Transplantation of cadaveric human islets can restore insuli

Transplantation of cadaveric human islets can restore insulin-independence in patients with type 1 diabetes (Shapiro et al., 2000; Ryan et al., 2001), but this approach has not been actively pursued for type 2 diabetes, likely due to the inadequate supply of donor islets, risk of immunosuppression, and perceived hurdle of insulin resistance. The obstacle of an insufficient cell supply may be overcome with the use of human embryonic stem cells (hESCs). We previously demonstrated that hESC-derived pancreatic progenitor cells reversed hyperglycemia in a mouse model of type 1 diabetes characterized by severe beta cell destruction and insulin deficiency (Rezania et al., 2012, 2013; Bruin et al., 2013). However, the efficacy of this stem cell-based therapy for treating hyperglycemia in an obesogenic and insulin-resistant environment, such as in type 2 diabetes, has not been reported. Based on evidence that intensive insulin therapy improves insulin sensitivity, glycemic control, and beta cell function in patients with type 2 diabetes (Weng et al., 2008; Kramer et al., 2013), we hypothesized that hESC-derived insulin-secreting cells may also be effective for this patient population. Our first aim was to establish a model of type 2 diabetes in immunodeficient mice that would be compatible with xenotransplantation. Different strains of rodents have widely variable susceptibility to high-fat diet (HFD)-induced obesity and/or hyperglycemia (Srinivasan and Ramarao, 2007; Svenson et al., 2007; Hariri and Thibault, 2010). Moreover, insulin resistance, a hallmark feature of type 2 diabetes (Kahn et al., 2006), is thought to be driven primarily by obesity-associated inflammation (reviewed in Kalupahana et al., 2012; Osborn and Olefsky, 2012), and recruitment of T cells (Feuerer et al., 2009; Nishimura et al., 2009; Winer et al., 2009) and hematoxylin (Winer et al., 2011) to insulin-sensitive tissues. SCID-beige mice are a spontaneous double-mutant model in which the scid mutation results in a lack of both T and B lymphocytes, and the beige mutation causes defects in cytotoxic T cells, macrophages, and NK cells (http://www.taconic.com). To our knowledge, the susceptibility of double-mutant SCID-beige mice to HFDs has not previously been examined as a potential model of type 2 diabetes. An important consideration in translating a stem cell-derived pancreatic progenitor therapy to clinical practice is the variability that will be encountered within the patient environment during the period of cell engraftment and maturation in vivo. This is particularly relevant given that macroencapsulated hESC-derived pancreatic progenitor cells are now being tested for safety, tolerability, and efficacy in a phase 1/2 clinical trial by Viacyte (ClinicalTrials.gov, Identifier: NCT02239354). We hypothesized that exposure to HFDs may impair the development of hESC-derived insulin-secreting cells, since obesity-associated lipotoxicity and inflammation contribute to beta cell dysfunction in patients with type 2 diabetes (reviewed in Potter et al., 2014). Furthermore, both human and rodent islets displayed beta cell dysfunction following transplant into HFD-fed rodents (Hiramatsu and Grill, 2001; Gargani et al., 2013). Here, we examined the impact of HFDs on hESC-derived progenitor cell development in vivo, and assessed whether a stem cell-based insulin therapy could improve glycemic control in mice with diet-induced obesity, insulin resistance, and hyperglycemia. We also investigated the efficacy of combining the cell therapy with one of three antidiabetic drugs: sitagliptin (a dipeptidyl peptidase-4 [DPP4 inhibitor]), metformin (suppresses hepatic gluconeogenesis and enhances insulin sensitivity), and rosiglitazone (a PPARγ agonist from the thiazolidinedione [TZD] class). Our studies demonstrated that a combination therapy was more effective in HFD-fed mice than either antidiabetic drugs or progenitor cell transplants alone. Moreover, neither HFDs nor antidiabetic drugs impacted the ability of hESC-derived cells to mature in vivo and appropriately secrete insulin in response to glucose.