| Biography: Dr. Josephine Egan is a board certified endocrinologist who received her endocrine training at the University of Virginia, Charlottesville. She has been with the NIA since July, 1990. Her early work related to investigating and quantitating insulin release from individual beta cells in the islets of Langerhans. Using this methodology, she outlined the abnormalities that occur in the aging beta cells of rats. More recently she has been working on ways to reverse these abnormalities, on ways to increase insulin secretion in Type 2 diabetes mellitus and on outlining the growth factors involved in beta cell replication. |
| Aging and Type 2 Diabetes: : Our section studies insulin secretion and beta cell function because it is a challenging and relevant scientific area of investigation. Diabetes is a very contemporary health problem that affects 16 million Americans. Ten percent of these individuals suffer from an absolute deficiency of insulin (type 1 diabetes), and the rest are diabetic because their beta cells do not provide an adequate amount of circulating insulin (type 2 diabetes). Patients with diabetes encounter a number of life threatening illnesses, so effective treatment of this disorder is a highly desired goal. As the prevalence of type 2 diabetes continues to increase with increasing age, understanding the pathogenesis of this disease is also highly relevant to the mission of our Institute. An in-depth understanding of what controls beta cell function and mass might reveal new therapeutic possibilities to prevent diabetes and/or treat patients with type 2 and type 1 diabetes. |
| Design of Drugs for Treating Type 2 Diabetes: Insulinotropic peptides are synthesized in enteroendocrine cells of the gut. When food is eaten, they are secreted into the blood stream, resulting in their increased concentrations in plasma. The two best described insulinotropic peptides are GLP-1 and GIP, sometimes collectively referred to as incretins. Often binding of incretins to their specific receptors on beta cells increases insulin release. GLP-1 maintains insulinotropic activity in type 2 diabetes and analogs of GLP-1 as well as agonists of the GLP-1 receptor are under development as treatments for diabetes. One such agonist, xendin-4, was given for 31 days to type 2 diabetic patients in a study by the NIA. Most recently we have been involved in studies of GIP physiology. Clinical work by other groups have shown that GIP is not an effective insulinotropic agent in type 2 diabetes. We have developed a more potent and longer-lasting GIP analog, which we are currently testing in a randomized double-blind clinical trial, again sponsored by the NIA, in type 2 diabetic patients. In parallel basic studies, we have been attempting to unravel the mechanism by which the enteroendocrine cells sense glucose and macronutrients, and the downstream signaling which ultimately results in exocytosis. We have uncovered a novel signaling pathway for hormone - secreting cells analogous to chemosensation in lingual cells. This pathway provides the mechanism by which the enteroendocrine cells release their peptide products into the blood stream in proportion to the calories eaten. If we can unravel this pathway, we might be able to develop non-nutrient based secretagogues of these hormones which would be useful to treat type 2 diabetes and obesity. |
| Regulation of Beta Cell Function and Mass: For a decade, our laboratory has investigated the molecular mechanisms responsible for the decline in beta cell function with aging and type 2 diabetes. We uncovered the fact that the gut peptide, GLP-1, plays a role in beta cell replication and differentiation. Other investigators have shown it to be an anti-apoptotic factor in beta cells. Recently we also showed that GLP-1 and exendin-4 upregulate pdx-1, a critical transcription factor for beta cells. Also recent work in our laboratory has shown that the Notch receptors and ligands are present and functional in beta cells. These play critical roles in determining cell fate choices related to proliferation, differentiation and apoptosis, in a context dependent manner. We have found that in unstimulated beta cells, Notch is mainly cytoplasmic, but with glucose stimulation, and even more so with exendin-4/GLP-1, it is translocated to the nucleus. Moreover, we have shown that activation of Notch leads to increases in IRS2 protein. Disruption of the gene for IRS2 in mice has already been shown to lead to beta cell failure. We are presently attempting to understand how Notch activation leads to increases in IRS2 protein as IRS2 plays an important role in islet proliferation, differentiation and survival. |
| Recent Publications: |
- Theodorakis MJ, Muller DC, Carlson O, Egan JM. Assessment of insulin sensitivity and secretion indices from oral glucose tolerance testing in subjects with fasting euglycemia but impaired 2-hour plasma glucose. Metabolism. 52(11): 1523-1524, 2003.
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| Doyle ME, Theodorakis MJ, Holloway HW, Bernier M, Greig NH, Egan JM. The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. Regul. Pept. 114(2-3): 153-158, 2003. |
- Egan JM, Meneilly GS, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 284(6): E1072-E1079, 2003.
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- Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J. Clin. Endocrinol. Metab. 87(8): 3768-3773, 2002.
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- Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J. Clin. Endocrinol. Metab. 87(3): 1282-1290, 2002.
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