Type diabetes mellitus is characterised

Type 2 diabetes mellitus is characterised by two major features: peripheral insulin resistance and impaired insulin secretion from pancreatic beta dinaciclib [1]. The condition occurs when the pancreatic beta cells are unable to compensate for increased insulin demand due to insulin resistance in peripheral tissues [2]. Thus, insufficient insulin secretion is a central component in the pathophysiology not only of type 1 diabetes, but also of type 2 diabetes [3]. Given that one of the main causes of insulin deficiency is a reduction in pancreatic beta cell mass [[4], [5], [6]], its expansion could represent an ideal therapeutic approach in the treatment of diabetes [7,8]. Proliferation of existing beta cells is an important mechanism that promotes postnatal expansion of beta cell mass in humans and rodents [9,10]. Therefore, it is important to elucidate the mechanisms underlying beta cell proliferation for increased beta cell mass. Beta cell proliferation can be induced experimentally in postnatal mice by several methods, including high-fat (HF) diet feeding, partial pancreatectomy and pregnancy [[11], [12], [13], [14], [15]]. The mouse model of HF diet-induced beta cell proliferation has been widely used in research [16]. We [17] previously demonstrated that wild-type mice fed an HF diet for 20 weeks showed marked beta cell hyperplasia, whereas mice with beta cell-specific glucokinase haploinsufficiency (Gck+/−) exhibited reduced beta cell hyperplasia, decreased beta cell proliferation, and impaired upregulation of Irs2, despite having a similar degree of insulin resistance to wild-type mice. These results suggested that a combination of glucokinase and Irs2 is critical for beta cell proliferation to occur in response to 20 weeks of HF diet feeding [17,18]. However, it has been unclear whether beta cell proliferation in this model is triggered by the HF diet itself or by the sustained metabolic changes related to HF diet-induced insulin resistance. In recent years, beta cell proliferation induced by short-term HF diet feeding has been reported [[19], [20], [21]]. Stamateris et al. [19] found that beta cell proliferation began within the first 7 days of HF diet feeding, concurrent with the onset of metabolic changes. Mosser et al. [20] showed that HF diet feeding induced beta cell proliferation as early as 3 days after HF diet initiation, and that enhanced beta cell proliferation occurred without the development of insulin resistance. These findings prompted us to examine the hypothesis that the mechanisms mediating beta cell proliferation in response to short-term HF diet feeding might be different from those activated by long-term. In the present study, we investigated whether glucokinase and Irs2 were required for beta cell proliferation induced by short-term HF diet feeding, as has been shown in long-term HF diet.
Methods
Results
Discussion In the current study, we found that beta cell proliferation was induced by HF diet feeding for only 1 week in 8-week-old male C57Bl/6J mice. Body weight, fed blood glucose levels and visceral fat weight were higher in mice fed an HF diet for 1 week than in mice fed SC. However, the glucose-lowering effect of insulin was equivalent in both groups of mice. Thus, the initiation of beta cell proliferation coincided with the onset of increases in body and visceral fat weight and hyperglycaemia, but not with the onset of insulin resistance in this model. These data are in keeping with previous reports of beta cell proliferation induced by HF diet feeding for 1 week [19,20]. Although insulin resistance was assessed by insulin tolerance test in one of these previous investigations and in our current study [19], Mosser's group [20] confirmed the absence of insulin resistance by hyperinsulinemic euglycaemic clamps and measurements of alpha-hydroxybutyrate. Therefore, beta cell proliferation in this model is not caused by a compensatory response to HF diet-induced insulin resistance.