Gastrointestinal System Involvement in Pediatric Patients with Acute SARS-CoV-2 Infection.

Objective: The prevalence of gastrointestinal symptoms in coronavirus disease-2019 (COVID-19) has been reported widely. In this study, the prevalence of gastrointestinal system (GIS) involvement in pediatric COVID-19 and its effect on prognosis were investigated. Methods: Children (aged 0-18 years) with acute COVID-19 were included in the study. The patients were grouped according to system involvement: isolated respiratory system (RS), isolated GIS, and combination of both (RS+GIS). These groups were compared in terms of demographic data, clinical characteristics, laboratory and imaging findings, and hospitalization. Results: A total of 223 pediatric patients were included in the study. Of these patients, 19 were asymptomatic, 12 were diagnosed with a multisystem inflammatory syndrome in children, 21 had chronic disorders that may affect disease severity, and 27 had symptoms not related to RS or GIS. The remaining 144 patients were classified according to system involvement: 79 (35.4%), 14 (6.3%), and 51 (22.9%) had isolated RS, isolated GIS, and RS+GIS involvement, respectively. The GIS group was much younger than the RS group (median, 30 and 150 months, respectively, p=0.006). Three patients from the RS group were followed in the intensive care unit (ICU). Moreover, 17 (21.5%) and 4 (7.8%) patients from the RS group had severe-critical respiratory symptoms, in the RS+GIS group had severe-critical respiratory symptoms (p=0.039). Conclusions: Our study showed that GIS involvement in children with COVID-19 is more prevalent than RS involvement in the younger age group. Respiratory symptom severity and ICU admission also decreased with accompanying GIS involvement. GIS involvement was still associated with a milder disease course after adjustment for age.

Fumarate Hydratase Deletion in Pancreatic ß Cells Leads to Progressive Diabetes.

We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic ß cells (Fh1ßKO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1ßKO mice led to dysregulated metabolism in ß cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1ßKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.

A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia.

The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.