NEW YORK, Feb. 12, 2020 /PRNewswire-PRWeb/ -- Researchers
at the Icahn School of Medicine at Mount
Sinai have discovered a novel combination of two classes of
drugs that, together, cause the highest rate of proliferation ever
observed in adult human beta cells—the cells in the pancreas that
produce insulin—without harming most other cells in the body. The
result is an important step toward a diabetes treatment that
restores the body's ability to produce insulin.
The finding involved one type of drug that is known to cause
beta cells to proliferate and another that is already in widespread
use in people with diabetes. Together, they caused the cells to
proliferate at a rate of 5 to 6 percent per day. The study was
published today in Science Translational Medicine online. For a
video about this study click here.
"We are very excited about this new drug combination because for
the first time ever, we are able to see rates of human beta cell
replication that are sufficient to replenish beta cell mass in
humans with diabetes," said Andrew
Stewart, MD, Director of the Mount Sinai Diabetes, Obesity,
and Metabolism Institute and lead author of the study.
Diabetes occurs when there are not enough beta cells in the
pancreas, or when those beta cells secrete too little insulin, the
hormone required to keep blood sugar levels in the normal range.
Approximately 30 million people in the
United States have diabetes and nearly 50 to 80 million more
are living with prediabetes (also called "metabolic syndrome").
Diabetes can lead to major medical complications: heart attack,
stroke, kidney failure, blindness, and limb amputation.
In type 1 diabetes, the immune system mistakenly attacks and
destroys beta cells. A deficiency of functioning beta cells is also
an important contributor to type 2 diabetes, the most common type
of diabetes. Thus, developing drugs that can increase the number of
healthy beta cells is a major priority in diabetes research.
According to Dr. Stewart, none of the diabetes drugs currently
on the market can induce beta cell regeneration in people with
diabetes. In parallel with the Mount
Sinai work, other researchers are studying pancreatic
transplantation, beta cell transplantation, and stem cell
replacement of beta cells for people with diabetes, but none of
these approaches is in widespread use.
"This is a very exciting discovery in the field of diabetes and
is a key next step in drug development for this disease," said
Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of
Medicine at Mount Sinai. "This
important work truly holds promise for so many people."
In 2015, Dr. Stewart and his team published a paper in Nature
Medicine that showed that harmine, a drug that inhibits the enzyme
dual specificity tyrosine-regulated kinase 1A (DYRK1A), induced
multiplication of adult human beta cells. In that study, his team
also discovered that harmine treatment led to normal control of
blood sugar and proliferation in human beta cells in diabetic mice
whose beta cells had been replaced with small numbers of
transplanted human beta cells. While this was a major advance, the
proliferation rate was lower than needed to rapidly expand beta
cells in people with diabetes.
This current paper builds upon a study that Dr. Stewart and his
team published in Cell Metabolism in December 2018 where they discovered that DYRK1A
inhibitors combined with another drug that inhibits transforming
growth factor beta superfamily members (TGFβSF), also known as a
family of proteins with various biological processes such as
growth, development, tissue homeostasis and immune system, could
cause beta cells to proliferate at a rate of 5 to 8 percent per
day. However, according to Dr. Stewart, TGFβSF's would likely have
side effects on other organs in the body that would prevent
clinical use.
The next challenge was developing ways to target regenerative
drugs to the beta cells while avoiding other cells and organs in
the body where they may elicit adverse effects.
In the study published today, titled "GLP-1 receptor agonists
synergize with DYRK1A inhibitors to potentiate functional human
beta cell regeneration," Dr. Stewart and his team combined DYRK1A
inhibitors like harmine with a class of beta cell-targeting drugs,
also known as GLP1R agonists, which are already in widespread use
in people with type 2 diabetes. They showed—in beta cells from
normal people and people with type 2 diabetes, both in the tissue
culture dishes and in human beta cells transplanted into mice—that
combining harmine (or any other DYRK1A inhibitor) with any of the
many GLP1R agonist drugs currently on the market for diabetes
yields high rates of human beta cell replication, and does so in a
way that is highly selective for the beta cell.
The project arose from the PhD thesis of an Icahn School of
Medicine graduate student, Courtney
Ackeifi, now a postdoctoral fellow in Dr. Stewart's lab and
first author of the paper, who explored a broad spectrum of
potential drug partners that could enhance the beta cell
regenerative efficacy and selectivity of harmine.
Dr. Ackeifi of the discovery said, "The beauty here is that the
combination of DYRK1A inhibitors with GLP1R agonists achieves the
highest rate of human beta cell replication possible, and does so
in a highly specific way. This is an important advance in the field
of diabetes because we may have found a way to convert a widely
used class of diabetes drugs into a potent human beta cell
regenerative treatment for all forms of diabetes."
"We know that a critical pathway to drive a cure for type 1
diabetes includes transplanting insulin-producing beta cells into
people or enticing their existing beta cells to start multiplying,"
explains Francis Martin, JDRF
Director of Research. "It is exciting to learn from the work of Dr.
Stewart and his team that GLP1R agonists could increase the effect
of the recently discovered agents that promote multiplication.
Using GLP1R offers a means to boost the effect while also improving
the safety of this type of drug."
The next goals of the project are to perform long-term studies
in animals transplanted with human beta cells, and to determine if
any cells or organs in the body other than beta cells are affected
by the new drug combination.
This work was supported by funding from: NIH grants T32 GM062754
(to CA), DK105015 (to AFS), DK105015-01A1S1 (to CA), P-30 DK 020541
(to AFS and AG-O) and UC4 DK104211 (to AFS), by JDRF Grants 2-SRA-
2015-62 (to AFS) and 2-SRA-2017 514-S-B (to AFS), and by the Icahn
School of Medicine at Mount
Sinai.
Also making key research contributions were Esra Karakose, PhD;
Hongtao Liu, BS; Jessica Wilson, BS; Ethan Swartz, BS; Cecilia Berroute, BS; Yansui Li, MD;
Kunal Kumar, PhD; Roberto Sanchez, PhD; Robert DeVita, PhD; Dirk
Homann, MD, PhD; Donald K.
Scott, PhD; and Adolfo Garcia-Ocaña, PhD from the Diabetes,
Obesity, and Metabolism Institute, the Department of
Pharmacological Sciences, and The Drug Discovery Institute at the
Icahn School of Medicine at Mount
Sinai.
Additional investigators included researchers from The Naomi
Berrie Diabetes Center and the Columbia Stem Cell Center at
Columbia University (Bryan J. González,
BS; Dieter Egli, PhD); The
Department of Pharmacology and The Alberta Diabetes Institute, The
University of Alberta, Edmonton, Alberta, Canada (Jocelyn E. Manning Fox, PhD; Patrick E. MacDonald, PhD); and the Center for
Integrative Genomics at the University of Lausanne in Switzerland (Bernard
Thorens, PhD).
About JDRF
JDRF is the leading global organization funding type 1 diabetes
(T1D) research. Our mission is to accelerate life-changing
breakthroughs to cure, prevent and treat T1D and its complications.
To accomplish this, JDRF has invested more than $2.2 billion in research funding since our
inception. We are an organization built on a grassroots model of
people connecting in their local communities, collaborating
regionally for efficiency and broader fundraising impact, and
uniting on a national stage to pool resources, passion, and energy.
We collaborate with academic institutions, policymakers, and
corporate and industry partners to develop and deliver a pipeline
of innovative therapies to people living with T1D. Our staff and
volunteers throughout the United
States and our six international affiliates are dedicated to
advocacy, community engagement and our vision of a world without
T1D. For more information, please visit jdrf.org or follow us on
Twitter: @JDRF.
About the Mount Sinai Health System
The Mount Sinai Health System is New York
City's largest academic medical system, encompassing eight
hospitals, a leading medical school, and a vast network of
ambulatory practices throughout the greater New York region. Mount Sinai is a national and international
source of unrivaled education, translational research and
discovery, and collaborative clinical leadership ensuring that we
deliver the highest quality care—from prevention to treatment of
the most serious and complex human diseases. The Health System
includes more than 7,200 physicians and features a robust and
continually expanding network of multispecialty services, including
more than 400 ambulatory practice locations throughout the five
boroughs of New York City,
Westchester, and Long Island. The Mount Sinai Hospital is
ranked No. 14 on U.S. News & World Report's "Honor Roll" of the
Top 20 Best Hospitals in the country and the Icahn School of
Medicine as one of the Top 20 Best Medical Schools in country.
Mount Sinai Health System hospitals are consistently ranked
regionally by specialty and our physicians in the top 1% of all
physicians nationally by U.S. News & World Report. For more
information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and
YouTube.
SOURCE Mount Sinai Health System