3.64x106) at day 3, and only two were undetectable at week 5. Post-infection BNT162b2 vaccination partially inhibited the SARS-CoV-2 mediated disruption of glucose levels (P=0.001, Fig. 1A). Liver glycogen levels following necropsy correlated positively with blood glucose levels at week 12 (r=0.74, P =0.003). Histopathological analysis revealed no marked evidence of long-term inflammation or fibrosis of pancreatic islets. Using the plasma proteomic data, we identified a signature of 15 SARS-CoV-2-modulated plasma proteins coinciding with early onset hyperglycemia during acute infection (P=0.001, Fig. 1B). These proteins are enriched for biological processes linked to chemotaxis (FDR=1.38E-06), and viral protein interaction with cytokines (FDR=1.01E-12) (Fig. 1C). Of these, CCL25 and glial cell derived neurotrophic factor (GDNF) remained persistently elevated post-acute infection and correlated with blood glucose levels (r=0.57, P=0.0003;and r=0.64, P<0.0001, respectively, Fig. 1D). Conclusion(s): Our AGM model validates phenotypes of metabolic PASC and offers an opportunity to mechanistically study the manifestations of PASC. Our preliminary data suggest that vaccine-preventable early insults by metabolicregulating immune factors may contribute to long-term dysregulated liver and systemic glucose homeostasis during PASC. These immune factors warrant further investigation for their mechanistic links to PASC. (Figure Presented).

New Onset Diabetes and Acute Pancreatitis- A Sequela of Long COVID?

Introduction: The association between worse COVID-19 outcomes and diabetes has been well-established in the literature. However, with more cases of new-onset diabetes and pancreatitis being reported with or after COVID-19 infection, it poses the question if there is a causal relationship between them. Case Description: 31 y/o female with COVID-19 infection 4-6 weeks ago with moderate symptoms (not requiring hospital admission or monoclonal ab), presented to ED with bandlike epigastric pain radiating to back, which is worsened with food, associated with nausea, vomiting, polyuria, and fatigue. Workup showed lipase 232, AST 180, ALT 256. Blood glucose was 281 and HbA1c was 12. CT A/P showed post cholecystectomy status, normal pancreas with mesenteric adenitis. MRCP showed hepatic steatosis with trace fluid around the pancreas s/o inflammation, and no evidence of choledocholithiasis or biliary dilatation. She denied alcohol use and autoimmune workup for pancreatitis was unremarkable. Islet cell antibodies were negative. The patient improved with fluid resuscitation and was discharged home on insulin with plans to transition to oral agents outpatient. Discussion(s): Long COVID is defined as a range of conditions or symptoms in patients recovering from COVID-19, lasting beyond 4 weeks after infection. A retrospective cohort study showed increased new-onset diabetes incidence in patients after COVID-19. This was redemonstrated in a systematic review and meta-analysis that showed a 14.4% increased proportion of new diagnoses of diabetes in patients hospitalized with COVID-19. Possible pathophysiology that have been attributed to this include undiagnosed pre-existing diabetes, hyperglycemia secondary to acute illness and stress from increased inflammatory markers during the cytokine storm, the effect of viral infections on the pancreas, and concurrent steroid use in patients with severe respiratory disease. The binding of SARS-CoV-2 to ACE2 receptors is thought to the other mechanism by which COVID can cause pancreatitis and hyperglycemia. Study showed increased lipase and amylase levels in patients with COVID and the increase in serum levels was proportional to the severity of the disease. Patients who died due to COVID-19 were also found to have degeneration of the islet cells. While, several studies have showed new onset diabetes and pancreatitis during an active COVID infections, we need larger cohort studies to comment on its true association or causation, especially in patients with long COVID symptoms. As more cases of new onset diabetes and pancreatitis with COVID-19 are being reported, there may be a need for more frequent blood sugar monitoring during the recovery phase of COVID-19.Copyright © 2023

New Onset of Type 1 Diabetes After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination

Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses the greatest threat of our times. SARS-CoV-2 vaccines are one of the most effective strategies against this infection. Diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, and new-onset diabetes as adverse effects of SARS-CoV-2 vaccination have been infrequently described in the literature. We hereby report a rare case of new-onset type 1 diabetes after SARS-CoV-2 vaccination. Case Description: An 18-year-old male presented to the outpatient office for evaluation of breast pain. On routine laboratory tests, he was noted to have fasting blood glucose of 200 mg/dL. On further questioning, he reported some polyuria, nocturia, and a 10-pound weight loss over the preceding month. He received the initial dose of Pfizer-BioNTech SARS-CoV-2 vaccine in May 2022 and the second dose in June 2022, approximately one month before the onset of symptoms. He denied any earlier viral infections and had no personal or family history of autoimmune conditions. On evaluation, his body mass index was 20 kg/m2, but otherwise, he had a normal physical exam, including a breast exam. Over the next few days, his blood glucose progressively increased to over 300 mg/dl. HbA1c was noted to be elevated at 8.6%, glutamic acid decarboxylase-65 (GAD-65) antibodies were remarkably high >250 IU/ml (normal 5 IU/ml), C-peptide was 1.51 ng/ml (normal 0.80 - 3.85 ng/ml), blood glucose 156 mg/dl, islet-cell antibody titer was 320 (< 1.25 JDF units) and insulin autoantibodies were negative. He was diagnosed with autoimmune Type 1 diabetes and a basal-bolus insulin regimen was initiated to improve glycemic control. On a one-month follow-up, his insulin requirements remained low but persistent and his glycemic control was acceptable. Discussion(s): Various viruses are known to play a fundamental role in the onset of type 1 diabetes via a variety of effects on pancreatic beta-cells because of either the direct lytic effects of viral replication or the inflammatory response to the virus, which is mediated by autoreactive T cells. The limited release of islet cell antigens induces molecular mimicry and paves the way for long-term autoimmunity and the development of type 1 diabetes mellitus. Our patient did not report any viral illnesses before the onset of his symptoms. He also did not have a family or personal history of autoimmune diseases. His onset of diabetic symptoms coincided temporally with receiving the SARS-CoV-2 vaccine. The detection of a considerable titer of GAD-65 antibodies proved autoimmunity. Clinicians must stay vigilant about this potential side effect of SARS-CoV2 vaccine so that a timely diagnosis can be made.Copyright © 2023

Could COVID-19 be a Causative Factor for Hyperglycaemia and Cause Diabetes Mellitus.

Since the outbreak of the COVID-19 pandemic, it has been suspected that its causative agent, the SARS-CoV-2 coronavirus, may cause transient or permanent hyperglycemia. This fact has resulted in a new focus of research interest related to the study of potential mechanisms leading to damage of pancreatic insulin-producing cells, as well as the possible impact of the virus on insulin sensitivity, which may manifest as metabolic disturbances in patients with COVID-19 and cause diabetes mellitus. Evidence from the literature suggests that Corona viruses can damage pancreatic (beta-cells by direct or indirect mechanisms and cause changes in insulin secretion and sensitivity. To what extent all these changes are valid claims that SARS-CoV-2 can trigger diabetes mellitus is still not fully proven.Copyright © 2022 Medical Information Center. All rights reserved.

SARS-CoV-2 Infection Causes Hyperglycemia in Cats.

Isolated reports of new-onset diabetes in patients with coronavirus disease 2019 (COVID-19) have led researchers to hypothesize that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human exocrine and endocrine pancreatic cells ex vivo and in vivo. However, existing research lacks experimental evidence indicating that SARS-CoV-2 can infect pancreatic tissue. Here, we found that cats infected with a high dose of SARS-CoV-2 exhibited hyperglycemia. We also detected SARS-CoV-2 RNA in pancreatic tissues of these cats, and immunohistochemical staining revealed the presence of SARS-CoV-2 nucleocapsid protein (NP) in islet cells. SARS-CoV-2 NP and spike proteins were primarily detected in glucagon-positive cells, and most glucagon-positive cells expressed ACE2. Additionally, immune protection experiments conducted on cats showed that blood glucose levels of immunized cats did not increase postchallenge. Our data indicate cat pancreas as a SARS-CoV-2 target and suggest that the infection of glucagon-positive cells could contribute to the metabolic dysregulation observed in SARS-CoV-2-infected cats.

COVID 19 Induced Hyperglycaemic Complications

Background: COVID 19 has two-way interaction with Type II Diabetes Mellitus. First, patient with DM are more prone for developing severe COVID 19. Second, moderate to severe COVID 19 can present with new onset DM or may lead to hyperglycaemia and hyperglycaemic complications in Type II DM patients. In this report we present 4 cases of COVID 19 associated Hyperglycaemic Complication (3 with Diabetic Ketoacidosis and 1 with Hyperglycaemic hyperosmolar state). Method(s): Case Series of patients admitted to Thumbay Hospital, Ajman. Result(s): We report 4 cases of COVID 19 patients who presented to us with hyperglycaemic complications. There of them had features of Diabetic Ketoacidosis and one had Hyperglycaemic hyperosmolar state. All were treated with IV Insulin infusion and IV Fluids. COVID 19 infection was managed as per MOH protocol. All patients recovered well and were discharged in stable condition. Discussion(s): COVID 19 is associated with new onset DM or may lead to hyperglycaemic complications in patients with Type II DM. There are three pathophysiological processes which may be responsible for this finding. One, SARS-CoV-2 virus is known to enter the body through angiotensin-converting enzyme (ACE) II receptors in the pulmonary pneumocytes leading to infection and inflammation. Similar ACE-II receptors are also expressed in key metabolic organs and tissues, including pancreatic beta cells, adipose tissue, the small intestine, and the kidneys. Direct infection of pancreatic beta-cells with SARS-CoV-2 virus with beta-cell cell injury is likely the underlying mechanism for development of new onset diabetes and hyperglycaemia in existing diabetic patients. Such direct beta cell infection can cause hyperglycaemic complications in asymptomatic or mild COVID 19 as well. Two, moderate to severe COVID 19 is associated with hyperinflammatory immune response leading to marked rise in inflammatory mediators such as C-reactive protein and ferritin. Such hyperinflammatory response can also lead to hyperglyacemia in patients with diabetes mellitus. Three, corticosteroids are mainstay treatment of patients with moderate to severe COVID 19 and would definitely contribute to worsening of hyperglycaemia in these patients. Our patients presented to us with hyperglycaemic complications before initiation of any treatment. It is likely that such a situation would be due to direct infection and destruction of beta cells with SARS-CoV-2 virus infection. Conclusion(s): Type II Diabetes Mellitus patients are high risk of developing hyperglycaemic complications due to COVID 19. This can lead to increased morbidity and mortality. Patients with Type II DM should seek medical attention even if they have mild to asymptomatic COVID 19 to monitor for hyperglycaemic complication which can develop irrespective of severity of stage of illness.

IDF2022-0635 Can COVID-19 infection provoke new-onset A-beta+ KPD (ketosis-prone diabetes)? - Insights from an Indian prospective study

Background COVID-19 as a trigger for A-beta+ ketosis-prone diabetes (KPD) [1,2] in previously normoglycemic individuals presenting with new-onset DKA, has been sparsely studied. Aim To study prospective changes in insulin secretion and insulin resistance in suspected A-beta+ KPD patients presenting with COVID-associated new-onset DKA. Method 22 previously non-diabetic, antibody-negative patients with new-onset DKA and RT-PCR positive COVID-19 (suspected A-beta + KPD), were followed up for one year. They were compared with 20 Type 1A and 18 Type 2 DM patients, with serial assessments (0,6 and 12 months) of insulin secretion rates (ISR) and multi-tissue insulin resistance (IR). 75-g OGTT with serial glucose, insulin and C-peptide estimation (0,15, 30,45, 60,90,120, 150 and 180 minutes) was used to derive IS, while hepatic and peripheral IR was calculated based on study by Ghani et al. [3]. Results At baseline, ISR in suspected KPD (n = 22) was significantly reduced but similar to Type 1A DM(p = 0.15). Serial ISR demonstrated complete recovery in 17 (77%) patients who became insulin independent at one-year follow-up (remission), while 5(23%) patients continued to require insulin (non-remission). KPD patients showed significant hepatic and peripheral IR at baseline compared to Type 1A DM (p < 0.05). The remission group (n = 17) showed significantly enhanced recovery of hepatic and peripheral insulin sensitivity at 6 and 12 months follow-up (all p < 0.01) compared to the non-remission (n = 5) group, with IR in the latter being comparable to Type 2 DM at follow-up (all p > 0.05). Younger age, lower BMI, initial severity of DKA and inflammation (IL-6 levels), along-with reduced 25-hydroxy-Vitamin-D levels were factors associated with poorer recovery of beta-cell secretion amongst the KPD patients. Conclusion This is the first prospective study to demonstrate progressive recovery of p-cell secretion in new-onset A-beta + KPD provoked by COVID-19 infection in Indian adults, with a distinctly different profile from Type 1A DM.Copyright © 2023 Elsevier B.V.

Could COVID-19 be a Causative Factor for Hyperglycaemia and Cause Diabetes Mellitus.

Since the outbreak of the COVID-19 pandemic, it has been suspected that its causative agent, the SARS-CoV-2 coronavirus, may cause transient or permanent hyperglycemia. This fact has resulted in a new focus of research interest related to the study of potential mechanisms leading to damage of pancreatic insulin-producing cells, as well as the possible impact of the virus on insulin sensitivity, which may manifest as metabolic disturbances in patients with COVID-19 and cause diabetes mellitus. Evidence from the literature suggests that Corona viruses can damage pancreatic (beta-cells by direct or indirect mechanisms and cause changes in insulin secretion and sensitivity. To what extent all these changes are valid claims that SARS-CoV-2 can trigger diabetes mellitus is still not fully proven.Copyright © 2022 Medical Information Center. All rights reserved.

Could COVID-19 be a Causative Factor for Hyperglycaemia and Cause Diabetes Mellitus.

Since the outbreak of the COVID-19 pandemic, it has been suspected that its causative agent, the SARS-CoV-2 coronavirus, may cause transient or permanent hyperglycemia. This fact has resulted in a new focus of research interest related to the study of potential mechanisms leading to damage of pancreatic insulin-producing cells, as well as the possible impact of the virus on insulin sensitivity, which may manifest as metabolic disturbances in patients with COVID-19 and cause diabetes mellitus. Evidence from the literature suggests that Corona viruses can damage pancreatic (beta-cells by direct or indirect mechanisms and cause changes in insulin secretion and sensitivity. To what extent all these changes are valid claims that SARS-CoV-2 can trigger diabetes mellitus is still not fully proven.Copyright © 2022 Medical Information Center. All rights reserved.

SARS-CoV-2 Host Receptors Expression in Human Pancreatic Islets Revealed Upregulation of ACE2 in Diabetic subjects

Background: It is well established that diabetic patients infected with COVID-19- are at higher risk of developing severe symptoms that may lead to death. Such observation argues for the possibility that SARS-CoV-2 may target and infect pancreatic islets. SARSCoV- 2 is thought to enter the cells through the binding of viral spike S1 protein to ACE2. The cellular entry process includes priming of the S protein by TMPRSS2 and ADAM17, which facilitate the binding and promote ACE2 shedding. To date, no conclusive evidence has emerged to address the expression of TMPRSS2 and ADMA17 or the interaction between SARS-CoV-2 and human pancreatic islets. Method(s): Microarray and RNA-sequencing (RNA-seq) expression data from human islets were used to profile the expression pattern of ACE2, ADAM17, and TMPRSS2 in diabetic and non-diabetic subjects. Result(s): Pancreatic islets express all three receptors regardless of diabetes status. ACE2 expression was significantly elevated in diabetic islets than non-diabetic. Female donors showed to have higher ACE2 expression compared to males, whereas ADAM17 and TMPRSS2 were not affected by gender. No difference in the expression of the three receptors in young (<=40 years old) compared to old (>=60 years old) islets. Obese donors (BMI>30) showed significantly higher expression levels of ADAM17 and TMPRSS2 as compared to non-obese (BMI<25). Expression of TMPRSS2 was associated positively with HbA1c and inversely with age, while ADAM17 and TMPRSS2 were associated positively with BMI. Muscle and subcutaneous adipose tissues showed similar expression of the three receptors in diabetic and nondiabetic donors. Conclusion(s): ACE2 expression is increased in diabetic human islets. More studies are warranted to understand the permissiveness of human pancreatic beta-cells to SARS-Cov-2 and whether variations of ACE2 expression could explain the severity of COVID-19 infection between diabetics and non-diabetic patients.

Bidirectional Relationship between Glycemic Control and COVID-19 and Perspectives of Islet Organoid Models of SARS-CoV-2 Infection.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to morbidity and mortality, with several clinical manifestations, and has caused a widespread pandemic. It has been found that type 2 diabetes is a risk factor for severe coronavirus disease 2019 (COVID-19) illness. Moreover, accumulating evidence has shown that SARS-CoV-2 infection can increase the risk of hyperglycemia and diabetes, though the underlying mechanism remains unclear because of a lack of authentic disease models to recapitulate the abnormalities involved in the development, regeneration, and function of human pancreatic islets under SARS-CoV-2 infection. Stem-cell-derived islet organoids have been valued as a model to study islets' development and function, and thus provide a promising model for unraveling the mechanisms underlying the onset of diabetes under SARS-CoV-2 infection. This review summarized the latest results from clinical and basic research on SARS-CoV-2-induced pancreatic islet damage and impaired glycemic control. Furthermore, we discuss the potential and perspectives of using human ES/iPS cell-derived islet organoids to unravel the bidirectional relationship between glycemic control and SARS-CoV-2 infection.

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.

New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection.

Type 1 diabetes (T1D) is a condition characterized by an absolute deficiency of insulin. Loss of insulin-producing pancreatic islet ß cells is one of the many causes of T1D. Viral infections have long been associated with new-onset T1D and the balance between virulence and host immunity determines whether the viral infection would lead to T1D. Herein, we detail the dynamic interaction of pancreatic ß cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host immune system with respect to new-onset T1D. Importantly, ß cells express the crucial entry receptors and multiple studies confirmed that ß cells are infected by SARS-CoV-2. Innate immune system effectors, such as natural killer cells, can eliminate such infected ß cells. Although CD4+ CD25+ FoxP3+ regulatory T (TREG ) cells provide immune tolerance to prevent the destruction of the islet ß-cell population by autoantigen-specific CD8+ T cells, it can be speculated that SARS-CoV-2 infection may compromise self-tolerance by depleting TREG -cell numbers or diminishing TREG -cell functions by repressing Forkhead box P3 (FoxP3) expression. However, the expansion of ß cells by self-duplication, and regeneration from progenitor cells, could effectively replace lost ß cells. Appearance of islet autoantibodies following SARS-CoV-2 infection was reported in a few cases, which could imply a breakdown of immune tolerance in the pancreatic islets. However, many of the cases with newly diagnosed autoimmune response following SARS-CoV-2 infection also presented with significantly high HbA1c (glycated hemoglobin) levels that indicated progression of an already set diabetes, rather than new-onset T1D. Here we review the potential underlying mechanisms behind loss of functional ß-cell mass as a result of SARS-CoV-2 infection that can trigger new-onset T1D.

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.

An Overview About Pediatric Type 1 Diabetes Mellitus

Background: Diabetes mellitus (DM) represents one of the most common metabolic diseases in the world, with rising prevalence in recent decades. Most cases are generally classified into two major pathophysiological categories: type 1 diabetes mellitus (DM1), which progresses with absolute insulin deficiency and can be identified by genetic and pancreatic islet autoimmunity markers, and type 2 diabetes mellitus (DM2), which is the most prevalent form and involves a combination of resistance to the action of insulin with an insufficient compensatory response of insulin secretion. In the last two decades, in parallel with the increase in childhood obesity, there has also been an increase in the incidence of DM2 in young people in some populations. Other forms of diabetes may affect children and adolescents, such as monogenic diabetes (neonatal diabetes, MODY – maturity onset diabetes of the young, mitochondrial diabetes, and lipoatrophic diabetes), diabetes secondary to other pancreatic diseases, endocrinopathies, infections and cytotoxic drugs, and diabetes related to certain genetic syndromes, which may involve different treatments and prognoses. DM1 is considered an immuno-mediated disease that develops as a result of gradual destruction of insulin-producing pancreatic beta cells that eventually results in their total loss and complete dependence on exogenous insulin. Clinical presentation can occur at any age, but most patients will be diagnosed before the age of 30 years