Factors contributing to altered insulin levels of PWD/PhJ and WSB/EiJ wild-derived inbred mice

Insulin is a key hormone in the regulation of blood glucose. Type 2 diabetes (T2D) results from insufficient insulin-producing β cells in pancreatic islets or insufficient insulin secretion to maintain glucose homeostasis. Genetic variability is a major factor affecting type 2 diabetes (T2D) development. Two inbred mouse strains derived from wild caught mice, PWD/PhJ (PWD) and WSB/EiJ (WSB), have novel genetic variation relative to the classically-studied mice, C57BL/6J (B6), which will assist genetic studies. PWD and WSB mice exhibit high and low insulin levels, respectively, without insulin resistance and obesity. The goal of this thesis was to investigate potential mechanisms behind the altered insulin levels of the PWD and WSB mice. We found evidence that factors affecting the insulin secretion pathway were altered in PWD mice. Specifically, these affect insulin secretion stimulated by nutrients, with possibly a minor factor affecting steps downstream of cell depolarization. These could contribute to the high insulin levels in PWD mice compared to B6 mice. There were no differences between PWD and B6 mice in islet structure or β cell mass. For WSB mice, we found their pancreas and islets fail to grow after birth compared to B6 mice. This may contribute to their low insulin levels at later ages. However, WSB mice also exhibited low insulin levels at young age when their β cell mass was still similar to B6 mice. Their insulin secretion pathway was investigated. Surprisingly, while WSB mice exhibited low insulin levels in in vivo secretion studies, they secreted high insulin levels in in vitro studies. Thus WSB mice may also have physiological differences evident in vivo that reduce their insulin secretion. The physiological mechanisms for the altered insulin levels of these strains are regulated by their genetic factors. This suggests that discovery of these novel genetic factors could provide new insights into processes that regulate insulin levels that may help lead to novel treatments T2D.Medicine, Faculty ofGraduat