Blocking Glucagon’s Action to Improve Diabetes Care

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In the toolkit of methods for successfully treating diabetes, insulin is not the only hammer available to hit the nail on the head. Researchers are targeting glucagon—a hormone that tells the body to produce sugar—as an effective method of treatment. In doing so, the same researchers may have also discovered a way to grow insulin-producing cells, and potentially cure the condition.

“We think diabetes is a bi-hormonal disease,” says Dr. Dung “Zung” Thai, Chief Medical officer of REMD Biotherapeutics. “The idea, as we are approaching it, is that it is possible to treat diabetes more effectively by eliminating excess glucagon activity rather than merely by taking insulin without eliminating excess glucagon action.”

Dr. Dung “Zung” Thai

What makes this idea intriguing is that glucagon is practically the opposite of insulin. It is a hormone that stimulates the liver to produce stored glucose, which is the fuel that the human body runs on. When the body needs that fuel, such as in response to the “fight or flight” need for fast energy, glucagon is the messenger that tells the liver to flood the body with glucose.

Like insulin, glucagon is also produced in the pancreas.

Type 1 diabetes is caused when beta cells in the pancreas that produce insulin are destroyed by the body’s own immune system and type 2 diabetes is caused by the body’s inability to metabolize and properly use insulin. The elimination, or in ability to properly use insulin, increases glucose levels derived from food. Additionally, recent research indicates that a lack of insulin also increases levels of glucagon, which in turn increases glucose production from the liver.

This research means that insulin and glucagon can function as partners in managing type 1 diabetes more successfully; that it is, in Thai’s words, a “bi-hormonal disease.”

Pursuing that line of reasoning, REMD, in partnership with Beijing-based Cosci-REMD Biotherapeutics, completed Phase 1 clinical testing on an antibody called REMD-477 that blocks “the action of glucagon” by binding to the glucagon receptor. In mouse models of type 1 diabetes, the glucagon receptor blockade “completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy,” according to a paper published in the Proceedings of the National Academy of Science of the United States of America.

The paper, submitted by Roger Unger, M.D., Professor and Touchstone/West Distinguished Chair in Diabetes Research at University of Texas Southwestern Medical Center, and a scientific advisor to REMD, was strident in stating its case that inhibiting glucagon action, and not merely administering insulin, can lead to  significant improvement in treating diabetes.  “Ninety years of insulin treatment in patients with type 1 diabetes (T1D) have made it clear that insulin alone cannot normalize glucose homeostasis or glycated hemoglobin (HbA1c) levels,” the paper said.

REMD reported to the American Diabetes Association’s 77th Scientific Sessions in June that a clinical trial testing a single injection of REMD-477 in twenty-one people (eight men and thirteen women) with type 1 diabetes “substantially reduced daily insulin requirements and glucose levels without increasing hypoglycemia (low blood glucose levels) in patients.”

More specifically, the results of the Phase 1 study demonstrated that “a single dose of REMD-477 decreased daily insulin use by up to 26 percent (12 units) during the in-patient period compared to placebo. Average daily glucose concentrations decreased by 20 to 31 mg/dL without increasing hypoglycemia in the first three weeks after release from the in-patient setting for patients on the REMD-477 arm of the study.”

Based on these promising findings, REMD began recruiting subjects for a Phase 2 clinical trial in September, Thai says.

The Phase 2 study, “is a multiple dose study to evaluate the efficacy, safety and pharmacodynamics of REMD-477 in subjects with type 1 diabetes mellitus (NCT03117998). This randomized, placebo-controlled, and double-blinded study will evaluate 75 patients who will be receive either once weekly injections of low dose REMD-477, high dose REMD-477, or placebo for 12 weeks, Thai said.

Adding to this potentially groundbreaking news, Thai says, is something else that might be even more groundbreaking.

“Findings from several type 1 diabetes mouse models suggest that treatment with our glucagon receptor antibody can increase insulin-producing beta cell mass,” Thai says. “The beta cells appear to be functional since levels of C-peptide and endogenous insulin are increased after antibody treatment. We hypothesize that the beta cells are derived from alpha cells (which produce glucagon). Under the right conditions, blocking glucagon action can increase alpha cell mass and these alpha cells transform through a process called trans-differentiation into insulin-producing beta cells.”

Thai says ongoing studies over the next year should give an indication of whether or not REMD-477 can effectively increase functional beta cell mass. He adds that it will take several years to really know for sure either way.

But, he says, the possibility is tantalizing.

“We believe that this program has the opportunity to be transformational for patients with type 1 diabetes,” Thai says. “Our hope is that the antibody will provide an additional treatment option to patients with type 1 diabetes to achieve better glucose control with reduced hypoglycemia risk.  If we could demonstrate evidence of beta cell regeneration, there would be tremendous enthusiasm to pursue the ultimate goal of curing type 1 diabetes.”

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2 Comments on "Blocking Glucagon’s Action to Improve Diabetes Care"

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Ivan

Hopefully this research is true.

Khürt Louis Williams
Khürt Louis Williams

This part — completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy— is what stood out for me. Have they done the tests with mice/people who are actively using insulin? Have they worked out a protocol for people with T1D who exercise (and hence need glucose to power muscles)? How does this affect the liver for people with low carbohydrate diets (ketogenic/paleo)?

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