Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine induced cell death

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8, is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of wild-type and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, wild-type islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNFα, IFNγ, IL1β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in wild-type islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to wild-type islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.

Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells

Ac3IV (Ac-CYIQNCPRG-NH2) is an enzymatically stable vasopressin analogue that selectively activates Avpr1a (V1a) and Avpr1b (V1b) receptors. In the current study we have employed streptozotocin (STZ) diabetic transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, to evaluate the impact of sustained Ac3IV treatment on pancreatic islet cell morphology and transdifferentiation. Twice-daily administration of Ac3IV (25 nmol/kg bw) to STZ-diabetic Ins1Cre/+;Rosa26-eYFP mice for 12 days increased pancreatic insulin (p<0.01) and significantly reversed the detrimental effects of STZ on pancreatic islet morphology. Such benefits were coupled with increased (p<0.01) beta-cell proliferation and decreased (p<0.05) beta-cell apoptosis. In terms of islet cell lineage tracing, induction of diabetes increased (p<0.001) beta- to alpha-cell differentiation in Ins1Cre/+;Rosa26-eYFP mice, with Ac3IV partially reversing (p<0.05) such transition events. Comparable benefits of Ac3IV on pancreatic islet architecture were observed in STZ-diabetic GluCreERT2;ROSA26-eYFP transgenic mice. In this model, Ac3IV provoked improvements in islet morphology which were linked to increased (p<0.05-p<0.01) transition of alpha- to beta-cells. Ac3IV also increased (p<0.05-p<0.01) CK-19 co-expression with insulin in pancreatic ductal and islet cells. Blood glucose levels were unchanged by Ac3IV in both models, reflecting the severity of diabetes induced. Taken together these data indicate that activation of islet receptors for V1a and V1b positively modulates alpha- and beta-cell turnover and endocrine cell lineage transition events to preserve beta-cell identity and islet architecture.

Etiology, Assessment and Management of WDHA (Watery Diarrhea, Hypokalemia, and Achlorhydria) and VIPoma

The syndrome of watery diarrhoea, hypokalemia, and achlorhydria (WDHA syndrome) is an uncommon disorder marked by severe, watery diarrhoea caused by non–beta pancreatic islet cell oversecretion of vasoactive intestinal peptide (VIP). The onset of the disease is gradual, and diagnosis is often months or years later. Long-term dehydration, electrolyte and acid-base abnormalities, and chronic renal failure are all linked to morbidity. Pancreatic endocrine tumours are extremely rare, with less than 10 incidences per million people. VIPomas are uncommon tumours that affect between 0.05 and 2.0 percent of people. The most prevalent symptom is diarrhoea, which affects at least 89 percent of patients. VIPoma is treated with a combination of medicine and surgery The goal of first medical treatment is to reduce symptoms and restore fluids and electrolytes as quickly as possible

Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers

High throughput sequencing has enabled the interrogation of the transcriptomic landscape of glucagon-secreting alpha cells, insulin-secreting beta cells, and somatostatin-secreting delta cells. These approaches have furthered our understanding of expression patterns that define healthy or diseased islet cell types and helped explicate some of the intricacies between major islet cell crosstalk and glucose regulation. All three endocrine cell types derive from a common pancreatic progenitor, yet alpha and beta cells have partially opposing functions, and delta cells modulate and control insulin and glucagon release. While gene signatures that define and maintain cellular identity have been widely explored, the underlying epigenetic components are incompletely characterized and understood. Chromatin accessibility and remodeling is a dynamic attribute that plays a critical role to determine and maintain cellular identity. Here, we compare and contrast the chromatin landscape between mouse alpha, beta, and delta cells using ATAC-Seq to evaluate the significant differences in chromatin accessibility. The similarities and differences in chromatin accessibility between these related islet endocrine cells help define their fate in support of their distinct functional roles. We identify patterns that suggest that both alpha and delta cells are poised, but repressed, from becoming beta-like. We also identify patterns in differentially enriched chromatin that have transcription factor motifs preferentially associated with different regions of the genome. Finally, we identify and visualize both novel and previously discovered common endocrine- and cell specific- enhancer regions across differentially enriched chromatin.

Tumour-Not So Sweet, Tumour-Induced Hypoglycemia: A Rare Case of Refractory Hypoglycemia in a Toddler

Tumour-induced hypoglycaemia is a rare complication/condition mainly seen in adults. It is caused due to increased production of insulin or insulin-like growth factor (IGF) 2 tumour cells. We present a 3-year-old paediatric patient with non-islet cell tumour induced hypoglycaemia (NICTH) secondary to rhabdomyosarcoma. She presented with abdominal mass and refractory hypoglycaemia, requiring high glucose infusion and steroids. Critical sample analysis during hypoglycaemia showed suppression of insulin, IGF-1, C-peptide, growth hormone, and ketones, with a high cortisol level. CT scan of abdomen and pelvis showed a huge retroperitoneal mass, later diagnosed as rhabdomyosarcoma. In a resource-limited setting, where IGF-2 is not possible, low serum insulin and IGF-1 levels during hypoglycaemia aids in diagnosis of NICTH. This is one of the first few reported paediatric cases with NICTH from India, and we believe that reporting this case would add more information to the existing literature. Thus, NICTH should be suspected in all malignancies presenting with intractable hypoglycaemia irrespective of their age.