In
a screen of more than 100,000 potential drugs, only one, harmine, drove human insulin-producing
beta cells to multiply, according to a study led by researchers at the Icahn
School of Medicine at Mount Sinai, published in Nature Medicine. Diabetes results from too few insulin-producing “beta
cells” in the pancreas. Insulin is the hormone required to keep blood sugar
levels in the normal range. In a
groundbreaking Mount Sinai study, researchers found that harmine drove the sustained
division and multiplication of adult human beta cells in culture, a feat that
had eluded the field for years.
In addition, harmine treatment tripled the
number of beta cells and resulted in improved better blood sugar control in
three groups of mice engineered to mimic human diabetes. “Our results provide a
large body of evidence demonstrating that the harmine drug class can make human
beta cells proliferate at levels that may be relevant for diabetes treatment,”
said senior study author Andrew Stewart, MD, Director of the Diabetes, Obesity
and Metabolism Institute at the Icahn School of Medicine. “While we still have a lot of work to do in improving the specificity
and potency of the harmine and related compounds, we believe these results
represent a key step toward more effective future treatment of diabetes.” Loss
of insulin-producing beta cells has long been recognized as a cause of Type 1
diabetes, in which the immune system mistakenly attacks and destroys beta
cells. In recent years, researchers concluded that a deficiency of functioning
beta cells also contributes to Type 2 diabetes. Thus, development of drugs that
can increase the numbers of healthy beta cells is a major priority in diabetes
research.
Re-Creating a Burst
As
humans develop, each cell divides into two, leading to many more cells in subsequent
generations as organs form. In the case of beta cells in the pancreas, most of this multiplication
comes in a burst during the first year of life and then declines during
childhood, leaving a limited supply to last a lifetime. During this burst, about
two percent of a child’s beta cells are dividing at any one time. The current
study found that harmine re-creates roughly the same amount of beta cell division,
in cell and animal tests. While
increasing the supply of beta cells seems an obvious approach, past attempts to
do so have met with limited success. Perhaps as a result of their unique genetic
program, adult beta cells strongly resist attempts to nudge them into cell
division.
Over
several years, Dr. Stewart and colleagues unraveled genes and signaling
pathways that drive multiplication (proliferation) of beta cells, and then
confirmed proposed mechanisms with gene therapy. Based on the current study
results, the team believes a particular enzyme, “dual specificity tyrosine-regulated
kinase-1a (DYRK1A)”, is the likely target of harmine. With this discovery,
DYRK1A, known from past studies to drive cell division in other cell types, becomes
a drug development target.
“We
found that harmine, likely by interacting with DYRK1A, increases levels of
other known drivers of cell division,” said Peng Wang, PhD, Assistant Professor of Medicine,
Endocrinology, Diabetes, and Bone Disease at the Icahn School of Medicine and first
author of the paper. “These drivers include
the protein c-MYC, the gene which was the basis of the screen we used to identify
harmine as a potential treatment.” Dr. Wang said the team designed a sensor to
glow (thanks to a firefly gene) when any compound activated the promoter DNA
snippet responsible for turning on the c-MYC gene. Of more than 100,000 compounds
analyzed in a high-speed robotic screen, harmine was among 86 that caused the
brightest glow, and was the only one that caused beta cell proliferation. The c-MYC
pathway appeared to be an unlikely therapeutic target for beta cell
regeneration because past studies identified that it caused beta cell death
when activated in high doses. However, researchers
found in the current study found that harmine causes only modest increases in
c-MYC levels, and no beta cell death.
The research
team will now focus on making changes to harmine and its relatives to find drug
candidates that target only beta cells. Harmine is derived from a flowering plant called
Harmal (peganum Harmala) found in the Middle East, and from some South American
vines. Drug development efforts based on harmine will need to grapple with its
known psychoactive effects on the brain, which may explain its traditional use in
spiritual ceremonies and as medicine.
