Effects of dietary and pharmacological interventions on pancreatic β-cell compensation in Nile rats: a model for spontaneous type 2 diabetes

• Author / Creator

  Huang, Hui

• Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass, which is referred to as β-cell compensation. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms underlying β-cell compensation are not fully understood. The previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR), a model developing T2D naturally when fed with a standard lab chow diet (Chow). In the present study, I hypothesized that in addition to cell mass adaption, NR is an animal model that demonstrates β-cell functional compensation and decompensation during the development of T2D. The results showed that, compared to healthy NRs fed with a fiber-rich diet (Hfib), young Chow-fed NRs exhibited enhanced β-cell insulin secretion in response to insulin resistance that failed with aging, along with the onset of prediabetes and eventually T2D. I further hypothesized that the β-cell adaptive response is associated with increased insulin processing and β-cell replication. While both compensatory processes existed at 13 weeks of age, I observed increased proinsulin secretion in the transition from compensation to decompensation at 25 weeks, indicative of impaired insulin processing. Meanwhile, finding of correlations of ER chaperones with plasma insulin and glucose concentration demonstrated a positive role of ER chaperones in insulin secretion. Moreover, restricted β-cell proliferation and an increase in insulin-positive duct-associated β-cells were observed at the compensation stage, indicating a neogenic mechanism of β-cell mass adaptation. β-cells at decompensation stage showed less neogenic cell structures with evidence of dedifferentiation. In contrast, the pathophysiological abnormalities of β-cells were prevented by Hfib diet. Besides diet modification, I also proposed that the β-cell decompensation in NRs could be alleviated by pharmacological intervention. Metformin is a first line antidiabetic medication which is also effective in preventing T2D. I treated Chow NRs during the compensation stage with a relatively low dose of metformin (20mg/kg body weight). The results showed an improvement in glucose tolerance and insulin secretion after 7 weeks of treatment, while the impaired glucose tolerance and insulin sensitivity seen in Chow NRs at 25 weeks (6 months) were alleviated with metformin. The activation of AMPK and downregulated hepatic gluconeogenic pathway indicated suppression of glucose production by metformin. Additionally, due to increased glucose-stimulated insulin secretion in vivo, I further hypothesized that metformin affects β-cell function. β-cell secretion capacity was preserved in the metformin group, which was correlated with changes in glucose sensing genes, indicating a protective role for metformin in β-cell function. However, in vitro metformin treatment of islets failed to exert change in insulin secretion, suggesting an indirect mechanism underlying β-cell preservation in vivo.
  In summary, results of this study demonstrate a model of T2D showing β-cell compensation in insulin secretion and cell expansion, which is accompanied by adaptive changes in ER chaperones and β-cell neogenesis. Failure of β-cell compensation leads to diabetes progression. The disease progression and β-cell decompensation can be prevented by Hfib diet and delayed by early treatment with metformin.

• Subjects / Keywords

  • beta-cell
  • compensation
  • Type 2 diabetes
  • animal model

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-k2ba-fb05

• License

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