May have found a partial cure for Type-1 Diabetes thanks to Miles Mathis

I'm Chromium6 (Cr6) on this board. I wanted to post a progress of my own bio-hacking with Harmine, BCG-Vaccines and Type-1 diabetes along with enhancers for better bio-effects.

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I don't want to make this claim lightly since I have had Type-1 diabetes for over 50 years and have lived with the effects of hyperglycemia and hypoglycemic effects on body and mind. After learning about Miles Mathis' Charge Field, I have become more active in bio-hacking to see what can done to remediate the "Conciousness" problem with the diabetic mind. As we know from literature, the brain relies on glutamate to fuel ATP for proper brain function.  When a diabetic brain falls below usually 60 mg/dl of glucose in the blood stream, the mind will be greatly affected with episodes of memory loss-incorrect idealization-failure of current reality-perception and a drift to "non-reality" and narrow perception.  It is similar to a psychedelic trip, hypoglycemia, and it can debilitate clear thinking.

My program which has allowed me to see accurately without issues is the following:

1. BCG vaccine - taken in May of 2019 which provided a massive amount of bovine-mycobacterium that my immune system had to handle.
2. PPD tests that present a small amount of mycobacterium to my immune system.
3. Harmine from Syrian Rue seeds which is known to initiate beta-cell genesis as does Ayahausca both are beta-carboline inihibitors.
4. Kratom which is a blood sugar enhancer and potentiates Harmine's effects (at least for me).
5. Benfotiamine-DHEA-IGF1-Berberine-trace minerals-PQQ - this combination has enhanced blood-sugar regulation.
6. NAD+ intake
7. Genipin (occasionally take on a weekend. Note that it will put you to sleep after taking it and can't be taken too often.)

The claim of the partial cure comes from the fact that I no longer suffer from hypoglycemia even after taking a large dose (10+ units) of R-Insulin. My blood-sugar does drop but my body is apparently using a novo-channel/reaction of sensitive glucagon to remediate the low blood sugar as seen with non-diabetics. This is new for me. I generally would lose my mind as the insulin reaction ensued. Note I still take insulin but my body responds to it more like a non-diabetic and not as a T1D as I have been for many years.

The claim of the partial cure is that I can skip or greatly lower my insulin injections and not face hyperglycemia hours later. I actually for the first time, forget to take insulin. This occurs particularly after taking Harmine.

The range of my blood sugars has narrowed considerably. I no longer face abnormal lows or abnormal high blood sugars. High blood sugars are generally above 250 mg/dl after a meal and lows below 70 mg/dl. I don't urinate frequently with slightly high blood sugar anymore.

Effects of this regimen have been the following:

1. Stable thinking without paranoia of low blood sugar.  I just go on with the day instead of massive self-checking in my mind and blood sugar tests.
2. Massive hair growth never seen before on my arms, pelvic area, legs, stomach and chest.  In the last 6 months, I have seen body-hair growing that has never existed since puberty in the early 1980s. This part is remarkable as it shows improved cell genesis that I never had before.
3. Muscle growth has been better. Reaction speed has improved.
4. Mental clarity is much more enhanced. I remember everything now and not just when my blood-sugar was in proper range.
5. Sexual power has improved. I feel much younger and my wife has noticed a lot of Positive changes.

I'll keep you all updated on this regimen. Looks to be working well and have lost weight and increased strength with it. Note berberine-metformin can lower proper muscle growth but the increase of IGF-1 can compensate for this effect.  

Related research applied:
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ORLANDO -- Patients with long-standing type 1 diabetes given the bacillus Calmette-Guerin (BCG) vaccine showed modestly better glycemic control through a mechanism that appeared to be epigenetic, according to a long-term follow-up study that has generated controversy here.

Starting after the third year of follow-up in the 46 patients in early-phase trials, hemoglobin A1c levels were lower among patients who got the two doses of the tuberculosis vaccine (6.18% vs 7.07% with placebo and 7.22% among untreated T1D patients, P=0.02).

Among the phase I randomized trial patients followed for 8 years, A1c levels were 6.65% versus 7.22% in the placebo group (P=0.0002), Denise Faustman, MD, PhD, of the Massachusetts General Hospital (MGH) Immunobiology Laboratory in Boston, and colleagues reported at the American Diabetes Association annual meeting, days after publication of the overall findings in npj Vaccines.

"The impact of BCG on blood sugars in human T1D appears to be the result of a novel mechanism; a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis" by epigenetic induction of the Treg cells that maintain tolerance to prevent autoimmune disease, according to the late-breaking poster.

"The phase I trial was not designed to track insulin use, but we have documented incidences of patients' [sic] significantly reducing or stopping insulin use for short time periods," a document from Faustman's institutional press release said. "These are observations not clinical trial outcomes. The ongoing phase II trial will closely monitor insulin use in all patients."

https://www.medpagetoday.com/meetingcoverage/ada/73696
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I don't recommend taking Kratom without checking with a doctor. It has helped though. Long used as a Type-2 Diabetes drug in Asia. May have health risks though with liver toxicity.
https://www.sciencedirect.com/science/article/abs/pii/S0376871617305586

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Harmine and Diabetes:

https://www.diabetes.co.uk/news/2015/mar/harmine-drug-that-restores-beta-cells-seen-as-key-diabetes-treatment-91533665.html

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https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028


Reversal of epigenetic aging and immunosenescent trends in humans

Gregory M. Fahy
Robert T. Brooke
James P. Watson
Zinaida Good
Shreyas S. Vasanawala
Holden Maecker
Michael D. Leipold
David T. S. Lin
Michael S. Kobor
Steve Horvath
First published: 08 September 2019
https://doi.org/10.1111/acel.13028
Citations: 1
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Abstract

Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
1 INTRODUCTION

Population aging is an increasingly important problem in developed countries, bringing with it a host of medical, social, economic, political, and psychological problems (Rae et al., 2010). Over the last several years, many biomedical approaches to ameliorating aging have been investigated in animal models, and some of these seem able to reverse general aspects of aging in adult mammals based on a variety of physiological measurements (Das et al., 2018; Ocampo et al., 2016; Zhang et al., 2017). However, to date, evidence that systemic aging can be reversed has not been substantiated by determinations of epigenetic age, which can now provide a simple but compelling indication of biological as opposed to chronological age (Horvath & Raj, 2018; Jylhava, Pedersen, & Hagg, 2017). In addition, there is a need to specifically address immunosenescence stemming from thymic involution (Bodey, Bodey, Siegel, & Kaiser, 1997). Thymic involution leads to the depletion of critical immune cell populations (Arnold, Wolf, Brunner, Herndler‐Brandstetter, & Grubeck‐Loebenstein, 2011), resulting in a collapse of the T‐cell receptor (TCR) repertoire in humans after the age of ~63 (Naylor et al., 2005), and is linked to age‐related increases in cancer incidence (Falci et al., 2013), infectious disease (Ventevogel & Sempowski, 2013), autoimmune conditions (Goronzy & Weyand, 2003), generalized inflammation (Goronzy & Weyand, 2003), atherosclerosis (Dai, Zhang, Wang, Wu, & Liang, 2018), and all‐cause mortality (Fernando‐Martinez et al., 2013; Roberts‐Thomson, Whittingham, Youngschaiyud, & Mackay, 1974; Strindhall et al., 2007). In contrast, maintained immune function is seen in centenarians (Strindhall et al., 2007). Although thymic function in aging also depends on the supply of T‐cell progenitors from the bone marrow, which declines in relation to the output of myeloid HSCs with age (Akunuru & Geiger, 2016), the net number of lymphoid precursors does not change with age (Montecino‐Rodriguez et al., 2019), and migration of T‐cell precursors from the bone marrow also appears to depend on thymic function (Haar, Taubenberger, Doane, & Kenyon, 1989).

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Hypothesis: Berberine Potential in Diabetic Osteopathy

Abstract
Possible therapeutic potential of berberine in diabetic osteopathy.

Diabetic osteopathy is a complication that leads to decreased bone mineral density, bone formation and having high risk of fractures that heals slowly. Diabetic osteopathy is a result of increase in osteoclastogenesis and decrease in osteoblastogenesis. Various factors viz., oxidative stress, increased inflammatory markers, PPAR-γ activation in osteoblast, activation of apoptotic pathway, increased glucose levels and inhibitory effect on parathyroid hormone etc. are mainly responsible for decreased bone mineral density. Berberine is an isoquinoline alkaloid widely used in Asian countries as a traditional medicine. Berberine is extensively reported to be an antioxidant, anti-inflammatory, antidiabetic, and having potential to treat diabetic complications and glucocorticoid induced osteoporosis. The osteoclastogenesis decreasing property of berberine can be hypothesized for inhibiting diabetic osteopathy. In addition, chronic treatment of berberine will be helpful for increasing the osteoblastic activity and expression of the modulators that affect osteoblastic differentiation. The apoptotic pathways stimulated due to increased inflammatory markers and nucleic acid damages could be reduced due to berberine. Another important consideration that berberine is having stimulatory effect on glucagon like peptide release and insulin sensitization that will be helpful for decreasing glucose levels and therefore, may exerts osteogenesis. Thiazolidinediones show bone loss due to activation of PPAR-γ in osteoblasts, whereas berberine stimulates PPAR-γ only in adipocytes and not in osteoblasts, and therefore the decreased bone loss due to use of thiazolidinediones may not be observed in berberine treatment conditions. Berberine decreases the advanced glycation end-products (AGE) formation in diabetic condition which will be ultimately helpful to decrease the stiffness of collagen fibers due to AGE-induced cross linking. Lastly, it is also reported that berberine has inhibitory effect on parathyroid hormone and enhances marker genes like osteocalcin, which are responsible for the osteoblastic activity. From these evidences, we hypothesized that berberine may have potential in the treatment of diabetic osteopathy.

Rahigude AB, Kaulaskar SV, Bhutada PS
Med. Hypotheses Oct 2012
PMID: 22840327

http://osteoporosis-studies.com/hypothesis-berberine-potential-in-diabetic-osteopathy/


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Metabolic features of the cell danger response
http://naviauxlab.ucsd.edu/wp-content/uploads/2016/09/cell_danger_response.pdf
https://chronicillnesstraumastudies.com/cell-danger-response-disease/

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Cr6, The positive results you've reported are wonderful - congratulations.

I must admit I'm taken aback by your bio-hacking post. I needed to think before replying. The technical details are of course well beyond me, nevertheless I can appreciate your sharing some your own circumstance, and some difficult choices you've made, such as your creating your own life-changing intake program. Quite an achievement.

I don't understand why you attribute your success to the charge field. Care to elaborate?
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LongtimeAirman wrote:.
Cr6, The positive results you've reported are wonderful - congratulations.

I must admit I'm taken aback by your bio-hacking post. I needed to think before replying. The technical details are of course well beyond me, nevertheless I can appreciate your sharing some your own circumstance, and some difficult choices you've made, such as your creating your own life-changing intake program. Quite an achievement.

I don't understand why you attribute your success to the charge field. Care to elaborate?
.

Thanks LTAM. Didn't want to make a big deal out of it. It is just something I decided to try after following Miles. That link on Harmine causing UV light fluorescence and how the human body creates energy with insulin and food got me looking into this deeper. Harmine radiates-directs the charge field on a wide spectrum in vivo. Taking a regimen now that is working for me pretty well. Would not say it is a full fix but getting rid of hypoglycemia has been fantastic.  

Just thought if I get hit by a car tomorrow or something like that at least I'll have a post here that others might use. I'm still insulin dependent but don't get hypoglycemia like I used to. This is after multiple days of testing this year. We'll see where it goes from here.

Most of this approach is from assorted research papers published over the last 5 years. All of my family is riddled with auto-immune issues related to the Thymus so it is genetic to some degree.

More at link:  https://www.scientificamerican.com/article/plant-hallucinogen-holds-hope-for-diabetes-treatment/

Plant Hallucinogen Holds Hope for Diabetes Treatment

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

   By Emily Willingham on December 21, 2018

Ayahuasca cooking. Credit: Lisa Johnson Getty Images

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.(Kratom for me apparently --Cr6)  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. (Enchanced glucagon production for me apparently...--Cr6)
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(Harmine with Mycobacterium and Shotgun 5x (Bis Picolinato Oxo Vanadium) and IGF-1/DHEA/Berberine/PQQ/Blue Green Algae is awesome. It channels ATP-Muscle creation...I'm much stronger for my size than most people my age, 50+, on this regimen. --Cr6)

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With COP (Creatinol-O-Phosphate) to promote anaerobic glycolysis and CPT (di-Na Creatine PhosphateTetrahydrate) — two designer creatines surmised in VPX labs to be resistant to conversion to creatinine.* This eliminates bloating and supports transport of intact COP and CPT into muscle tissue!
https://bang-energy.com/shop/shotgun-5x/

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Consequently, the goal of sugar-free SyntheSize is to promote massive increases in insulin without the use of high glycemic index carbohydrates and thus, prevent insulin resistance. Therefore, SyntheSize provides a carbohydrate free approach utilizing research-proven compounds to boost insulin that have no adverse effect on blood sugar. This method keeps the body highly sensitive and responsive to insulin resulting in greater lean muscle growth and destruction of fat tissue. Efficient insulin metabolism also allows you to continually access store body fat to use as energy. The end result of the Zero Impact Diet Strategy is a ripped and muscular physique! Making Carbohydrates Obsolete: In assembling the pieces of the scientific puzzle, SyntheSize was formulated to mimic the insulin response generated by high glycemic (high Gl) carbs (i.e. sugar) to activate beta-cells and stimulate whole body creatine retention! One of the solutions was to use bis-Picolinato Oxo-Vanadium (BPOV) which is a potent form of chemically altered Vanadium that makes beta-cells super responsive to insulin. Additionally, Beta-Alanine was employed to stimulate research-proven whole-body creatine retention! In fact, these two compounds are far more effective than sugar-laden N.O. supplements without the unwanted carb-induced side effects-water retention, bloating, and an increase in body fat. You train intensely to get lean, hard, and pumped with crisp, water-free muscle separation, and this is where sugar free SyntheSize out-performs the competition! Research has proven that the cutting-edge compounds contained in the Shotgun/SyntheSize Stack work synergistically to effectively stimulate insulin secretion. 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Whey and Casein Protein Hydrolysates are far superior to intact proteins such as whey, casein and egg for promoting nitrogen utilization and muscle growth. The powerful lean muscle building effect occurs after consuming Protein Hydrolysates prior to, during and after training. These specialized peptides dump into the blood rapidly causing super high blood levels of amino acids and increased production of the powerful anabolic hormone, insulin. These two physiological events result in a potent anabolic (muscle building) response in the body. Shotgun and SyntheSize both contain copious amounts of Whey and Casein Protein Hydrolysates. These potent protein fractions are comprised of 22% Glutamine Peptide, 41% total peptide bonded Essential Amino Acids (EAA's) and 21% peptide bonded BCAA's (Branched Chained Amino Acids)! This is important because muscle consists of 78% glutamine while BCAA's and EAA's are the most potent research-proven muscle building amino acids. 2) L-Leucine intermixed with Protein Hydrolysates has an even greater effect on insulin production and muscle growth than Protein Hydrolysates alone. Shotgun and SyntheSize are rich in added free from L-Leucine and Leucine Peptides. 3) Cutting Edge High Creatines: It is well documented in research that insulin transports Creatine into muscle tissue. Further, Creatine combined with protein increases creatine retention within the muscle cell and results in increased lean muscle mass. More insulin means more creatine equals greater muscle mass, quicker recovery and increased strength! Shotgun and SyntheSize contains the most anabolic proteins known to man and several cutting edge high tech Creatines, such as Creatinol-O-Phosphate & Di-Na Creatine Phosphate Tetrahydrate, that all exert specialized effects in promoting lean muscle growth, strength and ATP Resynthesis! 4) Beta-Alanine radically improves whole body Creatine retention and muscle Carnosine, consequently, vastly improving strength, repetition capability, endurance and lean muscle growth. The synergy of intermixing Protein Hydrolysates, Leucine, Creatine and Beta-Alanine along with resistance training results in explosive muscle growth! Beta-Alanine is so powerful you can actually feel it working within seconds because of the unique parasalsys action of the muscles and skin. 5) BPOV (bis-Picolinato Oxo-Vanadium) increases the beta cell's sensitivity and responsiveness to insulin. This is hugely important because the kinetics and dynamics of insulin dictate that it is not how much you product, but more importantly, how insulin responsive or efficient your body utilizes insulin to shuttle Creatine, Beta-alanine, Leucine and other muscle energetic compounds into the muscle cell to manufacture more lean muscle. Sixty-seven percent of Americans are insulin resistant to some degree. If you have any degree of insulin resistance, your ability to use insulin is compromised. Therefore, it doesn't really matter how much insulin your body releases because you are resistant to insulin's ability to build muscle (anabolism). Less overall carbohydrate consumption (glycemic load) and elimination of high glycemic index dietary carbs along with higher protein intake. BPOV supplementation and increasing muscle mass via resistance training are all factors that increase insulin sensitivity and utilization. 6) N.O. and Pumping Agents: Finally, we added some radical new compounds to induce a serious Nitric Oxide Pump. The Nitric Oxide Releasing Factor, GBBEE (Gamma-Butyrobetaine Ethyl Ester) was combined along with the most powerful NO-inducing-Arginine known to science called, ALCA (Acetyl-L-Carnitine Arginine HCI)-making all other forms of Arginine obsolete. Nitric Oxide (N.O.) is the mother of all compounds at filling the muscle (and other body parts) with nutrient dense, blood engorged hard dense pumps! 7) Spiking the Pump even further, MTB Pump (Magnesium Tashinoate B) was combined with the powerful compound BPOV noted for insulin-induced pumps and muscle fullness. And, of course, all of these cutting edge nutrients and compounds work in concert to set off a biochemical chain of events that aid in rapid muscle recuperation.---Protein Hydrolysate Matrix Yielding 22% Glutamine Peptide, 21% BCAA Peptide, & 41% EAA's: Casein Protein Hydrolysate, Whey Protein Hydrolysate, Whey Protein Isolate. Proprietary Muscle Volumizing, NO2, Insulinotrophic: Creatine Taurinate, Creatine Gluconate, CEX (Creatine Ethyl Ester HCI), Beta-Alanine, Di-L-Arginine Malate, COP (Creatinol-O-Phosphate), Creatine Magnesium Chelate, Creatine Monohydrate, Citrulline Malate, Gamma-Butryobetaine Ethyl Ester, MTB Pump (Magnesium Tanshinoate B), Bis Picolinato Oxo Vanadium (BPOV), Beta-Alanine Ethyl Ester, Di-Na Creatine Phosphate Tetrahydrate, Phosphates, Folate (as Folic Acid)-100 percent, Gamma-Butyrobetaine.

Diabetes: New drug cocktail increases human beta cell proliferation at rapid rates

Date:
December 20, 2018
Source:
The Mount Sinai Hospital / Mount Sinai School of Medicine
Summary:
Researchers have discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells -- the cells in the pancreas that produce insulin. The result is an important step toward a diabetes treatment that restores the body's ability to produce insulin.

FULL STORY

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells -- the cells in the pancreas that produce insulin. The result is an important step toward a diabetes treatment that restores the body's ability to produce insulin.

The finding involved one drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A) and another that inhibits transforming growth factor beta superfamily members (TGFβSF). Together, they caused the cells to proliferate at a rate of 5 to 8 percent per day. The study, titled "Combined Inhibition of DYRK1A, SMAD and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells," was published today in Cell Metabolism.

"We are very excited about this new observation because for the first time, we are able to see rates of human cell beta cell replication that are sufficient to replenish beta cell mass in human beings," said Andrew Stewart, MD, Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study. "We have discovered a drug combination that makes beta cells regenerate at rates that are suitable for treatment. The next big hurdle is figuring out how to deliver them directly to the pancreas."

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. 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 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. Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation.

https://www.sciencedaily.com/releases/2018/12/181220111759.htm

Curcumin is a fairly strong TGfB inhibitor.

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Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells.

Wang P1, Karakose E1, Liu H1, Swartz E1, Ackeifi C1, Zlatanic V1, Wilson J1, González BJ2, Bender A1, Takane KK1, Ye L3, Harb G3, Pagliuca F3, Homann D1, Egli D2, Argmann C4, Scott DK

Abstract

Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFβSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax- and SMAD-mediated transactivation of CDKN1C and CDKN1A. Notably, combined DYRK1A and TGFβ inhibition allows preservation of beta cell differentiated function.

https://www.ncbi.nlm.nih.gov/pubmed/30581122

Curcumin's regulation of TGF-β for cancer:

........

Role of TGF-β signaling in curcumin-mediated inhibition of tumorigenicity of human lung cancer cells

Raktima Datta, Sunil K. Halder, and Binhao Zhang

Additional article information

Abstract

Purpose

Curcumin has been shown to have potent anti-cancer activities like inhibition of cell proliferation, induction of apoptosis, and suppression of angiogenesis. Transforming growth factor-β (TGF-β) signaling plays a complex role in tumor suppression and promotion depending on the tumor type and stage. However, the effect of curcumin on TGF-β signaling in cancer cells and the role of TGF-β signaling in curcumin-induced anticancer activities have not been determined. Here, we investigate the role of curcumin on TGF-β signaling, and whether TGF-β signaling is involved in the antitumor activities of curcumin.

Methods
Human non-small cell lung cancer (NSCLC) cell lines, ACC-LC-176 (without TGF-β signaling), H358, and A549 (with TGF-β signaling) were treated with curcumin to determine cell growth, apoptosis, and tumorigenicity. Antitumor activities of curcumin were determined using these cell lines and an in vivo mouse model. We also tested the effect of curcumin on TGF-β/Smad signaling by western blotting and by luciferase assays.

Results
Curcumin inhibited cell growth and induced apoptosis of all three NSCLC cell lines in vitro and in vivo. It significantly reduced subcutaneous tumor growth by these three cell lines irrespective of TGF-β signaling status. Curcumin inhibited TGF-β-induced Smad2/3 phosphorylation and transcription in H358 and A549 cells, but not in ACC-LC-176 cells.

Conclusions
Curcumin reduces tumorigenicity of human lung cancer cells in vitro and in vivo by inhibiting cell proliferation and promoting apoptosis. These results suggest that TGF-β signaling is not directly involved in curcumin-mediated growth inhibition, induction of apoptosis, and inhibition of tumorigenicity.

Keywords: Curcumin, NSCLC, TGF-β, Smad, Tumorigenicity, Apoptosis
Introduction
Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide among both men and women (Siegel et al. 2012). Despite the advancement in the understanding and treatment, the overall 5-year survival for all patients diagnosed with lung cancer remains less than 15 %, a rate that has barely changed over the last 30 years. Clearly more efforts are needed to improve our understanding of lung cancer biology in order to improve treatment and prevention strategies. Lung cancer is sometimes sensitive to either chemotherapy or radiation therapy, depending on types and stages. Despite recent advances in therapy of lung cancer, side effects of treatment and multidrug resistance remain the main obstacle of lung cancer treatment. Exploring novel agents with minimum side effects and maximum sensitivity attracts attention for lung cancer research.

Curcumin, an active component of the spice turmeric derived from Curcuma longa, has been used extensively as a coloring and flavoring agent of food in Asian countries. It is used in traditional medicine and is known to have anti-oxidant, anti-inflammatory, antifibrotic, and anticancer activities. Curcumin has been documented to suppress cancer cell proliferation and to promote apoptosis in a variety of tumor cells (Radhakrishna Pillai et al. 2004; Su et al. 2010; Yang et al. 2012b; Shishodia et al. 2007). This compound is also reported to inhibit migration and invasion of human lung cancer cells (Lin et al. 2009). It has been reported to have low toxicity to mammals at high doses (Samaha et al. 1997; Carroll et al. 2011; Cheng et al. 2001). These advantages make curcumin a strong candidate as a novel anticancer agent, either alone or in combination with other chemotherapeutic drugs. A phase I clinical trial documented that curcumin in combination with docetaxel-based chemotherapy improved biological and clinical outcomes in patients with advanced breast cancer (Bayet-Robert et al. 2010). Recently, a phase II clinical trial of curcumin was reported to prevent the development of colorectal neoplasia (Carroll et al. 2011). Modulation of multiple target genes, including Akt, mitogen-activated protein kinases (MAPK), nuclear factor-κB (NF-κB), matrix metalloproteinase (MMP), tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), and cell cycle regulatory proteins, has been implicated in the anticancer activity of curcumin (Lin et al. 2009; Thangapazham et al. 2006; Yang et al. 2012a; Kim et al. 2005). Therefore, it is important to study the mechanism of function of curcumin in further detail due to its excellent potential for therapeutic intervention of lung cancer.

Transforming growth factor-β signaling pathway plays a pivotal but complex role in tumor development and progression depending on tumor types and stages. TGF-β signaling regulates various biological processes including cell growth, differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling (Massague 1998). Alterations in TGF-β signaling are linked to a variety of human diseases including cancer, inflammation, and tissue fibrosis. Ligand binding to TGF-β receptors initiates Smad2/3/4 complex formation and translocation to the nucleus (Smad pathway) to control gene expression. TGF-β signaling can also activate MAPK pathways (non-Smad pathway) in concert with other growth factors (Derynck and Zhang 2003). Previous studies from our laboratory provided evidence for TGF-β as a lung cancer suppressor (Anumanthan et al. 2005; Halder et al. 2011), and Smad pathway plays a critical role in this tumor suppressor function of TGF-β (Samanta et al. 2012). Several growth factors and exogenous small molecule inhibitors function as tumor suppressors or promoters through cross-talking with the TGF-β signaling pathway. Curcumin, as a tumor suppressor, was reported to regulate TGF-β signaling cascade in neonatal lung fibroblast (Sakurai et al. 2011), renal cells (Gaedeke et al. 2004), keloid fibroblasts (Hsu et al. 2010), and scleroderma fibroblasts (Song et al. 2011). However, to our knowledge, nothing is known about the effect of curcumin on TGF-β signaling in lung cancer cells of epithelial origin and whether TGF-β-induced tumor suppressor function is involved in curcumin-mediated antitumor activities.

In this study, we have investigated the role of curcumin on cell proliferation, apoptosis, and tumorigenicity in lung cancer cells. Our results have demonstrated that curcumin inhibits cell proliferation, induces apoptosis, and suppresses tumorigenicity in human NSCLC cells in vitro and in vivo and that TGF-β signaling has no role in these functions of curcumin. We also have observed that curcumin inhibits TGF-β-induced Smad2 and Smad3 phosphorylation and transcription in TGF-β-sensitive lung cancer cell lines. This evidence indicates that TGF-β signaling is not directly involved in curcumin-mediated effects on NSCLC cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295202/