Indeed, landmark studies by Clark, Cnop, and colleagues uncover that human cells and cells may also be very long lived (24, 25). diabetes results from autoimmune destruction of pancreatic cells, which decreases the total number of cells capable of secreting insulin and other Coumarin 7 hormones (1). Normal glucose homeostasis becomes disrupted in type 1 diabetes as a result of gradual reduction in cell mass and subsequent failure of the residual insulin-secreting cells to compensate. Traditional views of type 2 diabetes pathophysiology centered on resistance to peripheral insulin action as the primary driver of altered glucose homeostasis, informed by early observations of insulin resistance in type 2 diabetes (2). Defective cell function is another early hallmark of type 2 diabetes; abnormalities in insulin secretion have been documented in some individuals many years before the onset of overt type 2 diabetes (3, 4), and many have concluded that insufficient cell function also plays a central role in type 2 diabetes pathophysiology (5, 6). In the end, increased insulin demand combined with defective insulin secretion results in cells that are unable to adequately compensate for increased metabolic demand. Insufficient insulin secretion leads to ambient hyperglycemia, which worsens cell function and ultimately leads to a downward spiral of impaired Coumarin 7 glucose homeostasis and frank type 2 diabetes. Thus, insufficient cell function is a central component in Coumarin 7 the pathophysiology of both types of diabetes. cell regeneration as an antidiabetic therapeutic strategy cell replacement strategies have historically focused on transplantation of islets or engineered insulin-secreting cells, but have lately broadened to include studies aimed at regeneration of endogenous cell function. Recent developmental biology studies revealed that the vast majority of adult cells are derived from other cells in mice (7C9). This observation reinvigorated studies on mature cells, in the hope that such work would lead to the development of novel antidiabetes therapies (10), assuming that the underling cause of cell loss could be somehow overcome. However, substantial challenges remain to create safe and durable clinical therapies that robustly regenerate cell function. Cell selectivity is a notable concern, as some putative cell mitogenic signals may also promote growth of other cells. For example, the glucagon-like peptide receptor signals, which are putative cell regenerative signals, may also activate calcitonin-producing parafollicular cells (C cells) of the medullary thyroid (11). Aging impairs human cell function Age-associated deteriorations in cell function may contribute to type 2 diabetes risk (Figure ?(Figure1).1). The vast majority of patients diagnosed with the disease are in the fifth and sixth decades of life (12). The prevalence of gestational Coumarin 7 diabetes, which is closely related to type 2 diabetes, is similarly increased in mothers of advanced age (13). Moreover, islets from aged donors result in worse transplantation outcomes compared with those from young Coumarin 7 donors (14). Studies in humans suggest that aging may independently impair cell function (15C18). The mechanism of age-related cell dysfunction is difficult to discern, in that aging may exert a distinct influence on human cell turnover as well as function (Table ?(Table1).1). Indeed, Donath and colleagues report that islets from aged human donors have Rabbit Polyclonal to SRPK3 reduced amounts of cell turnover compared with those from younger donors (19). Open in a separate window Figure 1 Proposed model of cell regeneration capacity.Basal cell replication capacity continuously decreases from early adulthood to middle age. As basal cell replication drops to very low levels, adaptive capacity is greatly decreased. Table 1 Cell turnover Open in a.