Impact of fetal and neonatal environment on beta cell function and development of diabetes.

The global epidemic of diabetes is a serious threat against health and healthcare expenses. Although genetics is important it does not explain the dramatic increase in incidence, which must involve environmental factors. Two decades ago the concept of the thrifty phenotype was introduced, stating that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes. As the pancreatic beta cells are crucial in the regulation of metabolism this article will describe the influence of normal pregnancy on the beta cells in both the mother and the fetus and how various conditions like diabetes, obesity, overnutrition and undernutrition during and after pregnancy may influence the ability of the offspring to adapt to changes in insulin demand later in life. The influence of environmental factors including nutrients and gut microbiota on appetite regulation, mitochondrial activity and the immune system that may affect beta cell growth and function directly and indirectly is discussed. The possible role of epigenetic changes in the transgenerational transmission of the adverse programming may be the most threatening aspect with regard to the global diabetes epidemics. Finally, some suggestions for intervention are presented.

A critical role for CK2 in cytokine-induced activation of NFκB in pancreatic ß cell death.

This study aimed to assess the role of constitutive protein kinase CK2 in cytokine-induced activation of NFκB in pancreatic ß cell death. The CK2 inhibitors DRB (5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole) (50 µM) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) (5 µM), which decreased CK2 activity by approx. 65 %, rescued INS-1E ß cells and mouse islets from cytokine (IL-1ß, TNF-α plus IFN-γ)-induced ß cell death without affecting H2O2- or palmitate-induced ß cell death. Western blot analysis revealed that while DRB or DMAT did not influence cytokine-induced IκBα degradation, they inhibited NFκB-dependent IκBα resynthesis, demonstrating that cytokine-induced NFκB activity is dependent on CK2. Both DRB and DMAT inhibited the constitutive phosphorylation of NFκB p65 at serine 529, while leaving cytokine-induced phosphorylations of NFκB p65 at serines 276 and 536 unaltered. In comparison, putative phosphorylation sites for CK2 on HDACs 1, 2, and 3 at serines 421/423, 394, and 424, respectively, which may stimulate NFκB transcriptional activity, were unchanged by cytokines and CK2 inhibitors. Whereas IL-1ß and TNF-α stimulate IκBα degradation and NFκB activation, IFN-γ potentiates cytokine-induced ß cell death through activation of STAT1. DRB and DMAT inhibited IFN-γ-stimulated phosphorylation of STAT1 at serine 727, while leaving IFN-γ-induced phosphorylation of STAT1 at tyrosine 701 unaffected. Inhibition of cytokine-induced ß cell death by CK2 inhibitors was, however, not dependent on IFN-γ, and IFN-γ did not affect CK2-dependent IκBα turnover. In conclusion, it is suggested that cytokine-induced activation of NFκB in ß cells is dependent on CK2 activity, which phosphorylates NFκB p65 at serine 529.