Research Description
Roux-en-Y gastric bypass (RYGB) is the single-most effective treatment for type 2 diabetes, with persistent remission in 85% of cases. The Diabetes Surgery Summit-II guidelines, endorsed by 45 international professional societies, recommend inclusion of “metabolic” surgery in treatment algorithms for type 2 diabetes. The mechanisms underlying glycemic improvement, however, are controversial, since it occurs independent of weight loss, and is significantly greater than that observed with comparable dietary weight loss or gastric banding. Following RYGB, orally ingested nutrients bypass part of the stomach, duodenum, and proximal jejunum, resulting in earlier and greater nutrient exposure to the distal jejunum, ileum, and proximal colon. Consistent reports of postprandial elevations of glucagon-like-peptide 1 (GLP-1) and other gut-derived hormones led to the suggestion that RYGB glycemic reductions result from enhanced secretion of one or more antidiabetic hindgut factors. Alternatively, it has been suggested that diabetes resolution may result from omission of an as yet uncharacterized pro-diabetic foregut factor. Furthermore, a minority of RYGB patients develop severe, disabling, and life-threatening hypoglycemia, for which there is no current treatment. The proposed research, utilizing a unique and rigorous human experimental model, will address the foregut versus hindgut hypotheses related to RYGB glycemic reductions, thereby addressing an important gap in current knowledge, and potentially identifying novel foregut peptides that represent potential targets for new antidiabetic therapies. It will further address mechanisms related to exaggerated effect of hindgut stimulation as a major contributor to severe hypoglycemia in select individuals, thereby enabling presurgical risk stratification and desperately-needed postsurgical treatment strategies.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?Given the increasing use of Roux-en-Y gastric bypass surgery (RYGB), it is critical to understand the physiologic basis of its metabolic benefits, including resolution of type 2 diabetes. This project investigates the role of the enteroinsular axis and the mechanisms underlying diabetes resolution following RYGB. Our unique cohort of post-RYGB patients with postbariatric hypoglycemia, including those with gastrostomy-tubes placed in remnant stomach as a means for nutrition that does not provoke hypoglycemia, presents a unique opportunity to study the role of altered nutrient transit in mediating glycemic responses to RYGB. The rigorous studies proposed will yield novel information regarding the role of hindgut stimulation and foregut bypass in diabetes resolution and development of HH following RYBG, directly revealing novel treatment targets for both conditions.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?We now know that hormones secreted by the gut play an important role in regulating glucose metabolism. The mechanisms by which it does this are still not well understood. Following Roux-en-Y gastric bypass surgery, which produces long-term remission from diabetes in 85% of individuals, hormones secreted by the gut are differentially stimulated due to altered nutrient transit. GLP-1, secreted by the ileum (hindgut) in response to a nutrient load, is a particularly potent inducer of insulin secretion, and leads to glucose lowering after RYGB surgery, and in some cases, severe hypoglycemia. There are likely hormones secreted by the stomach and proximal intestine (foregut) that play a role too: it has been hypothesized that glucose-elevating hormones are secreted as a defense against hypoglycemia but that after gastric bypass surgery, these are no longer stimulated due to bypass, and thereby contribute to the glucose lowering effects of the surgery. We will address the foregut and hindgut hypotheses of glucose lowering following RYGB to gain better understanding of gut-related factors that contribute to glucose lowering and seek to identify novel peptides via proteomic analyses of a pool of RYGB subjects with gastrostomy tubes placed in the foregut who are able to undergo nutrient stimulation of both foregut and hindgut.
Why important for you, personally, to become involved in diabetes research? What role will this award play?This award is very important to me personally not only because the enteroinsular axis (gut-insulin-glucose metabolism) is a new kid on the block that requires rigorous physiologic studies in humans to better understand how it contributes to glucose metabolism, but also because the subjects who develop severe hypoglycemia after RYGB are largely ignored in society and there is no treatment for this devastating and very dangerous condition. it is shocking that all the funds that go into preventing hypoglycemia in patients with diabetes are not matched in any way by efforts to better understand the cause of this condition, ways to predict who is at risk, and methods to treat it. The results of this small but rigorous study may very well enable the community of scientists and health care providers to identify new treatments for diabetes and/or hypoglycemia, particularly reactive hypoglycemia that affects RYGB and/or other GI surgery patients.
In what direction do you see the future of diabetes research going?I am hoping that with new technologies we will identify even more classes of drugs to treat type 2 diabetes and prevent its complications. I also hope that eventually, prediabetes and diabetes will be further subphenotyped into categories that allow for treatment targeted towards the underlying dominant physiologic abnormality. I hope to help move the field in this direction.