β cell dysfunction is the leading cause of diabetes. Adult β cells have matured glucose-stimulated insulin secretion (GSIS), whereas fetal and neonatal β cells are insensitive to glucose and are functionally immature. However, how β cells mature and acquire robust GSIS is not fully understood. Here, we explored the potential regulatory proteins of β cell maturation process and the capacity for GSIS. Combined with the data from public databases, we found that the gene expression of Mitofusin2 (Mfn2) showed an increasing trend from mouse neonatal β cells to mature β cells. Moreover, its protein expression increased during mouse embryonic pancreas development and β cell differentiation from mouse embryonic stem cells. Knocking down Mfn2 reduced Urocortin3 (Ucn3) expression, GSIS, and ATP production in induced β cells, while overexpressing it had the opposite effect. However, neither Mfn2 knockdown nor overexpression affected the differentiation rate of insulin-positive cells. In immature and mature β cells, Mfn2 and its correlated genes were enriched in tricarboxylic acid (TCA) cycle-related pathways. The expressions of Sirtuin 3 (Sirt3) and isocitrate dehydrogenase 2 (NADP+) and mitochondrial (Idh2) were Mfn2-regulated during β cell differentiation. Inhibiting Idh2 or Sirt3 reduced cellular ATP content and insulin secretion levels that increased by Mfn2 overexpression. Thus, Mfn2 modulated the induced β cell GSIS by influencing the TCA cycle through Sirt3/Idh2 activation. We demonstrated that Mfn2 promoted embryonic stem cell-derived β cell maturation via the Sirt3/Idh2 pathway, providing new insights into β cell development. Our data contribute to understanding diabetes pathogenesis and offer potential new targets for β cell regeneration therapies.

A 44-year-old hypertensive male was admitted with a type A aortic dissection originating just above the aortic valve and involving the innominate, left subclavian, left renal, and bilateral iliac arteries. The celiac, superior mesenteric, and splenic arteries were not involved in the dissection. An echocardiogram revealed an aortic root diameter of 4.7 cm with moderate aortic insufficiency due to aortic valve prolapse. At the time of surgery, cardiopulmonary bypass was established with right axillary artery and right atrial cannulation. The aortic root and ascending aorta were replaced with a #25 Carbomedics composite conduit (Sorin Group Italia S.R.L., Milan, Italy). The aortic specimen showed no evidence of any connective tissue disease. During the postoperative period, the patient developed acute renal failure which required institution of continuous renal replacement therapy. On the 10th postoperative day, the patient became hypotensive and developed midepigastric pain, hematemesis, and bloody stools. His hematocrit decreased from 12.2 to 4.5 g/dL and his international normalized ratio was 2.3. Coumadin was discontinued and vitamin K and fresh frozen plasma were administered. He continued to have hematemesis and gastroscopy showed active bleeding from a 3.5 × 4.0 cm mass in the posterior wall of the gastric fundus (Figure 1). An abdominal computed tomography scan showed no gastric mass, but instead, revealed an enlarged spleen (135.47 × 43.49 × 110 mm 3 postop vs 98.38 × 33.92 × 93.50 mm 3 preop), with the upper pole compressing the posterior wall of the gastric fundus creating a mass-like effect (Figure 2). These findings were confirmed at the time of laparotomy and a splenectomy and partial gastrectomy was performed. FIGURE 1The gastroscopy showed the mass was at the posterior wall of the fundus, 3.5 cm × 4 cm. There was extravasated blood surrounding the mass J Card Surg. 2018;33:853-854.wileyonlinelibrary.com/journal/jocsThe pathology showed no evidence of any gastric tumor or splenic emboli or ischemic changes other than congestion. The splenic artery had no evidence of dissection. The patient tolerated the procedure well and was subsequently discharged on coumadin without any further hematemesis.