Susanne Michelle Clee
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Graduate Student Supervision
Master's Student Supervision (2010 - 2018)
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.
Novel inbred mouse strains have been developed from wild-caught mice, and they display enhanced genetic diversity compared to the commonly used strains. We hypothesized that their unique genotypes may yield aspects of disease susceptibility previously unobserved in the commonly used strains. We examined two of these strains, PWD/PhJ (PWD) and WSB/EiJ (WSB), for obesity and type 2 diabetes (T2D)-related traits in response to high fat diet (HFD) feeding and compared them to the C57BL/6J (B6) strain. We identified PWD mice as a model of primary hyperinsulinemia. They had increased insulin levels at a young age while they were lean and insulin sensitive. They were protected from early development of diet-induced obesity, although they later developed obesity similar to B6 mice that may be induced by chronic hyperinsulinemia. PWD mice are a novel model of primary hyperinsulinemia as a cause of obesity. WSB mice are a model of extraordinary resistance to HFD-associated obesity and T2D. They have a higher energy expenditure that may have contributed to their protection from HFD-induced obesity. PWD and WSB mice modeled novel aspects of disease susceptibility and are interesting models for further study to determine the mechanisms associated with the pathogenesis of obesity and T2D.