Novel drug candidate regenerates pancreatic cells lost in diabetes

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, funded by JDRF and the National Institutes of Health, and published online today in Nature Medicine.

Diabetes results from too few insulin-producing "beta cells" in the pancreas secreting too little insulin, the hormone required to keep blood sugar levels in the normal range. The disease affects 380 million people worldwide, and leads to major medical complications: heart attack, stroke, kidney failure, blindness and limb amputation.

The Mount Sinai study 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 led to better control of blood sugar 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 have concluded that a deficiency of functioning beta cells also contributes importantly to Type 2 diabetes. Thus, developing 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, both in cell and animal tests.

While increasing the supply of beta cells seems an obvious approach, past attempts to do so have been 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 for 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 of these that caused beta cell proliferation. The c-MYC pathway appeared to some researchers to be an unlikely therapeutic target for beta cell regeneration because past studies had found it to cause beta cell death when activated in high doses. However, 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 the harmine and its relatives (harmalogs) 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.

The study was funded by grants from JDRF, the leading research and advocacy organization funding type 1 diabetes research (17-2011-598 and 1-2011-603).

"We believe that beta cell regeneration will play a key role in ultimately curing type 1 diabetes, and JDRF is pleased to support Dr. Stewart's research into renewing these cells in humans," said Patricia Kilian, PhD, director of the JDRF Regeneration Research Program. "If successful, this early research could lead to drugs that restore beta cells in people with type 1 diabetes, realizing the vision of a future free from insulin therapy."

A significant number of natural compounds have been shown to regulate the behavior of the cells, in collaboration with cellular proteins. CCN2/connective tissue growth factor (CTGF) has been reported to have essential roles in cartilage development, chondrocyte proliferation and differentiation as well as regulation of the extracellular matrix metabolism. Previous studies demonstrated the capability of CCN2 to regenerate surgical defects in articular cartilage of rat knee. Also, transgenic mice over-expressing cartilage-specific CCN2 were shown to be more resistant to aging-related cartilage degradation. We hypothesized that small molecules that induce CCN2 in chondrocytes could be novel candidates to increase the resistance to aging-related cartilage degradation, or even to correct cartilage degenerative changes incurred in OA. Therefore, this study screened a compound library and identified the β-carboline alkaloid harmine as a novel inducer of CCN2 in human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes. Harmine increased the expression of the cartilage markers aggrecan and COL2α1, as well as that of the master regulator of chondrogenesis, SOX-9. Moreover, harmine notably induced chondrogenesis of prechondrocytic ATDC5 cells in micromass cultures. The chondroprotective effect of harmine was investigated under inflammatory condition by stimulation with TNFα, and harmine was shown to ameliorate TNFα-induced decrease in expression of CCN2 and cartilage markers. These findings uncover novel chondrogenic effects of harmine and indicate harmine as a potential drug for prevention and/or repair of cartilage degradation.

uni, I was inspired by the Mohammedian quote (taking a "certain measure" of harmal every morning for 40 days curing diseases, etc.) to try it, but I very much stumbled in remaining consistent with the dosages. Sometimes I would skip days, sometimes I would do it in the evenings... I got discouraged when I started feeling like I was wading around in psychic soup all day. Then I realized that that mental malleability needed to be directed by the "light" of tryptamines, otherwise stagnation would occur.

So, yeah, they should just go shulgin on the molecule until they can justify human trials

Question for you brilliant people of the nexus.

Would any kind of attempt at harmine extraction, purification coupled with some type of ROA to spur beta cell regeneration in a type 1 diabetes patient be even long shot feasible for a amateur, green, kitchen chemist?

If so, any suggestions on how it would be done?

I am assuming in the study they injected the pure harmine into the pancreas? Would any kind of ROA be worth a shot?

Something this promising right in my reach seems like it should be at least worth a shot.

If I were to try treating diabetes I would probably suggest starting with about 50mg of harmine HCl taken orally in capsules twice a day continuously for a period of a few months, this would be non-psychoactive. You could slowly increase the dose up to maybe 100-150mg before there would be significant psychoactive effects.

[quote=arcologist]
Would you worry about any dietary interactions with this kind of dose?

From what I can gather, it doesn't sound like it should really be an issue.

Insulin would be the only other medication in the mix.