Type 2 diabetes drug as good as exenatide at reducing HbA1c
Diabetic is doing a glucose level finger blood test

A series of studies led by University of Utah (U of U) Health scientists demonstrated how injections of an experimental antibody treatment can essentially reverse type 1 diabetes (T1D) in mouse models by converting cells that normally produce a hormone that controls glucose production into cells that generate insulin. The researchers found that a single dose of the human antibody acted to inhibit the actions of glucagon, and sparked a remarkable transformation in the pancreas of diabetic mice, leading to a nearly 7-fold increase in insulin cell mass and the suppression of diabetic symptoms.

“These animals go from requiring insulin injections to never requiring a diabetes treatment again,” said William L. Holland PhD, a U of U Health assistant professor of nutrition and integrative physiology. “They maintain normal blood glucose long after we stop the treatment. What this implies for millions of people who have type 1 diabetes is that there is a chance we could eventually regenerate their own insulin-producing capacity, restore their normal blood glucose balance, and hopefully help them make progress toward being free of the disease.”

Holland is corresponding author of the team’s published paper in the Proceedings of the National Academy of Sciences (PNAS). The University of Utah researchers and their collaborators do caution that they are still far from their ultimate goal, however. “This research is certainly promising, but it is likely just the first step of many before we can determine if this approach will work in humans with type 1 diabetes,” Holland acknowledged. “We have a long, long way to go.”

The U of U Health researchers collaborated on the studies with scientists from Vanderbilt University Medical Center, Baylor College of Medicine, Lilly Research Laboratories, the University of Texas Southwestern Medical Center, the Veteran’s Administration in Dallas, and the Juvenile Diabetes Research Foundation (JDRF). The team reported its findings in a paper titled, “Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.”

The hormones glucagon and insulin work in tandem to keep blood glucose levels under control. Both are produced by groups of pancreatic cells known as islets of Langerhans. Type 1 diabetes disrupts the normal glucose control mechanism by triggering the body’s immune system to attack and destroy insulin-producing β-cells. As a result, most people with type 1 diabetes rely on insulin injections or pumps to deliver the hormone. “By the time, individuals are diagnosed with type 1 diabetes, they’ve probably lost 90% of the cells that produce insulin in their bodies,” explained E. Danielle Dean, PhD, a study co-author and assistant professor of medicine at Vanderbilt University Medical Center. “So, in order for a person to achieve glucose control without treating themselves with insulin, you’ve got to convince the cells in the body that produce insulin to increase their numbers.”

Interestingly, while glucagon’s role in the metabolic manifestations of diabetes remains “a subject of debate,” the authors noted, targeted disruption of glucagon action has gained traction as a potential treatment for diabetes. “Glucagon receptor (GcgR) antagonists include small-molecule inhibitors and humanized antibodies which antagonize glucagon receptor activation,” they continued. And more recently, “our work demonstrated evidence that the blockage of glucagon action improves glycemia in type 1 diabetic rodents.”

The team had previously tested a GcgR-antagonizing antibody, Ab-4, in models of diabetic mice, and were struck by “the remarkable finding” that the animals demonstrated stable, normal glucose levels, even after treatment was withdrawn. Following on from these studies, the team’s newly reported research assessed the efficacy of the GcgR antagonist Ab-4 to potentially enhance β-cell mass and restore stable glucose control.

The researchers first induced diabetes in mice, triggering the death of insulin-producing β-cells in the pancreas. When these mice were then given the human monoclonal antibody Ab-4, which blocks glucagon binding in the liver, the animals’ blood glucose levels normalized and circulating blood levels of insulin were restored.

To investigate what was happening in greater detail, the researchers tracked glucagon-producing α-cells using a fluorescent protein marker that glows red. They found that an increased number of glowing red cells were also producing insulin, suggesting that these glucagon-producing cells had started making insulin instead. These initial studies were demonstrated in mice that were able to regenerate insulin-producing cells without interference from the immune system.

Next, the scientists turned their attention to non-obese diabetic (NOD) mice. These animals spontaneously develop diabetes because their overly aggressive immune systems readily provoke the death of insulin-producing β-cells. This condition closely resembles type 1 diabetes in humans. When the investigators administered the Ab-4 monoclonal antibody to these animals, they found that the treatment restored insulin production and triggered regeneration of abundant numbers of insulin-producing cells in the pancreas.

“Collectively, these results suggest that inhibiting glucagon receptor action can promote recovery of functional β-cell mass in murine models of type 1 diabetes,” the team commented. “Our studies presented here suggest that blockade of glucagon signaling lowers glycemia in mouse models of type 1 diabetes while enhancing formation of functional β-cell mass and production of insulin-positive cells from α-cell precursors … in the context of type 1 diabetes, this α-cell hyperplasia may be of benefit by providing a unique source to develop new insulin-producing cells.”

“It is a very intriguing finding that our treatment protects and restores insulin-producing beta cells even in the presence of a persistent immune response,” Holland said. “It appears that the immune cells can no longer kill the new β-cells.”

Many potential therapies that increase β-cell mass in mice have failed to have the same effect in human islets or in patients. To investigate if their approach may feasibly work in humans, the researchers grafted human islets into immunodeficient, diabetic mice. They then selectively killed the mouse β-cells, leaving only the human islets in place. Treating these mice with Ab-4 also enhanced glucose control and increased the amount of circulating human insulin in the animals’ bloodstreams, confirming a benefit to human islets. These effects were still detectable 40 days following treatment.

“These studies provide hope that a once-weekly injection of a human antibody against the glucagon receptor can enhance functional β-cell mass,” the authors concluded. “Changing small amounts of residual β-cells can have a huge improvement in the quality of life for millions of patients with type 1 diabetes.”

Moving forward, the researchers are beginning to investigate how glucagon-producing α-cell convert into insulin-producing cells and avoid being damaged by the immune system.

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