Plant Hallucinogen Holds Hope for Diabetes Treatment

A potent molecular cocktail containing a compound from ayahuasca spurs rapid growth of insulin-producing cells

Plant Hallucinogen Holds Hope for Diabetes Treatment
Ayahuasca cooking.

For centuries, some indigenous groups in South America have relied on a brew made from the parts of a local vine and a shrub. The effects of this drink, called ayahuasca, would begin with severe vomiting and diarrhea, but the real reason for drinking the tea was the hallucinating that followed. These visions were thought to uncover the secrets of the drinker’s poor health and point the way to a cure.

Modern techniques have revealed that one of the compounds underlying these mystic experiences is the psychoactive drug harmine. What these first users of ayahuasca couldn’t have known was that, one day, this ingredient in their enlightening brew would be positioned as a key to treating diabetes.

Such a cure is a long way off, but researchers took another step toward it when they combined naturally occurring harmine with a compound synthesized from scratch in a lab. Together, the pair can coax the insulin-producing pancreatic cells, called beta cells, into replicating at the fastest rates ever reported, according to findings published December 20 in Cell Metabolism.

Type 1 diabetes arises when the body turns on these cells and destroys them. Type 2 diabetes develops when these same cells wear out and can no longer make insulin. Either effect is a point of no return because the beta cells we make in early life are the only ones we’ll ever have.

If this pair of compounds eventually inches into the treatment toolbox, refreshing a faded cell population could become a reality and a possible treatment for diabetes.  “Looking back 10 years or so, we questioned whether human beta cells could even be coaxed into dividing,’ says Justin Annes, assistant professor of medicine and endocrinology at Stanford University, who also works on beta cell proliferation, with a separate investigator group. “But what began as a fantasy has become aspiration, and perhaps in the coming years, will be a reality.”

One stop on the trip to that reality was a 2015 study showing that harmine treatment of beta cells in a dish promoted their increase at a rate of about 2 percent per day. A promising beginning, says study author Andrew Stewart, scientific director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, but a little too slow for someone who needs a replacement population.

In this newest study, Stewart and his colleagues show that combining harmine with a synthetic inhibitor of another molecule kicks up the rate to 5–8 percent on average, and as high as 18 percent using some growth recipes. The one–two punch of this chemical pair isn’t the only possible combination, and other groups also are working on various pairings, Stewart says. Annes and his colleagues have identified several compounds that hold similar promise for pushing insulin-producing cells to reproduce.

“Basically, we’re all competing, but we all know each other so we share reagents and ideas,” says Stewart. “Different people have identified different drugs that make beta cells replicate.” His lab chose harmine because it’s the one they pulled out of their screening of 100,000 compounds in 2015, but “I don’t think harmine is especially better than any other one,” he says.

In 2006, another group of researchers plucked harmine from a molecular haystack in a search for chemicals that interact with a protein associated with Down syndrome. Studies that followed showed harmine’s role in many body systems, including the gut and the brain, explaining in part the effects of ayahuasca on its earliest adopters.

Harmine interferes with an enzyme called dual-specificity tyrosine-regulated kinase 1A, or DYRK1A. Like harmine, DYRK1A operates in a host of tissues.  It helps, for one, in shaping the central nervous system during embryonic development. First identified because of its key involvement in Down syndrome, its routine duty is to add chemical tags to molecules to switch them on or off.

The other molecule in the synergizing pair is an inhibitor of a group of proteins in the transforming growth factor-beta superfamily (TGFβSF). As with DYRK1A, these proteins are active in a large number of body processes, including cell proliferation.

Stewart and his team homed in on TGFβSF and DYRK1A after probing the secrets of cells from benign pancreatic tumors called insulinomas. They reasoned that if they could pinpoint what made these tumors grow, they could co-opt that information to encourage growth of normal beta cells. Their exploration uncovered DYRK1A and TGFβSF-related targets.

Inhibiting these molecules in human beta cells in a dish shuts down the cell regulators that usually keep the brakes on cancer’s out-of-control cell growth. Because harmine and TGFβSF inhibitor release this brake and DYRK1A and TGFβSF are active in many tissues, any treatment involving the pair of inhibitors must be closely targeted. “Certainly, we have a long way to go before these medications can be used in humans,” says Annes, calling the concern about cancer risk “reasonable.”

Adding to that concern is that harmine affects other cell types, says Klaus Kaestner, professor of genetics and associate director of the Penn Diabetes Research Center at the University of Pennsylvania, who was not involved in the study. In 2016, his group reported that harmine triggers many types of hormone-producing cells to divide, including other cells in the pancreas.

Stewart and his colleagues are sorting through a number of potential chemical tags that might help guide the inhibitors to the right location. But for now, says Stewart, “we are Amazon and have a bunch of parcels, and we know that they’re for you, but we don’t know the address.”

Type 1 diabetes poses another hurdle. Although the immune system targets and destroys these cells in this form of diabetes, a small pool of beta cells often remains, Stewart says. What’s unknown is if a new population grown from these cells would simply attract further immune destruction. Stewart says that if the harmine-TGFβSF inhibitor combination ever makes it to trials, the population it might initially suit best are those who have type 2 diabetes. Then the journey from a South American rainforest to a clinical treatment would be complete.

Human clinical trial of drug shown to completely reverse diabetes in human islets, mice

New research conducted at the University of Alabama at Birmingham has shown that the common blood pressure drug verapamil completely reverses diabetes in animal models. Now, thanks to a three-year, $2.1 million grant from the JDRF, UAB researchers will begin conducting a potentially groundbreaking clinical trial in 2015 to see if it can do the same in humans.

The trial, known as “the repurposing of verapamil as a beta cell survival therapy in type 1 diabetes,” is scheduled to begin early next year and has come to fruition after more than a decade of research efforts in UAB’s Comprehensive Diabetes Center.

The trial will test an approach different from any current diabetes treatment by focusing on promoting specialized cells in the pancreas called beta cells, which produce insulin the body needs to control . UAB scientists have proved through years of research that high blood sugar causes the body to overproduce a protein called TXNIP, which is increased within the beta cells in response to diabetes, but had never previously been known to be important in beta cell biology. Too much TXNIP in the pancreatic beta cells leads to their deaths and thwarts the body’s efforts to produce insulin, thereby contributing to the progression of diabetes.

But UAB scientists have also uncovered that the drug verapamil, which is widely used to treat high blood pressure, irregular heartbeat and migraine headaches, can lower TXNIP levels in these beta cells—to the point that, when mouse models with established diabetes and blood sugars above 300 milligrams per deciliter were treated with verapamil, the disease was eradicated.

“We have previously shown that verapamil can prevent diabetes and even reverse the disease in mouse models and reduce TXNIP in human islet beta cells, suggesting that it may have beneficial effects in humans as well,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and principal investigator of the verapamil clinical trial. “That is a proof-of-concept that, by lowering TXNIP, even in the context of the worst diabetes, we have beneficial effects. And all of this addresses the main underlying cause of the disease—beta cell loss. Our current approach attempts to target this loss by promoting the patient’s own beta cell mass and insulin production. There is currently no treatment available that targets diabetes in this way.”

The trial will enroll 52 people between the ages of 19 and 45 within three months of receiving a diagnosis of type 1 diabetes. Patients enrolled will be randomized to receive verapamil or a placebo for one year while continuing with their insulin pump therapy. In addition, they will receive a continuous glucose monitoring system that will enable them to measure their blood sugar 24 hours a day, seven days a week.

Fernando Ovalle, M.D., director of UAB’s Comprehensive Diabetes Clinic and co-principal investigator of the study, helped develop the clinical trial and will oversee all clinical aspects of the trial, including subject recruitment, treatment, testing, and data acquisition and analysis. Recruitment for the trial will begin in early 2015.

“Currently, we can prescribe external insulin and other medications to lower blood sugar; but we have no way to stop the destruction of beta cells, and the disease continues to get worse,” Ovalle said. “If verapamil works in humans, it would be a truly revolutionary development in a disease affecting more people each year to the tune of billions of dollars annually.”

Battling a health crisis

Diabetes, which is the nation’s seventh-leading cause of death, raises risks for heart attacks, blindness, kidney disease and limb amputation. Recent federal government statistics show that 12.3 percent of Americans 20 and older have diabetes, either diagnosed or undiagnosed. Another 37 percent have pre-diabetes, a condition marked by higher-than-normal blood sugar. That is up from 27 percent a decade ago.

While a new report in the Journal of the American Medical Association showed rates at which new cases are accumulating have slowed in recent years, the numbers remain high and are still increasing overall, with 8.3 percent of adults diagnosed with the disease as of 2012. And no slowing of the disease has been seen in new cases among blacks and Hispanics or in overall rates among people with high school educations or less.

Plus, the annual cost to treat the disease is exorbitant—and rising. The American Diabetes Association reports that the disease cost the nation $245 billion in 2013.

Researchers have known for some time that beta cells are critical in type 1 and type 2 diabetes. The cells are gradually lost in both types of the disease due to programmed cell death, but the exact triggers for the deaths were previously unknown. Somewhat surprisingly, it was also noted that, after years—decades, even—of living with type 1 diabetes, where beta cells were thought to be completely destroyed early on by the autoimmune process, patients still had a measurable amount of beta cell function; it just was not enough to maintain a normal blood sugar.

Shalev says replacing this beta cell mass by transplantation has proved more difficult and problematic than initially thought, but creating an environment that would enable beta cells to survive and possibly regenerate or become functional again does provide an attractive alternative by increasing the body’s own beta cell mass. UAB lab studies have shown verapamil to be extremely effective in this area, which has helped to make this clinical trial—funded by the JDRF, the largest charitable supporter of type 1 diabetes research—a possibility now.

JDRF is funding this study as part of its beta cell restoration research program whose goal is to restore a person’s ability to produce their own insulin—in essence, a biological cure for type 1 diabetes.

“A first step towards that goal may be the ability to improve the survival and functioning of a person’s beta cells shortly after diagnosis,” said JDRF director of Discovery Research, Andrew Rakeman, Ph.D. “This study represents the result of years of investment in basic research at JDRF. We are now at the stage of translating basic laboratory research into potential significant new therapies for type 1 diabetes and we’re excited to support Dr. Shalev’s team to test this concept in a study of people with type 1 diabetes. Finding a therapy to improve beta cell survival and functioning would put JDRF’s efforts to find a cure on a new trajectory.”

Ovalle will manage all patients with the use of insulin pumps and continuous glucose sensors and co-manage patients who are already seeing another endocrinologist remotely. UAB’s clinic team will analyze patients’ blood sugar control and their ability to produce insulin. They will also use a more complex test known as c-peptide response as a way to measure beta cell insulin production and functional beta cell mass.

One of the truly unique and different aspects of this clinical trial is that, unlike most type 1 diabetes trials, the verapamil trial does not include the use of any immunosuppressive or immune modulatory medications, which often have very severe side effects.

“This trial is based on a well-known blood pressure medication that has been used for more than 30 years and is unlikely to have any severe side effects,” Shalev said. “This study is also backed by a lot of strong mechanistic data in different mouse models and human islets, and we already know the mechanisms by which verapamil acts. Finally, unlike any currently available diabetes treatment, the trial targets the patient’s own natural beta cell mass and insulin production.”

A first step

Shalev says the trial is a first step in the direction of such a novel diabetes treatment approach.

“While in a best-case scenario, the patients would have an increase in beta cells to the point that they produce enough insulin and no longer require any insulin injections—thereby representing a total cure—this is extremely unlikely to happen in the current trial, especially given its short duration of only one year,” Shalev said.

Shalev expects verapamil to have a much more subtle yet extremely important effect.

“We know from previous large clinical studies that even a small amount of the patient’s own remaining beta cell mass has major beneficial outcomes and reduces complications,” Shalev said. “That’s probably because even a little bit of our body’s own beta cells can respond much more adequately to very fine fluctuations in our blood sugar—much more than we can ever do with injections or even sophisticated insulin pumps.”

Because verapamil’s mode of action is different from current drugs or interventions, this opens up an entirely new field for diabetes drug discovery—one that UAB’s Comprehensive Diabetes Center is already engaged in with the Alabama Drug Discovery Alliance, a partnership between UAB’s School of Medicine and Southern Research Institute. The group is actively looking for small therapeutic molecules that inhibit TXNIP to protect the and treat diabetes.

“We want to find new drugs—different from any current diabetes treatments—that can help halt the growing, worldwide epidemic of and improve the lives of those affected by this disease,” Shalev said. “Finally, we have reason to believe that we are on the right track.”

FDA opens dialogue on interim results of CV safety in diabetes drug trials

The FDA has launched a dialogue on how to handle confidentiality of the interim results for cardiovascular outcomes in diabetes treatment trials while new trials are still ongoing.

“General agreement was expressed that this is a balancing act,” said Lisa LaVange, PhD, director for the Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research at the FDA. “Balance is needed to give effective therapies to patients as soon as possible, but not jeopardizing our primary questions of interest about cardiovascular safety.”

To demonstrate a new diabetes therapy is not associated with an unacceptable increase in CV risk, guidance from the FDA has required that pre-marketing data show the incidence of events is no more than an 80% increase compared with the control group; this means the upper bound of the two-sided 95% CI for risk ratio is less than 1.8.

Further, if the risk ratio is determined to be between 1.3 and 1.8, and the remaining risk-benefit analysis supports therapy approval, a post-marketing trial is generally required to show the risk ratio is less than 1.3.

Safe dissemination

Viewpoints were put forth on how various groups involved in a trial could safely learn such detailed interim data without undermining the trial’s integrity and jeopardizing its continuation.

“People have to believe that the purpose of medical research is providing high integrity, high quality outcome results,” said Steven E. Nissen, MD, MACC, chairman of the department of cardiovascular medicine at Cleveland Clinic. “The most important thing here is to have standards about who gets to know and who doesn’t get to know and for what reasons they get to know.”

Steven E. Nissen, MD, MACC

Steven E. Nissen

Groups discussed included: the sponsor, enlisted by the Agency to conduct post-marketing trials related to risks; the Data Monitoring Committee (DMC), established to review interim results and make recommendations to the sponsor; the drug company’s management; staff and trial participants; and the public.

“Any options that are likely to compromise the equipoise of the trial, that could irreversibly bias the investigators and subjects and could limit the likelihood of collecting the required number of CV events, are not really tenable or recommended,” said Matthew T. Roe, MD, MHS, a member of the American Heart Association (AHA) Mission Lifeline Scientific Task Force.

Previous FDA guidance on best practices for the DMC’s recommended procedures were established to “safeguard confidential interim data from the project team, investigators, sponsor representatives, or anyone else outside of DMC and the statistician(s) performing the interim analyses,” according to the Federal Register.

Raising concerns

Among the concerns raised about widespread disclosure of results was a change in recruitment or treatment administration, along with loss of objectivity in reporting safety events or managing the remainder of the trial. Conversely, knowing the results early could offer more timely marketing opportunities, providing patients access to new therapies sooner.

John Jenkins, MD, director for the Office of New Drugs, Center for Drug Evaluation and Research at the FDA,noted the diabetes field only deals with “full” approval — not “conditional” or “interim.”

“We accept HbA1c as a validated surrogate for approval of drugs to treat diabetes, assuming the benefits outweigh the risks,” Jenkins said. This means the interim analyses are used to assess CV safety as part of that equation, he added, with post-marketing requirements issued thereafter; to date, all therapies have met the 1.3 risk ratio.

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