This application is to provide the candidate with scholarly training, mentorship, and protected time with the goal of becoming an independent clinical researcher. Dr. Salehi will study the functions of gastrointestinal (Gl) hormones and neural signaling in glucose metabolism by focusing on the physiologic changes following Roux-en-Y gastric bypass (RYGB). RYGB has been reported to reverse type 2 diabetes (T2DM) immediately after surgery before any significant weight loss. In addition, a growing number of patients have been recognized with life-threatening hyperinsulinemic hypoglycemia several years following their surgery. These findings suggest that the RYGB procedure alters the regulation of (-cell function to promote insulin secretion. While the mechanisms by which RYGB improves glucose metabolism or alters islet cell function in patients after RYGB are not understood, recent studies suggest that increased secretion of Gl hormones, primarily glucagon-like peptide 1 (GLP-1), may contribute to enhanced insulin secretion in general, and to a greater extent in patients with hypoglycemia. However, there is also reason to suspect that changes in neural signaling may influence islet cell function in concert with Gl hormones after RYGB, since these patients have an earlier insulin peak and a larger glucagon secretion in response to food ingestion. The proposed research is designed to address the role of RYGB on insulin secretion by determining 1) the contribution of stimulatory factors (neural and Gl hormone) on islet cell function;and 2) the islet cell responsiveness to the physiologic stimulatory factors, in RYGB patients with and without hypoglycemia and non-operated controls. The first goal will be achieved by comparing the effects of cholinergic or GLP-1 blockade on the release of postprandial islet hormones. The second goal will be accomplished by measuring beta-cell responsiveness to exogenous GLP-1, sham feeing, or oral glucose ingestion. To achieve her career objectives, the candidate proposes a five-year training program to learn skills in laboratory research methods, statistical analysis, and islet cell physiologic studies focusing on the role of Gl hormones and neural regulatory factors. Her primary sponsor is highly accomplished investigator in glucose metabolism and Gl hormones and the secondary sponsor in neural signaling and islet cell physiology. Understanding the physiologic mechanisms whereby RYGB influences islet cell function, both improving glucose metabolism and causing hypoglycemic syndrome can lead to the development of new therapeutic options for T2DM as well as surgical refinements or medical therapies for those patients who develop hypoglycemia.
Better understanding of metabolic consequences of RYGB is critical given the rising use of gastric bypass surgeries due to dramatic increase of obesity in the population. The results of this project will provide insights to apply to treatment of diabetes as well as modification of bariatric techniques to reduce the late-complications of hypoglycemia in the groups of patients at risk.
|Salehi, Marzieh; Gastaldelli, Amalia; D'Alessio, David A (2018) Beta-cell sensitivity to glucose is impaired after gastric bypass surgery. Diabetes Obes Metab 20:872-878|
|Salehi, Marzieh; D'Alessio, David A (2016) Mechanisms of surgical control of type 2 diabetes: GLP-1 is the key factor-Maybe. Surg Obes Relat Dis 12:1230-5|
|Salehi, Marzieh; Woods, Stephen C; D'Alessio, David A (2015) Gastric bypass alters both glucose-dependent and glucose-independent regulation of islet hormone secretion. Obesity (Silver Spring) 23:2046-52|
|Salehi, Marzieh; Gastaldelli, Amalia; D'Alessio, David A (2014) Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology 146:669-680.e2|
|Salehi, Marzieh; D'Alessio, David A (2014) Effects of glucagon like peptide-1 to mediate glycemic effects of weight loss surgery. Rev Endocr Metab Disord 15:171-9|
|Salehi, Marzieh; Gastaldelli, Amalia; D'Alessio, David A (2014) Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab 99:2008-17|
|Salehi, Marzieh; Gastaldelli, Amalia; D'Alessio, David A (2014) Evidence from a single individual that increased plasma GLP-1 and GLP-1-stimulated insulin secretion after gastric bypass are independent of foregut exclusion. Diabetologia 57:1495-9|
|Eckerle Mize, Dara L; Salehi, Marzieh (2013) The place of GLP-1-based therapy in diabetes management: differences between DPP-4 inhibitors and GLP-1 receptor agonists. Curr Diab Rep 13:307-18|
|Salehi, Marzieh; Aulinger, Benedict; D'Alessio, David A (2012) Effect of glycemia on plasma incretins and the incretin effect during oral glucose tolerance test. Diabetes 61:2728-33|
|Salehi, Marzieh; Prigeon, Ronald L; D'Alessio, David A (2011) Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes 60:2308-14|