Mt Sinai Researchers Move Closer to a Cure for Diabetes.
New research confirms a novel route for human beta cell regeneration.
Diabetes researchers and bioinformaticians from the Icahn School of Medicine at Mount Sinai have developed a new understanding of how human beta cell regenerative drugs work. These drugs, developed at Mount Sinai, may hold promise for more than 500 million people with diabetes in the world.
Diabetes develops when cells in the pancreas known as beta cells become unable to produce insulin, a hormone that is essential to regulating blood sugar levels. While great progress has been made toward discovering a durable therapy, none are scalable therapeutic options for millions of diabetics across the globe.
For more than 15 years, researchers at the Icahn School of Medicine at Mount Sinai have worked tirelessly to find a solution to cure diabetes by identifying a drug that could make human beta cells regenerate.
In 2015, Mount Sinai researchers discovered the first such drug, called harmine. Harmine is a member of a class of drugs called DYRK1A inhibitors. In 2019 and 2020, the researchers reported that DYRK1A inhibitors can synergize with TGF-beta signaling as well as GLP-1 receptor agonist (GLP-1RA) drugs such as semaglutide (e.g., Ozempic) and exenatide (Byetta) to induce more robust levels of human beta cell regeneration. Finally, in July 2024, they showed that harmine alone increases human beta cell mass by 300 percent, and if a GLP-1RA is added, by 700 percent.
A key question has been how harmine causes beta cells to regenerate. In the newest study, the research team reports that the new, regenerated beta cells may be coming from an unexpected source: a second pancreatic cell type called alpha cells. Since alpha cells are abundant in people with type 1 and type 2 diabetes, they may be able to serve as a source for new beta cells in both common types of diabetes.
“This is an exciting finding that shows harmine-family drugs may be able to induce lineage conversion in human pancreatic islets,” says Esra Karakose, PhD, Assistant Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai and corresponding author of the study. “It may mean that people with all forms of diabetes have a large potential ‘reservoir’ for future beta cells, just waiting to be activated by drugs like harmine.”
“It has been remarkable and rewarding to watch this multi-group story unfold over the past 15 years,” added Andrew F. Stewart, MD, Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute. He and Peng Wang, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai, conceived of and performed the initial high-throughput drug screen that led to the discovery of harmine,
“A simple pill, perhaps together with a GLP1RA like semaglutide, is affordable and scalable to the millions of people with diabetes,” said Dr. Stewart.
On another fron -t Novo Nordisk Researchers Engineer Glucose-Sensitive Insulin Switch.
Novo Nordisk researchers have solved a chemistry and biology riddle that has been pursued for nearly half a century: designing a glucose-sensitive insulin with auto-adjustable bioactivity. According to research published in Nature, the molecule, designed using computational chemistry and structural biology with reversible bioactivity, demonstrated responsiveness to a glucose range relevant to diabetes and led to protection against hypoglycemia in animal models while partially covering glycemic variability.
These results hold promise for improving the treatment of diabetes by potentially lowering the risk of hypoglycemia and partly covering the need for fast-acting insulin at mealtime, thus improving both the short-term and long-term risks and complications associated with diabetes. This method also lays the groundwork for showing that molecular switches can be created to enable autonomous control of molecular bioactivity in response to changes in another molecule’s concentration, even within a narrow range like blood glucose levels.
Since the 1970s, efforts have been made to engineer an insulin that can adjust its bioactivity in response to fluctuating blood glucose levels, thereby enhancing glycemic control while mitigating the risk of hypoglycemia. Even though there have been many publications and patents on the subject, no mechanism has yet been shown to be compelling enough to treat diabetes. Most studies have focused on systems that can release insulin from subcutaneous depots in response to changes in glucose levels. Even so, these systems are limited by irreversibly, and insulin entering the bloodstream takes time to work.
An apparent more effective strategy is to give insulin glucose-responsive properties that let it respond to glucose reversibly. To achieve such an insulin molecule would require two key properties: glucose binding with optimal sensitivity to the fluctuating glucose levels in diabetics (from approximately 2 to 20–30 mM) and a mechanism to reversibly “shut off” insulin receptor binding activity at low glucose levels. To address glucose sensitivity, Merck created a system that changed insulin clearance and, consequently, insulin action in response to blood glucose. Still, because of its incredibly low efficacy, this system did not merit advancement past phase I clinical trials. The closest example of a reversely glucose-sensitive insulin was created by Thermalin and Indiana University School of Medicine. It was insensitive to glucose but sensitive to fructose at high concentrations.
The Novo Nordisk researchers took inspiration from recent work by Ziylo and University of Bristol researchers who created a macrocycle with a glucose-binding cavity that ensures a relevant affinity for glucose and selectivity over other carbohydrates and possibly interfering small molecules. By using this macrocycle to form an insulin conjugate, NNC2215 showed that when glucose was increased from 0 to 20 mM, its insulin receptor binding affinity increased by 12.5 times, and when it was increased from 3 to 20 mM, it increased by 3.2 times.
The Novo Nordisk team tested NNC2215 in three in vivo animal models. First, in a rather straightforward acute rat model, the glucose sensitivity in vivo was confirmed by administering l-glucose at a dose that triggered the insulin effect of NNC2215 without inducing endogenous insulin release. When l-glucose activated NNC2215, d-glucose lowered dose-dependently, and NNC2215 was concurrently dose-dependently cleared by l-glucose. Second, during a glucose challenge in insulinopenic streptozotocin (STZ)-diabetic rats, the Novo Nordisk researchers also noticed an activation of NNC2215, equivalent to 30% more human insulin. Finally, NNC2215’s glucose-sensitive insulin receptor binding and cellular effects showed a protective effect against hypoglycemia in vivo using a pig model that resembles acute diabetes.
In conclusion, insulin conjugates with characteristics like NNC2215 can potentially improve diabetes treatment by reducing the risk of hypoglycemia and partially substituting for the need for fast-acting insulin during meals. Compared to existing insulin therapies, combining these two characteristics should enable more aggressive insulin titration to reach normal glucose levels without raising the risk of hypoglycemia. This could reduce the risks and complications of diabetes in the short and long term.
New research confirms a novel route for human beta cell regeneration.
Diabetes researchers and bioinformaticians from the Icahn School of Medicine at Mount Sinai have developed a new understanding of how human beta cell regenerative drugs work. These drugs, developed at Mount Sinai, may hold promise for more than 500 million people with diabetes in the world.
Diabetes develops when cells in the pancreas known as beta cells become unable to produce insulin, a hormone that is essential to regulating blood sugar levels. While great progress has been made toward discovering a durable therapy, none are scalable therapeutic options for millions of diabetics across the globe.
For more than 15 years, researchers at the Icahn School of Medicine at Mount Sinai have worked tirelessly to find a solution to cure diabetes by identifying a drug that could make human beta cells regenerate.
In 2015, Mount Sinai researchers discovered the first such drug, called harmine. Harmine is a member of a class of drugs called DYRK1A inhibitors. In 2019 and 2020, the researchers reported that DYRK1A inhibitors can synergize with TGF-beta signaling as well as GLP-1 receptor agonist (GLP-1RA) drugs such as semaglutide (e.g., Ozempic) and exenatide (Byetta) to induce more robust levels of human beta cell regeneration. Finally, in July 2024, they showed that harmine alone increases human beta cell mass by 300 percent, and if a GLP-1RA is added, by 700 percent.
A key question has been how harmine causes beta cells to regenerate. In the newest study, the research team reports that the new, regenerated beta cells may be coming from an unexpected source: a second pancreatic cell type called alpha cells. Since alpha cells are abundant in people with type 1 and type 2 diabetes, they may be able to serve as a source for new beta cells in both common types of diabetes.
“This is an exciting finding that shows harmine-family drugs may be able to induce lineage conversion in human pancreatic islets,” says Esra Karakose, PhD, Assistant Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai and corresponding author of the study. “It may mean that people with all forms of diabetes have a large potential ‘reservoir’ for future beta cells, just waiting to be activated by drugs like harmine.”
“It has been remarkable and rewarding to watch this multi-group story unfold over the past 15 years,” added Andrew F. Stewart, MD, Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute. He and Peng Wang, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai, conceived of and performed the initial high-throughput drug screen that led to the discovery of harmine,
“A simple pill, perhaps together with a GLP1RA like semaglutide, is affordable and scalable to the millions of people with diabetes,” said Dr. Stewart.
On another fron -t Novo Nordisk Researchers Engineer Glucose-Sensitive Insulin Switch.
Novo Nordisk researchers have solved a chemistry and biology riddle that has been pursued for nearly half a century: designing a glucose-sensitive insulin with auto-adjustable bioactivity. According to research published in Nature, the molecule, designed using computational chemistry and structural biology with reversible bioactivity, demonstrated responsiveness to a glucose range relevant to diabetes and led to protection against hypoglycemia in animal models while partially covering glycemic variability.
These results hold promise for improving the treatment of diabetes by potentially lowering the risk of hypoglycemia and partly covering the need for fast-acting insulin at mealtime, thus improving both the short-term and long-term risks and complications associated with diabetes. This method also lays the groundwork for showing that molecular switches can be created to enable autonomous control of molecular bioactivity in response to changes in another molecule’s concentration, even within a narrow range like blood glucose levels.
A short history of engineering insulin
Since the 1970s, efforts have been made to engineer an insulin that can adjust its bioactivity in response to fluctuating blood glucose levels, thereby enhancing glycemic control while mitigating the risk of hypoglycemia. Even though there have been many publications and patents on the subject, no mechanism has yet been shown to be compelling enough to treat diabetes. Most studies have focused on systems that can release insulin from subcutaneous depots in response to changes in glucose levels. Even so, these systems are limited by irreversibly, and insulin entering the bloodstream takes time to work.
An apparent more effective strategy is to give insulin glucose-responsive properties that let it respond to glucose reversibly. To achieve such an insulin molecule would require two key properties: glucose binding with optimal sensitivity to the fluctuating glucose levels in diabetics (from approximately 2 to 20–30 mM) and a mechanism to reversibly “shut off” insulin receptor binding activity at low glucose levels. To address glucose sensitivity, Merck created a system that changed insulin clearance and, consequently, insulin action in response to blood glucose. Still, because of its incredibly low efficacy, this system did not merit advancement past phase I clinical trials. The closest example of a reversely glucose-sensitive insulin was created by Thermalin and Indiana University School of Medicine. It was insensitive to glucose but sensitive to fructose at high concentrations.
NNC2215 responds to glucose and reduces hypoglycemia
The two characteristics of glucose sensitivity and reversibility served as the foundation for the development of the NNC2215 insulin variant by Novo Nordisk researchers. NNC2215 relies on macrocycles, which are cyclic molecules that resemble drugs and have a large molecular size and a large binding surface with the receptors. The ability of macrocycles to affect biological and physiochemical properties and their superior selectivity over their acyclic counterparts has sparked a growing interest in medicinal chemistry. The approval of contemporary pharmaceutical agents like Lorlatinib for treating non-small cell lung cancer (NSCLC) demonstrates the noteworthy clinical relevance of drug-like macrocycles.The Novo Nordisk researchers took inspiration from recent work by Ziylo and University of Bristol researchers who created a macrocycle with a glucose-binding cavity that ensures a relevant affinity for glucose and selectivity over other carbohydrates and possibly interfering small molecules. By using this macrocycle to form an insulin conjugate, NNC2215 showed that when glucose was increased from 0 to 20 mM, its insulin receptor binding affinity increased by 12.5 times, and when it was increased from 3 to 20 mM, it increased by 3.2 times.
The Novo Nordisk team tested NNC2215 in three in vivo animal models. First, in a rather straightforward acute rat model, the glucose sensitivity in vivo was confirmed by administering l-glucose at a dose that triggered the insulin effect of NNC2215 without inducing endogenous insulin release. When l-glucose activated NNC2215, d-glucose lowered dose-dependently, and NNC2215 was concurrently dose-dependently cleared by l-glucose. Second, during a glucose challenge in insulinopenic streptozotocin (STZ)-diabetic rats, the Novo Nordisk researchers also noticed an activation of NNC2215, equivalent to 30% more human insulin. Finally, NNC2215’s glucose-sensitive insulin receptor binding and cellular effects showed a protective effect against hypoglycemia in vivo using a pig model that resembles acute diabetes.
In conclusion, insulin conjugates with characteristics like NNC2215 can potentially improve diabetes treatment by reducing the risk of hypoglycemia and partially substituting for the need for fast-acting insulin during meals. Compared to existing insulin therapies, combining these two characteristics should enable more aggressive insulin titration to reach normal glucose levels without raising the risk of hypoglycemia. This could reduce the risks and complications of diabetes in the short and long term.
