Bethany Cummings with a student in her lab.

Finding New Targets for Diabetes Treatment

by Jackie Swift

Even if you don’t know much about diabetes, you’re probably aware that a crucial component of the disease is lack of the hormone insulin, which lowers blood sugar. But there’s another hormone you may not have heard of that’s just as important: glucagon, which raises blood sugar. “Normally we think of diabetes from a very insulin-centric point of view,” says Bethany P. Cummings, Biomedical Sciences. “Research has focused on it because the discovery of insulin about 100 years ago changed diabetes from a deadly disease into something you could live with. But glucagon is a major player, too. It’s overproduced in diabetes. There’s a lot of data showing that if you can inhibit it, you can dramatically improve diabetes outcomes.”

Cummings and her lab want to understand the metabolic mechanisms that control the production of glucagon and other hormones that play a role in diabetes in order to come up with new targets for diabetes treatment. As their jumping-off point, the researchers explore the metabolic effects of bariatric surgery, the surgical manipulation of the gut that is usually performed for weight loss. “Bariatric surgery also produces other benefits,” Cummings explains. “It causes remarkably high rates of type 2 diabetes remission. This happens almost immediately after surgery, prior to any weight loss.”

Bariatric Surgery Increases Production of Antidiabetic Hormone GLP-1

The Cummings lab focuses specifically on the most common type of bariatric surgery in the United States, the vertical sleeve gastrectomy (VSG) in which the surgeon removes 70 to 80 percent of the patient’s stomach. Using mouse models of VSG, Cummings and her colleagues have zeroed in on pancreatic islets, patches of endocrine tissue located throughout the pancreas. The islets are where alpha cells produce glucagon, as well as a small amount of an antidiabetic hormone called glucagon-like peptide-1 (GLP-1) that is primarily produced in the gut after eating. However, alpha cells shift to producing more GLP-1 after VSG surgery, which increases the body’s ability to lower blood sugar levels. The researchers are investigating why and how that comes about. The evidence points to the influence of another type of islet cell, the beta cell, which is the site of insulin production.

“We’ve found that when we increase GLP-1 signaling on the beta cell, that cell then secretes something—we don’t know what—that acts to reprogram the alpha cell so that it makes more GLP-1,” Cummings says. She and her colleagues are now doing proteomic studies to identify the nature of the beta cells’ secretions. In collaboration with Charles G. Danko, Biomedical Sciences, they’re also carrying out single-cell RNA sequencing on human islets to see if their mouse-model findings are relevant to humans and to help identify the essential mediators of this process.

“It’s been exciting,” Cummings says. “We’ve applied a new, single-cell RNA sequencing technology to the study of human islets, and that has translated what we found in mouse models into humans. It shows that our work has relevance, which is useful toward identifying a target for a therapeutic drug approach. We’re hoping our data will help guide the development of a high-throughput chemical library screen for drug identification.”

“It’s been exciting… We’re hoping our data will help guide the development of a high-throughput chemical library screen for drug identification.”

New Role for Bile Acid Receptor TGR5

Among the many other metabolic effects of bariatric surgery, Cummings is also interested in the dramatic elevation of bile acids. These molecules are secreted in the gut and aid in the digestion of fats and cholesterol. They have many different chemical properties so their metabolic effects vary. Some will disrupt cell membranes and promote inflammation; others are protective and decrease inflammation.

To study the connection of bile acids to diabetes, Cummings is focusing on a major bile acid receptor called TGR5, which is known to improve metabolic regulation by increasing GLP-1 secretion, among other things. “We use mouse models that lack TGR5 to see if VSG surgery can still be effective in creating a healthier bile acid profile,” Cummings says. “We found the effect was largely blunted if TGR5 isn’t present. Our work revealed a new role for TGR5 in the metabolic bile acid processes that happen in the liver.”

Gut Microbiome Influences Bile Acids

Continuing their focus on bile acids, the Cummings lab also explores the interrelationship of bile acids and gut microbiome. “Bile acids are synthesized in the liver and then go into the gut to help digest lipids,” Cummings explains. “When they’re in the gut, the gut microbes further modify them. We’re interested in finding ways to shift the composition of the gut microbiome to make a healthier bile acid profile.”

Joining with Jessica R. Allegretti at Harvard Medical School, Cummings and her colleagues carried out a study to see if they could positively shift the microbiomes of patients with obesity but no overt metabolic disease. The Allegretti group performed fecal microbiome transfer (FMT) in test patients by putting stool from a healthy donor into pills that the patients then took, while a control group took placebos.

While FMT did not cause weight loss, when the Cummings lab analyzed blood samples from both groups of test patients to look for changes in glucose regulation, they found that glucose regulation in patients with FMT treatment remained stable compared to those who received a placebo.

“There are several potential mechanisms for this,” Cummings says. “The most likely seems to be that FMT shifted recipients’ microbiomes and their bile acid profiles to be more similar to the donor. This points to the gut microbiome as a good target for controlling metabolic disease, maybe through intervening to upregulate pathways of interest related to bile acid metabolism.”

Falling in Love with Metabolism and Nutrition

Cummings became interested in metabolic research as a pre-veterinary undergraduate student, when she worked for four years in an animal lab that studied metabolism and nutritional biology. “I fell in love with metabolism and nutrition,” she says. “It stuck with me. Ultimately we all eat, so it’s relevant to everyone, and obesity and diabetes rates are ever increasing.”

When she went on to graduate school, she pursued dual degrees in physiology and veterinary medicine and struggled to figure out how to marry her two interests. “Then I heard about the latest findings that bariatric surgery seemed to cure diabetes,” she says. “No one knew how. I thought, ‘That’s perfect. I’ll use my veterinary skills to develop rodent models for bariatric surgery to understand metabolic disease better.’”