Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is characterised by inappropriate insulin secretion causing profound hypoglycaemia and brain damage if inadequately controlled. Pancreatic tissue isolated from patients with diffuse CHI shows abnormal proliferation rates, the mechanisms of which are not fully resolved. Understanding cell proliferation in CHI may lead to new therapeutic options, alongside opportunities to manipulate β-cell mass in patients with diabetes. We aimed to generate cell-lines from CHI pancreatic tissue to provide in vitro model systems for research. Three pancreatic mesenchymal stem cell-lines (CHIpMSC1-3) were derived from patients with CHI disease variants: focal, atypical and diffuse. All CHIpMSC lines demonstrated increased proliferation compared with control adult-derived pMSCs. Cell cycle alterations including increased CDK1 levels and decreased p27Kip1 nuclear localisation were observed in CHIpMSCs when compared to control pMSCs. In conclusion, CHIpMSCs are a useful in vitro model to further understand the cell cycle alterations leading to increased islet cell proliferation in CHI

Hydrogen Production via the Oxy-Steam Reforming of LNG or Methane on Ni Catalysts

Ni catalysts supported on ZrO2, 5%CeO2-ZrO2, and 5%La2O3-ZrO2 were prepared via the impregnation method and tested in the oxy-steam reforming of methane and liquified natural gas (LNG). All tested catalysts exhibited high catalytic activity in the studied process at 700 and 900 °C. The improvement of the stability of Ni catalysts after the addition of CeO2 oxide in the studied oxy-steam reforming of LNG process was confirmed. In addition, high activity and selectivity towards hydrogen was proven in the oxy-steam reforming process at 900 °C over a 20%Ni/5%CeO2-ZrO2 catalyst. It was also proved that the addition of CeO2 onto a ZrO2 carrier leads to a decrease in the NiO and metallic Ni crystallite sizes that were detected by the X-Ray diffraction (XRD) technique. The solid solution formation between NiO and ZrO2 and/or NiO and CeO2 was proved. Superior reactivity in the oxy-steam reforming of CH4 and the LNG process exhibited a 20%Ni/ZrO2 catalyst, which showed the highest methane conversions at 500 and 600 °C, equal to 63% and 89%, respectively. In addition, also in the case of the LNG reforming reaction, the most active catalyst was the 20%Ni/ZrO2 system, which demonstrated 46.3% and 76.9% of the methane conversion value at 500 and 600 °C and the total conversion of others hydrocarbons (ethane, propane and butane). In addition, this catalytic system exhibited the highest selectivity towards hydrogen formation in the oxy-steam reforming of the LNG reaction equal to 71.2% and 71.3% at 500 and 600 °C, respectively. The highest activity of this system can be explained by the uniform distributions of Ni species and their highest concentration compared to the rest of the monometallic Ni catalysts. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) results also confirmed a strong interaction of NiO with ZrO2 in the case of the 20%Ni/ZrO2 catalysts. The presence of selected NiZrO+ ions emitted from the investigated surface of the 20%Ni/ZrO2 system was detected

Correction: Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism.

[This corrects the article DOI: 10.1371/journal.pone.0222350.]

mTOR inhibitors for the treatment of severe congenital hyperinsulinism:perspectives on limited therapeutic success

Context: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited. Objective: We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI. Design, Setting, and Patients: This was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded. Main Outcome Measure(s): We examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy. Results: mTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas. Conclusion: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI. </jats:sec