Jetton Lab Research
Dr. Jetton's research has focused on the physiological integration of tissues that govern glucose homeostasis and adaptive pancreatic islet ß-cell growth and function. Our current studies are concentrated on neural and dietary regulation of ß-cell mass homeostasis.
Pancreatic “islets” are richly vascularized "micro-organs" consisting of aggregates of at least five distinct peptide hormone-secreting cell types dispersed throughout the exocrine pancreas. Their principal function is blood glucose regulation. ß-cells have a significant capacity to compensate for increased insulin demands in response to somatic growth, pregnancy, normal periods of insulin resistance (e.g., puberty and aging), and pathological insulin resistance often associated with poor diet and lack of exercise. ß-cells compensate to the increased insulin requirements by enhancing their secretion of insulin and increasing their mass via several growth mechanisms. A failure of these adaptive mechanisms leads to type 2 diabetes, whereas autoimmune destruction of ß-cells underlies type 1 diabetes.
The steady state ß-cell mass is determined by a dynamic balance of cell recruitment (via proliferation,"neogenesis," and transdifferentiation), individual cell growth (hypertrophy), and cell death and clearance via apoptosis. In rodent models we have established that
- ß-cell neogenesis (newly differentiated cells) occurs from pancreatic exocrine tissue and contributes significantly to rapidly increased ß-cell mass, and can be the prime means of short-term ß-cell growth as opposed to proliferation of pre-existing ß-cells
- the insulin receptor signaling cascade via protein kinase B/Akt and CREB is a central mediator of ß-cell growth and survival processes
- the vagus nerve conveys growth and survival signals to ß-cells
- ß-cell α7nAChRs function to maintain ß-cell mass homeostasis through modulating islet cytokine and PI3-kinase dependent signaling pathways
Our work has bearing on the future development of strategies to increase functional ß-cell mass in patients with diabetes. There is substantial interest in ß-cell replacement strategies for the future management of insulin-dependent diabetes. These strategies will require amplification of pancreatic islet tissue in vitro or ex vivo for transplantation, inducing new islet tissue by stimulating their growth within the patient, or pharmacologic manipulations to improve ß-cell function and survival while also curtailing immune destruction.
We use a wide variety of complementary analytical techniques including
- multiple-labeling immunofluorescence, confocal microscopy, electron microscopy, and laser capture microdissection
- morphometry and subcellular image analyses
- immunochemistry (immunoblot/ELISA) and quantitative PCR
- metabolic studies and whole-body measurements of glucose homeostasis