Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk.

While pancreatic beta-cell proliferation has been extensively studied, the role of cell death during islet development remains incompletely understood. Using a genetic model of caspase inhibition in beta cells coupled with mathematical modeling, we here discover an onset of beta-cell death in juvenile zebrafish, which regulates beta-cell mass. Histologically, this beta-cell death is underestimated due to phagocytosis by resident macrophages.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system.

Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells.

Enteroviral infections are not associated with type 2 diabetes.

Introduction: For more than a century, enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D). Uncontrolled viral response pathways repeatedly presented during childhood highly correlate with autoimmunity and T1D. Virus responses evoke chemokines and cytokines, the "cytokine storm" circulating through the body and attack cells especially vulnerable to inflammatory destruction.

Correction: Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes.

[This corrects the article DOI: 10.1371/journal.pone.

Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix?

Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy.

Correction: UCP-2 and UCP-3 Proteins Are Differentially Regulated in Pancreatic Beta-Cells.

[This corrects the article DOI: 10.1371/journal.pone.

Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer.

A critical decline of functional insulin-producing pancreatic β-cells is the central pathologic element of both type 1 and type 2 diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key mediator of β-cell failure and the identification of neratinib as MST1 inhibitor with potent effects on β-cell survival represents a promising approach for causative diabetes therapy. Here we report a case of robust glycemia and HbA1c normalization in a patient with breast cancer-T2D comorbidity under neratinib, a potent triple kinase inhibitor of HER2/EGFR and MST1.

PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes.

The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis.

MST1 deletion protects β-cells in a mouse model of diabetes.

The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic β-cell mass as a result of improved β-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of β-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced β-cell mass and improved insulin secretion without changes in insulin sensitivity.

How β cells can smell insulin fragments.

In this issue of Cell Metabolism, Cheng et al. identify olfactory receptor Olfr109 in β cells with increased expression in islets from mouse models of obesity and type 1 and type 2 diabetes. Binding of a small insulin fragment to Olfr109 fosters islet inflammation, β cell failure, and diabetes progression.

Deathly triangle for pancreatic β-cells: Hippo pathway-MTORC1-autophagy.

A progressive decline in the macroautophagic/autophagic flux is a hallmark of pancreatic β-cell failure in type 2 diabetes (T2D) but the responsible intrinsic factors and underlying molecular mechanisms are incompletely understood. A stress-sensitive multicomponent cellular loop of the Hippo pathway kinase LATS2 (large tumor suppressor 2), MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) and autophagy regulates β-cell survival and metabolic adaptation. Chronic metabolic stress leads to LATS2 hyperactivation which then induces MTORC1, subsequently impairing the cellular autophagic flux and consequently triggering β-cell death.

Localization of enteroviral RNA within the pancreas in donors with T1D and T1D-associated autoantibodies.

Enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D), but reliable methods to ascertain localization of single infected cells in the pancreas were missing. Using a single-molecule-based fluorescent hybridization (smFISH) method, we detected increased virus infection in pancreases from organ donors with T1D and with disease-associated autoantibodies (AAb). Although virus-positive β cells are found at higher frequency in T1D pancreases, compared to control donors, but are scarce, most virus-positive cells are scattered in the exocrine pancreas.

The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis.

Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development.

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.

Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes.

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells.

GLP-2 Is Locally Produced From Human Islets and Balances Inflammation Through an Inter-Islet-Immune Cell Crosstalk.

Glucagon-like peptide-1 (GLP-1) shows robust protective effects on β-cell survival and function and GLP-1 based therapies are successfully applied for type-2 diabetes (T2D) and obesity. Another cleavage product of pro-glucagon, Glucagon-like peptide-2 (GLP-2; both GLP-1 and GLP-2 are inactivated by DPP-4) has received little attention in its action inside pancreatic islets. In this study, we investigated GLP-2 production, GLP-2 receptor (GLP-2R) expression and the effect of GLP-2R activation in human islets.

LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes.

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult β-cell within the pancreatic islets. The repression of LDHA under normal physiological condition and its inappropriate upregulation under a diabetogenic environment is well-documented in rodent islets/β-cells but little is known about LDHA expression in human islet cells and whether its abundance is altered under diabetic conditions.

Enteroviruses and T1D: Is It the Virus, the Genes or Both which Cause T1D.

Type 1 diabetes (T1D) is a chronic autoimmune disorder that results from the selective destruction of insulin-producing β-cells in the pancreas. Up to now, the mechanisms triggering the initiation and progression of the disease are, in their complexity, not fully understood and imply the disruption of several tolerance networks. Viral infection is one of the environmental factors triggering diabetes, which is initially based on the observation that the disease's incidence follows a periodic pattern within the population.

STRIPAK Is a Regulatory Hub Initiating Hippo Signaling.

Signaling modules that integrate the diverse extra- and intracellular inputs to the Hippo pathway were previously unknown. By biochemical and molecular interrogation, Chen et al. established a molecular framework, the RhoA-RHPN-NF2/Kibra-STRIPAK axis, that regulates the status of Hippo core kinases and connects upstream signals to initiate and orchestrate the Hippo pathway.

Lung Surfactant Accelerates Skin Wound Healing: A Translational Study with a Randomized Clinical Phase I Study.

Lung surfactants are used for reducing alveolar surface tension in preterm infants to ease breathing. Phospholipid films with surfactant proteins regulate the activity of alveolar macrophages and reduce inflammation. Aberrant skin wound healing is characterized by persistent inflammation.