The Research Grant Report: Marzieh Salehi, MD

| December 1, 2022

by Tammy Kindel, MD, PhD, FACS, FASMBS; Shaina R. Eckhouse, MD, FACS, FASMBS; and Omar M. Ghanem, MD, FACS

Dr. Kindel is a bariatric surgeon and Associate Professor of Surgery at the Medical College of Wisconsin in Milwaukee, Wisconsin. Dr. Eckhouse is a bariatric surgeon at Washington University in St. Louis, Missouri. Dr. Ghanem is a bariatric surgeon at the Mayo Clinic in Rochester, Minnesota.

Bariatric Times. 2022;19(12):15.

Marzieh Salehi, MD, was the recipient of the 2006 American Society for Metabolic and Bariatric Surgery (ASMBS) research grant, funded by the ASMBS Foundation, for her study, titled “The role of glucagon like peptide-1 in glucose metabolism and weight loss following gastric bypass surgery.” The grant amount was for $25,000. In this article, we aim to highlight Dr. Salehi’s clinical and research career and the clinical implications of her study. Additionally, we will explore the vital role that the ASMBS Foundation grant had in helping her build an extramurally-funded research career. 

Dr. Salehi, can you please share your clinical and research background as an endocrine and metabolic researcher and elaborate on the scope of your current practice?

Dr. Salehi: I am a board-certified endocrinologist and translational investigator with more than 15 years of experience in human research related to metabolism, obesity, and diabetes. I started my academic career as a clinician, and by cultivating an active subspecialized practice, I became recognized as a regional and national expert on polycystic ovary syndrome with metabolic syndrome and diabetes related to islet auto-transplantation, as well as glucose abnormalities after bariatric surgery. The latter condition has led the majority of my research effort, for which I have received funding from the ASMBS, American Heart Association (AHA), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The focus of my research has been on studying glucose metabolism mediated by the gut-liver-pancreas axis activity, particularly in the state of obesity and weight loss using in vivo studies in humans. These are state-of-the-art experimental procedures that have been in use for glucose metabolism studies since the mid-1970s to assess metabolic function that we have successfully used in post-bariatric surgery patients.

You were awarded an ASMBS research grant in 2006, funded by the ASMBS Foundation. Could you explain the aims of this grant?

Dr. Salehi: Several prospective studies had previously demonstrated that diabetes remission occurs within days of undergoing Roux-en-Y gastric bypass (RYGB), prior to any significant weight loss. Furthermore, in 2005, two independent groups of investigators reported a late complication of hypoglycemia after RYGB that was exclusively postprandial and associated with excessive insulin secretion. These findings, which were indicative of an endocrine mechanism of action, led to our hypothesis that the reconfiguration of the intestinal transit in RYGB will increase the release of insulinotropic gastrointestinal hormones, termed incretins, that improve insulin secretion and glucose metabolism. The aims were to determine the role of incretin hormones on insulin secretion and glucose tolerance in patients with and without hypoglycemia after RYGB.  

What were the results of the ASMBS research grant funded by the ASMBS Foundation?

Dr. Salehi: Our findings indicated that RYGB increased postprandial insulin secretion at the same levels of glycemia—the so called “incretin effect.” Furthermore, we demonstrated that the contribution of glucagon like peptide-1 (GLP-1), one of the two main insulinotropic peptides, to prandial hyperinsulinemia was significantly greater in those with a history of RYGB, compared to nonsurgical subjects.  

Did the research grant funded by the ASMBS Foundation lead to further research projects? If so, could you share how you were able to take this initial grant funding and leverage this for further funding, including any current research projects?

Dr. Salehi: The preliminary data obtained with the ASMBS Foundation support was the foundation to obtain further support from the AHA, as well as from the NIDDK, including my current R01 funding investigating the effect of RYGB and sleeve gastrectomy on glucose metabolism mediated by hormonal and nonhormonal insulinotropic factors.

Dr. Salehi, do your studies support or refute that GLP-1 is the primary reason for the improvement in hyperglycemia after bariatric/metabolic surgery, and do you believe new pharmacotherapies can match the impact of surgery on hemoglobin A1c  (HbA1c) control?  

Dr. Salehi: Using GLP-1 receptor antagonists, we and others have shown that RYGB increases GLP-1 secretion by 5- to 10-fold and GLP-1-induced insulin secretion by 2- to 3-fold. However, an unequivocal role of GLP-1 in altered glucose tolerance after RYGB has only been demonstrated in patients with the late complication of postprandial hyperinsulinemic hypoglycemia. 

The altered gastrointestinal anatomy after RYGB, and to a lesser extent, sleeve gastrectomy, changes various prandial hormones that could act in concert with GLP-1 to improve glycemia after RYGB. In fact, the sizable antidiabetic effects of bariatric surgery have propelled the development of unimolecular co-agonists integrating multiple hormonal signals, such as glucagon, GLP-1, and glucose-dependent insulinotropic peptide (GIP), and have become a vision of various pharmaceutical efforts. However, to date, RYGB remains the most effective treatment for obesity and diabetes.

Finally, what have you learned in your studies about the etiology of postprandial hyperinsulinemic hypoglycemia after RYGB, and how is this syndrome best treated?

Dr. Salehi: While the underlying mechanisms by which RYGB causes hypoglycemia are not completely understood, affected patients have a greater meal-induced insulin and GLP-1 response, compared to those without hypoglycemia after RYGB. We have demonstrated, for the first time, that blocking the GLP-1 signal with receptor antagonists corrects hypoglycemia in every affected individual, primarily by reducing insulin secretion. These findings were the foundation for the drug development to treat affected patients with a GLP-1 receptor antagonist.

We have also found that systemic appearance of ingested glucose is much greater in patients with hypoglycemia, compared to asymptomatic subjects, after RYGB, raising the possibility that enhanced nutrient delivery and absorption might play a role in the pathogenesis of hyperinsulinemia after RYGB, independent of enhanced GLP-1 action. Furthermore, we have found that insulin degradation and clearance after eating is impaired in those with hypoglycemia, compared to those without hypoglycemia, after RYGB, leading to higher prandial insulin concentrations and lower nadir glucose in the affected individuals. 

Additionally, we recently reported that islet-cell and glucose counterregulatory response to insulin-induced hypoglycemia is impaired in those with RYGB or sleeve gastrectomy, likely predisposing susceptible individuals to develop hypoglycemia after bariatric surgery. 

Based on the complex pathophysiologic mechanisms of postprandial hypoglycemia after RYGB, treatment strategies that selectively lower the pace of nutrient flux into the small intestine may also be effective.  

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Category: ASMBS Foundation News and Update, Past Articles

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