| Summary: | The pancreatic beta-cell is the sole arbiter of the production and secretion of insulin, a hormone that is necessary for the storage of soluble circulating nutrients such as monosaccharides, amino acids, and fatty acids, as insoluble energy-rich macromolecules such as glycogen, proteins, and triglycerides. The production and secretion of insulin is tightly regulated by the circulating glucose concentration, and is thus normally matched to maintain glycemia in a tight physiological window. The evolution of mammals was characterized by oscillating periods of famine and feasting, and as such we have evolved mechanisms to protect against starvation. During energy replete conditions, insulin is remarkably effective at facilitating the storage of surplus nutrients However, modern Western man rarely experiences starvation, and our exceptional ability to store excess nutrients has catalyzed one of the most preventable and widespread global epidemics, obesity-linked type 2 diabetes mellitus (T2DM). Insulin insufficiency to manage glycemia is a hallmark of insulin resistance and obesity-linked T2DM and it has been frequently assumed that a defect in insulin secretory capacity as well as decreased insulin production both contribute to the inability of the beta-cell to properly manage glycemia during the progression of T2DM. Ultimately, these beta-cells will fail as a consequence of the combined stressors related to the pathology of the disease. However, insulin production during obesity-linked T2DM has not been assessed, and it remains unclear if the dysfunctions driving beta-cell demise are causal to the pathogenesis of T2DM or simply reflective of an overworked beta-cell population attempting to meet metabolic demand.
The present work proposes that the beta-cell is capable rapidly adjusting the rate of proinsulin biosynthesis in response to changes in metabolic demand, and that drastic changes in whole-cell morphology cater to these changes. We also propose that the 'dysfunctional' phenotype commonly associated with beta-cells in early T2DM is, in fact, fully functional and is simply reflective of increased proinsulin biosynthesis. To address this central hypothesis, this work is divided into two interrelated chapters that investigate the in vivo and in vitro beta-cell response to: 1) the evolutionarily relevant challenge of prolonged fasting and subsequent refeeding and 2) the epidemiologically relevant challenge of obesity-mediated hyperglycemia.
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