Defining Alpha and Beta-Cell Crosstalk for the Treatment and Prevention of Diabetes

Principal Investigator: Bethany Cummings

Department of Biomedical Sciences
Sponsor: DoD - U.S. Army
Grant Number: W81XWH-18-1-0206
Title: Defining Alpha and Beta-Cell Crosstalk for the Treatment and Prevention of Diabetes
Project Amount: $312,041
Project Period: June 2018 to December 2019

DESCRIPTION (provided by applicant): 

The epidemic of type 2 diabetes mellitus (T2DM) is a leading health concern of our time. T2DM is the predominant form of diabetes, accounting for over 95% of all diabetes cases and is a leading cause of death world-wide. Fortunately, there is an intervention that is effective in the prevention and treatment of T2DM, bariatric surgery.

Bariatric surgery, such as gastric bypass, is a surgical manipulation of the gut that is performed for the purpose of weight loss and is the most effective long-term treatment for obesity. Bariatric surgery also has a remarkable effect to cure T2DM. However, due to the high costs and risks associated with surgery, this treatment option is not available to the millions of patients suffering from T2DM. Identifying the mechanisms by which bariatric surgery cures T2DM will reveal new drug targets for the treatment and prevention of T2DM. Surprisingly, it is not the weight loss that cures T2DM. Patients often experience a return to normal blood glucose levels and discontinuation of all diabetes medications within hours to days after bariatric surgery, prior to weight loss. Therefore, the effect of bariatric surgery cure T2DM is not simply due to body weight loss. Vertical sleeve gastrectomy (VSG) is the most commonly performed bariatric procedure in the U.S. due to its surgical simplicity relative to other bariatric procedures, coupled with its remarkable efficacy in producing weight loss and T2DM remission. Therefore, we have developed a mouse model of VSG to determine the mechanisms by which bariatric surgery cures T2DM, with the ultimate goal of “bypassing the knife” to pharmaceutically mimic the benefits of bariatric surgery.

In addition to curing T2DM, VSG causes remarkable changes in hormone production by the gut. Therefore, VSG provides a unique tool with which to understand the critical, yet poorly characterized, function of the gut in blood glucose regulation. One of the most dramatic changes seen after VSG is a 10-fold increase in glucagon-like peptide-1 (GLP-1) secretion in response to a meal. GLP-1 is classically defined as a gut-derived hormone that regulates blood glucose levels, primarily through its effects on pancreatic islets. Pancreatic islets control blood glucose levels by producing two central hormones: insulin (produced by islet beta-cells to lower blood glucose) and glucagon (produced by islet alpha-cells to increase blood glucose). Dysfunction of pancreatic islets is the primary driver of T2DM onset and progression. Therefore, designing drugs that improve islet function holds much promise for the treatment and prevention of T2DM. GLP-1 plays a critical role in islet function by increasing insulin secretion and decreasing glucagon secretion; however, we still do not fully understand how.

We have discovered a novel system by which GLP-1 regulates islet function by applying our mouse VSG model to a mouse model that does not have the GLP-1 receptor in pancreatic islets. Based on these findings, we propose to pursue two central goals: First, we will define the biologic role of alpha-cell-derived GLP-1 using our unique mouse model. It was previously thought that the gut was the only location for GLP-1 production. However, recent work reveals that islet alpha-cells can produce GLP-1 as well. Despite this fact, the role of alpha-cell GLP-1 in islet function is unknown, due to the lack of appropriate models. Second, we will define the factors secreted from beta-cells in response to GLP-1R signaling to identify an anti-diabetogenic factor that reprograms alpha-cells to produce GLP-1 instead of glucagon. Although GLP-1 and glucagon are produced from the same precursor, each precursor can only be processed into either GLP-1 or glucagon, not both. Glucagon is a key driver of T2DM and; thus, is an attractive target for T2DM treatment. However, development of a glucagon receptor inhibitor has been fraught with set-backs, suggesting that targeting glucagon production may be a more feasible approach. We will perform a screen to identify the factor(s) secreted from beta-cells in response to GLP-1R signaling. This will reveal a novel list of candidate factors with which to amplify alpha-cell GLP-1 production at the expense of glucagon. Results from these studies will bring the field of T2DM closer to achieving the ultimate goal of developing a drug that pharmaceutically mimics the effect of VSG to cure T2DM. Developing a drug that mimics benefits of bariatric surgery will provide an alternative to surgery that is safer and more affordable and; therefore, available to a broader population.