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.

Stem Cells and Type 1 Diabetes: What the Future Has in Store


Stem cell

 

A pancreas transplant has always stood out as a possible ‘cure’ for type 1 diabetes (T1D), but one problem has been obvious: there just are not enough organ donors-on the order of 10,000 a year-while there are between 1 and 2 million people with T1D in the U.S. In a kidney transplant, a healthy donor can donate one of two functioning kidneys with a generally low-risk surgery, and still have normal kidney function. A similar approach with part of the pancreas would be unsafe. In addition, a pancreas transplant is generally less successful than a kidney transplant, and there are higher risks of serious side effects after pancreatic transplant surgery. The math is even worse when trying to transplant insulin-producing islets, because more than one donor is needed per recipient, which has stopped islet cell transplant from taking hold outside of a few centers. Furthermore, transplants of any sort require lifelong use of powerful and expensive medications that suppress immune function and can also cause serious side effects.

But what if we could transplant insulin-producing cells made in the lab? Wouldn’t that solve the donor dilemma? Yes, but the recipient with by far the most common form of T1D would still require immune suppression. Their immune system already destroyed, and is continuing to destroy, their insulin- producing beta cells. This would be true even if the insulin producing cells were derived from their own tissue. But what if we could protect new insulin-producing cells from the recipient’s immune system another way?

It is now possible to manufacture insulin-producing cells in the lab, using multiple different techniques developed by a multitude of researchers (Type 1 Diabetes Treatments Based on Stem Cells, Arana et al., Current Diabetes Reviews, 2018, 14, 14-23). That is a huge step forward, and a tribute to the benefit of supporting basic and applied research. Researchers are working on ways to ‘hide’ the new cells from the recipient’s immune system by altering the cells immune ‘appearance’, or more selectively suppressing the immune attack by the host. Hopefully, those efforts will pay off someday. But how about putting the new cells behind a barrier that the immune system cannot get through?

ViaCyte, a privately-held bioresearch company, reported some intriguing results at this year’s American Diabetes Association Scientific Sessions: the two-year data from the ongoing Safety, Tolerability, and Efficacy of PEC-Encap™ Product Candidate in type 1 diabetes (STEP ONE) clinical trial. The PEC-Encap consists of stem cell-derived cells that can develop into insulin-producing cells, encapsulated in a delivery device that is surgically implanted under the skin, called the Encaptra® Cell Delivery System. This system is designed to block immune access to the new cells but allow insulin, glucagon, glucose and other nutrients to pass through the membrane. The results indicate that the PEC-Encap product did not trigger a specific immune response against the new cells or the device itself, and it appeared to be safe. That’s the good news. Unfortunately, few of the implanted devices allowed enough new blood vessel growth from the host to sufficiently nourish the new cells, so in most cases, the new insulin-producing cells did not last. This appeared to result primarily from a foreign body reaction, a non-specific response of the recipient’s immune system that is similar to what one might find develop around a splinter. ViaCyte is now working on modifying the system to improve the potential for long-term survival of the manufactured insulin-producing cells.

If these or other similar efforts are successful, a large percentage of those with T1D could ultimately receive a functional ‘cure’. In addition, those with long-term type 2 diabetes (T2D) who can no longer produce much insulin, a common state that makes blood sugar management very difficult, might also benefit from this promising new therapy.

A second, perhaps less ambitious device is also under development, PEC-Direct™, one which would still require the use of immunosuppression medication. However, since the cells can be generated in a lab in potentially unlimited numbers, there is no need for organ donors. Thus, a much larger group of people might be able to benefit from transplanted insulin-producing cells, albeit with the need for immunosuppression. The current plan is to consider such a transplant for those with T1D who suffer from recurrent severe hypoglycemia episodes or have hypoglycemia unawareness, conditions which are life-threatening. Those who are unable to manage T1D effectively due to highly variable blood glucose levels, so-called ‘brittle’ diabetes, could also benefit. Together, such groups are thought to represent about 10% of all people with T1D.

In summary, there is great news in the stem cell arena; insulin-producing cells can be made in unlimited numbers. While not yet ready for clinical use in people with diabetes, rapid progress is being made. We waited for finger sticks to become available, so we could finally see what we so desperately needed to see–where is my blood glucose, right now. We waited for insulin pumps and better insulins, so we could do what we so desperately needed to do, right now-tame T1D’s wild blood glucose fluctuations. We waited for continuous glucose monitoring, so we could know what we so desperately needed to know- where is my blood sugar going, right now. Stems cells have the potential to deliver what we all still so desperately want- relief from the 24/7/365 burden of thinking and acting like a beta cell. Stay tuned, T1D nation!

Nicholas B. Argento, MD, Diabetes Technology Director, Maryland Endocrine and Diabetes

A new way to generate insulin-producing cells in Type 1 diabetes .


A new study by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has found that a peptide called caerulein can convert existing cells in the pancreas into those cells destroyed in type 1 diabetes-insulin-producing beta cells. The study, published online July 31 in Cell Death and Disease, suggests a new approach to treating the estimated 3 million people in the U.S., and over 300 million worldwide, living with type 1 diabetes.

“We have found a promising technique for type 1 diabetics to restore the body’s ability to produce insulin. By introducing caerulein to the pancreas we were able to generate new —the cells that produce insulin—potentially freeing patients from daily doses of insulin to manage their blood-sugar levels.” said Fred Levine, M.D., Ph.D., professor and director of the Sanford Children’s Health Research Center at Sanford-Burnham.

The study first examined how mice in which almost all beta cells were destroyed—similar to humans with —responded to injections of caerulein. In those mice, but not in normal mice, they found that caerulein caused existing in the pancreas to differentiate into insulin-producing beta cells. Alpha cells and beta cells are both endocrine cells meaning they synthesize and secret hormones—and they exist right next to one another in the pancreas in structures called islets. However, alpha cells do not normally become beta cells.

The research team then examined human pancreatic tissue from type 1 diabetics, finding strong evidence that the same process induced by caerulein also occurred in the pancreases of those individuals. The process of alpha cells converting to beta cells does not appear to have any age limitations—it occurred in young and old individuals—including some that had type 1 diabetes for decades.

“When caerulein is administered to humans it can cause pancreatitis. So our next step is to find out which molecule(s) caerulein is targeting on alpha cells that triggers their transformation into beta cells. We need to know this to develop a more specific drug,” said Levine.

Caerulein is a peptide originally discovered in the skin of Australian Blue Mountains tree frogs. It stimulates gastric, biliary, and pancreatic secretions, and has been used in humans as a diagnostic tool in pancreatic diseases.

“In addition to creating new beta cells, another issue that needs to be addressed to achieve a cure for type 1 diabetes is that any new beta cells will be attacked by the present in every patient with type 1 diabetes. We are currently working with Linda Bradley, Ph.D., professor in the Immunity and Pathogenesis Program, and co-author of the study, to couple our approach with an approach to reining in the autoimmune response,” added Levine.

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