Studying molecular factors that mediate bariatric surgery’s beneficial effect on type 2 diabetes, Joslin investigators identify one that could be targeted therapeutically without surgery.

More than a quarter of a million people undergo bariatric surgery each year in the United States. Around 90% of those with type 2 diabetes who undergo gastric bypass, a procedure that restructures the stomach, successfully remove their elevations in blood glucose levels after a year, and half of that group maintains this state of remission for five years.

Weight loss is only part of the recipe for success—even before they start losing weight, patients experience changes in metabolism that help them maintain normal levels of blood glucose. So what drives those changes?

Using a powerful new statistical tool to analyze the results of a pioneering clinical trial, Joslin Diabetes Center researchers have identified molecular factors that may be key to achieving improved glucose control after bariatric surgery. Among the factors, levels of a protein called growth hormone receptor (GHR) in the blood of patients with type 2 diabetes are a surprisingly strong mediator of clinical benefit—more statistically significant, in fact, than weight loss.

A better understanding of such metabolic factors eventually may make it possible to deliver the benefits of bariatric surgery without actual procedures. "It would be nice to get these changes affecting glucose metabolism without having to cut someone open," said Jonathan Dreyfuss, PhD, Director of Joslin's Bioinformatics & Biostatistics Core and co-lead-author on a Nature Communications paper presenting the research.

We want to devise new strategies for medical management to improve our care, harnessing the effects of the surgery in non-surgical methods

Mary-Elizabeth Patti, MD, a Joslin principal investigator and corresponding author on the paper.

The research builds on SLIMM-T2D (Surgery or Lifestyle with Intensive Medical Management in the Treatment of Type 2 Diabetes), a clinical trial co-led by Joslin and Brigham and Women's Hospital.

The group of people with type 2 diabetes who choose bariatric surgery is often quite distinct from those who don't, which limits what can be learned from population studies of people who get the surgery, Patti noted. But SLIMM-T2D was a randomized trial, dividing patients into two groups that were given either medical therapy or a well-established form of bariatric surgery known as Roux-en-Y gastric bypass.

"Randomization allowed us to examine the differences between medical therapy and surgery in a precise way that we can't achieve from population-based studies," she said.

Patti and her colleagues compared weight loss, hemoglobin A1C measurements (which reflect blood glucose levels) and levels of proteins and metabolites (body chemicals involved in metabolism) in blood samples gathered from the two groups in the SLIMM-T2D trial over time.

The statistical tool that Dreyfuss developed revealed that the growth hormone receptor (GHR) protein, which enables signaling by the growth hormone protein, was the lead mediator of improvements in glucose levels.

As its name suggests, growth hormone is a key molecular player for growth during childhood and puberty. The hormone also plays important metabolic roles in adults, among them countering the impact of insulin on blood glucose, Patti said. That is, if glucose levels drop, the growth hormone pathway can kick in and help to boost glucose.

"Here we have the first data that surgery may actually reduce growth hormone signaling and thus contribute to reduction in glucose," Patti said. "That makes sense, but it wasn't something that was on people's radars as a mechanism for the effects of bariatric surgery."

Among other findings from SLIMM-T2D, the team showed that surgery dramatically altered the levels of a group of metabolites called "branched-chain amino acids". This discovery was consistent with previous evidence that these metabolites are important in diabetes-related metabolism, said Patti.

Her team followed up with studies in animal models to see if those models would exhibit corresponding mechanisms for GHR metabolism. Among the supporting evidence, the scientists found, genetically modifying mouse liver cells to decrease the production of GHR also decreased glucose production. Similarly, the production of GHR dropped in the livers of rats that underwent bariatric surgery.

Patti and her team plan to follow up with other research in animal models to probe the molecular pathways triggered by GHR mechanisms.

In the meantime, she emphasized, "many people with type 2 diabetes, especially early in the course of the disease, should think about bariatric surgery as a treatment approach."

"Not everyone wants surgery and not everyone can get surgery," Patti added. "It's not an easy thing to go through, it takes a lot of work, and it's a challenging approach. But it has very durable long-term effects."

SLIMM-T2D was a partnership between Joslin diabetes experts and surgeons at Brigham and Women's Hospital, while the analysis and validation of its protein and metabolite measurements was a joint effort between bioinformatics and laboratory science at Joslin. "When our target is a clinical disease, we need people with different expertise, different areas of interest and different focuses to work together," she said. "This is an example of how Joslin allows cross-disciplinary collaboration to occur easily."

Yixing Yuchi of Joslin was co-lead-author on the paper. Other Joslin contributors included Xuehong Dong, Vissarion Efthymiou, Hui Pan, Kathleen Foster and Allison Goldfine. Co-authors also included Donald Simonson, Ashley Vernon, Florencia Halperin, Pratik Aryal and Barbara Kahn of Harvard Medical School; Anish Konkar, Yinong Sebastian, Brandon Higgs, Joseph Grimsby and Cristina Rondinone of MedImmune; Simon Kasif of Boston University; Randy Seeley of the University of Michigan; and Vera Djordjilović of the University of Venice. Lead funding came from the National Institutes of Health, the Charles King Trust and the Patient-Centered Outcomes Research Institute. MedImmune provided an unrestricted investigator-initiated research grant for assays.