## 1 Introduction  
Type 1 diabetes (T1D) is a chronic autoimmune disease leading to the complete destruction of insulin-producing beta cells. Clinical studies have shown that islet cell transplantation is an effective treatment option in some patients with T1D. However, the clinical application of pancreas and islet cells transplantation is limited by the shortage of organ donors and problems in the isolation of large numbers of high quality islets from organ donors [1].  
Porcine islets are a promising source for islet cell replacement therapies due to the high similarity in the regulation of glucose homeostasis as compared to human islets, the unlimited availability and the novel molecular techniques to generate less immunogenic porcine tissues by genetic engineering of donor pigs [2; 3; 4]. Previous studies have demonstrated that pancreata from neonatal, pre-weaning piglets have several advantages over adult pigs, including an easier isolation process to yield high quality islets and lower costs [5; 6; 7]. Neonatal porcine islets-like clusters (NPICCs) are immature with respect to glucose-stimulated insulin secretion (GSIS), and display some characteristics of islet progenitor cells. After transplantation, NPICCs from young piglets need 4-12 weeks to restore normoglycemia and normal glucose tolerance in immunocompromised diabetic mice [8; 9]. It is thought that this spontaneous maturation process includes differentiation of islet and ductal progenitor cells into endocrine cells as well as beta cell proliferation [10; 11]. How to improve and accelerate this postnatal differentiation is still poorly understood.  
Further improvements of culture conditions after NPICC isolation are necessary to get more insight into the regulatory mechanisms involved in beta cell maturation in order to optimize the cell product for NPICC transplantation. Positive effects on in vitro maturation have been described by treatment with glucagon-like peptide 1 (GLP-1) and cholecyst-tokinin [12], exendin-4 [11; 13], a combination of insulin-like-growth factor-1, foetal calf serum and sodium butyrate [14], and prolongation of the culture period up to 12 days [15]. Several studies have shown that some short-chain fatty acids (SCFAs, chain length of one to five carbon atoms) directly promote the survival and function of beta cells. It has been reported that acetate and propionate increased GSIS in mouse and human islets [16; 17], whereas other studies found an inhibition of GSIS in mouse and rat islets by propionate [18; 19; 20]. Recently, no significant effects of acetate and propionate on insulin and glucagon secretion were detected using the perfused mouse pancreas model [21]. In a perfusion model, butyrate significantly suppressed insulin secretion at high but not at low glucose concentrations [21]. These conflicting results suggest that acetate, propionate and butyrate may have differential effects on different islet cell types. In addition, it is possible that interspecies differences exist between human and rodent islets. Metabolic studies using SCFAs and porcine islets are not available thus far.  
In the present study, we investigated the potential of SCFAs to optimize NPICC culture conditions and promote differentiation of islets into insulin-positive porcine beta cells. We found that butyrate and specific inhibitors of histone deacetylases (HDAC) significantly upregulated insulin gene and protein expression, suggesting that butyrate treatment may be useful to enhance beta cell maturation and increase beta cell mass.