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    Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

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    yoly
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    Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by yoly on Tue Jul 10 2018, 12:59

    Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    https://www.uab.edu/news/research/item/9585-human-clinical-trial-reveals-verapamil-as-an-effective-type-1-diabetes-therapy

    Researchers at the University of Alabama at Birmingham Comprehensive Diabetes Center have discovered a safe and effective novel therapy to reduce insulin requirements and hypoglycemic episodes in adult subjects with recent onset Type 1 diabetes by promoting the patient’s own beta cell function and insulin production — the first such discovery to target diabetes in this manner.

    The findings, published today by Nature Medicine, reveal that regular oral administration of verapamil, a common blood pressure medication first approved for medical use in 1981, enabled patients to produce higher levels of their own insulin, limiting their need for insulin injections to balance out their blood sugar levels.

    The randomized, double-blind, placebo-controlled human trial identified verapamil as a safe, effective, and promising therapy — a groundbreaking finding in the field of diabetes research.

    Anath Shalev 2017Anath Shalev, M.D.“The data collected from our clinical trial gives us every indication to believe that individuals with Type 1 diabetes have the promise of a treatment approach that would reduce their external insulin requirements and improve their blood sugar control and quality of life, thanks to the effects that verapamil has in promoting the body’s own beta cell function,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and principal investigator of the trial. “While this research is not an end-all cure for Type 1 diabetes, these findings are getting us closer to disease-altering therapies that can enable individuals with Type 1 diabetes to have more control over their disease and maintain some of their body’s own insulin production.”

    In 2014, Shalev’s UAB research lab discovered that verapamil completely reversed Type 1 diabetes in animal models and sought to test the effects of the drug in human subjects in a clinical trial, funded by a $2.1 million grant from the JDRF. Verapamil has been Food and Drug Administration approved and available for prescription for the treatment of high blood pressure for more than three decades. However, Shalev’s research marks the first time that the drug has been tested for safety and efficacy in treating Type 1 diabetes.

    Type 1 diabetes occurs as the result of one’s immune system attacking the beta cells in the pancreas that produce insulin to regulate and maintain optimal blood sugar levels. When beta cells are being destroyed, a person’s ability to produce insulin declines, causing blood sugar levels to rise and making the person more and more dependent on external insulin. The UAB clinical trial discovered that when a patient takes verapamil, beta cell function is preserved, enabling the body to produce more of its own insulin. This lessened the clinical trial participants’ reliance on external insulin, which all individuals with Type 1 diabetes must have to effectively regulate their blood sugar levels.

    “At JDRF, we are excited and encouraged by the recent findings from the UAB Comprehensive Diabetes Center’s clinical trial. This data has the potential to change how we think about treating and ultimately curing T1D,” explains Andrew Rakeman, Ph.D., assistant vice president of research at JDRF. “We look forward to continued clinical studies that will build on and confirm these findings, expanding to additional patient populations and guiding how, when and in who verapamil might have the most impact in T1D.”

    The verapamil clinical trial monitored 24 patients age 18 to 45, each over the course of one year. Eleven patients received verapamil and 13 received placebo. All clinical trial participants were diagnosed with Type 1 diabetes within three months of their start in the trial and continued with their prescribed insulin pump therapy throughout the duration of the study. Researchers monitored the placebo and verapamil groups’ total daily dose of insulin, the amount of insulin produced, the percent change in insulin production, and their HbA1C levels. In addition, the number of hypoglycemic events that the patients experienced were recorded, and the percent of time each patient registered in healthy blood glucose ranges were analyzed using a continuous glucose monitoring system.

    “Although this is a smaller sample group, our trial results give us promise that subjects with Type 1 diabetes have therapy options and that we are nearing a more effective way to deal with this disease,” said Fernando Ovalle, M.D., director of UAB’s Comprehensive Diabetes Clinic and co-principal investigator of the study. “Beyond verapamil allowing subjects with Type 1 diabetes the ability to live a life with less external insulin dependence, these findings will impact the quality of life that they can have. Hopefully, by improving overall blood sugar control it will also limit their risks for other comorbidities, including heart attack, blindness, kidney disease, and more.”

    While this study specifically addressed findings in adult subjects diagnosed within three months of the trial’s start, Shalev notes that future long-term studies are needed to help determine the effect of verapamil on both the pediatric Type 1 diabetes population, and individuals with Type 1 diabetes who have been living with and/or diagnosed with the disease longer than three months. Furthermore, verapamil’s effects on Type 2 diabetes have not been tested or studied in prospective controlled trials; Shalev said and future studies that explore the potential for this regimen to positively impact Type 2 diabetes are therefore also needed. However, in mouse models of Type 2 diabetes and in recent epidemiological studies verapamil use has been associated with lower risk of developing Type 2 diabetes and with better blood sugar control.

    “This trial’s results affirm that we are on the right track and are entering a new phase of discovery as it relates to this disease,” Shalev said. “Diabetes impacts more than 30 million people in America alone, and hopefully our breakthrough will ultimately lead to approaches that can help improve the lives of all those affected by this disease.”

    Long birder
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by Long birder on Tue Jul 10 2018, 18:50

    Causes worse heart failure and reduces the effectiveness of the heart to pump blood!
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    chris c
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by chris c on Tue Jul 10 2018, 22:02

    Fascinating!

    While Type 1 in children generally progresses rapidly from "healthy" to "die without insulin" and the same process in generally slower with adult onset, there have been some interesting examples of prolonged "honeymoon" resulting from low carb diets, presumably reducing the demand for insulin and thus whatever process is carrying off the beta cells.

    There are even a few individuals, including children, who seem to have gone into permanent - or at least long term - honeymoon, so obviously the process that actually destroys the beta cells can be slowed or stopped.

    Sadly just about everything improves diabetes in mice and fails to work in humans, so anything that does is well worth looking into to determine which pathways may be affected.
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by yoly on Thu Jul 12 2018, 11:28

    The way it works is by TXNIP inhibition.
    (Complete study on link)
    TXNIP in Metabolic Regulation: Physiological Role and Therapeutic Outlook

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543564/

    Abstract
    Background & Objective:

    Thioredoxin-interacting protein (TXNIP) also known as thioredoxin binding protein-2 is a ubiquitously expressed protein that interacts and negatively regulates expression and function of Thioredoxin (TXN). Over the last few years, TXNIP has attracted considerable attention due to its wide-ranging functions impacting several aspects of energy metabolism. TXNIP acts as an important regulator of glucose and lipid metabolism through pleiotropic actions including regulation of β-cell function, hepatic glucose production, peripheral glucose uptake, adipogenesis, and substrate utilization. Overexpression of TXNIP in animal models has been shown to induce apoptosis of pancreatic β-cells, reduce insulin sensitivity in peripheral tissues like skeletal muscle and adipose, and decrease energy expenditure. On the contrary, TXNIP deficient animals are protected from diet induced insulin resistance and type 2 diabetes.

    Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers
    (Complete article in link)
    http://europepmc.org/articles/PMC3314354

    Abstract

    Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element–binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by yoly on Thu Jul 12 2018, 11:33

    Both metformin and berberine seem to have some effect on TXNIP.

    A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of Thioredoxin-interacting protein (Txnip) gene expression.

    https://www.ncbi.nlm.nih.gov/pubmed/22561086/

    Abstract

    Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (Txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding Txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that Txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the Txnip gene promoter is reduced, suggesting that the transcription of the Txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on Txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the Txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes.

    Berberine, an isoquinoline alkaloid suppresses TXNIP mediated NLRP3 inflammasome activation in MSU crystal stimulated RAW 264.7 macrophages through the upregulation of Nrf2 transcription factor and alleviates MSU crystal induced inflammation in rats

    https://www.sciencedirect.com/science/article/pii/S1567576916305331

    Abstract

    The current study was designed to investigate the therapeutic potential of berberine on monosodium urate (MSU) crystal stimulated RAW 264.7 macrophages and in MSU crystal induced rats. Our results indicate that berberine (25, 50 and 75 μM) suppressed the levels of pro-inflammatory cytokines (interleukin–1beta (IL-1β) and tumor necrosis factor alpha (TNFα)) and intracellular reactive oxygen species in MSU crystal stimulated RAW 264.7 macrophages. The mRNA expression levels of IL-1β, caspase 1, nucleotide–binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3), thioredoxin interacting protein (TXNIP) and kelch–like ECH–associated protein 1 (Keap1) were found downregulated with the upregulation of nuclear factor erythroid–2–related factor 2 (Nrf2) transcription factor and its associated anti-oxidant enzymes: Heme oxygenase I (HO–1), superoxide dismutase (SOD1), glutathione peroxidase (GPx), NADPH quinone oxidoreductase–1 (NQO1) and catalase (CAT) in MSU crystal stimulated RAW 264.7 macrophages upon berberine treatment. Subsequently, western blot analysis revealed that berberine decreased the protein expression of IL-1β and caspase 1 and increased Nrf2 expression in RAW 264.7 macrophages. Immunofluorescence analysis also explored increased expression of Nrf2 in MSU crystal stimulated RAW 264.7 macrophages by berberine treatment. In addition, the paw edema, pain score, pro-inflammatory cytokines (IL-1β and TNFα) and articular elastase activity were found significantly reduced in berberine (50 mg/kg b·wt) administered MSU crystal-induced rats. Conclusively, our current findings suggest that berberine may represent as a potential candidate for the treatment of gouty arthritis by suppressing inflammatory mediators and activating Nrf2 anti-oxidant pathway.
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by chris c on Thu Jul 12 2018, 21:50

    pdfs

    http://diabetes.diabetesjournals.org/content/diabetes/61/4/848.full.pdf

    http://sci-hub.tw/10.1016/j.cellsig.2012.04.017

    http://sci-hub.tw/10.1016/j.intimp.2016.12.031

    All very interesting although TXNIP sounds like high tech cat food.

    I take a low dose of amlodipine which is another calcium channel blocker. In the past I was on losartan, ARBs are supposedly better for diabetics, but from this work maybe not. More reading to be done, thanks!

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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by Long birder on Fri Jul 13 2018, 13:04

    @chris c wrote:pdfs

    http://diabetes.diabetesjournals.org/content/diabetes/61/4/848.full.pdf

    http://sci-hub.tw/10.1016/j.cellsig.2012.04.017

    http://sci-hub.tw/10.1016/j.intimp.2016.12.031

    All very interesting although TXNIP sounds like high tech cat food.

    I take a low dose of amlodipine which is another calcium channel blocker. In the past I was on losartan, ARBs are supposedly better for diabetics, but from this work maybe not. More reading to be done, thanks!

    ARBs only needed for diabetics with high insulin.
    High insulin, like low sodium in normo tensives, activates the RAAS.  This increases arterial constriction and increases aldosterone.
    They won't work for you, Chris, your RAAS will be inactive because you are high sodium and low carb.
    D.
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by chris c on Mon Jul 16 2018, 23:13

    Well despite everything my BP is still high, I blame the five decades undiagnosed causing permanent damage. MY BP dropped with low carb but not back to normal. Once again insulin is hidden behind the curtain.

    The theory was that ACE and ARBs are kidney protective while CCBs aren't. In fact I knew a doctor who had decided belt and braces and took both, but research showed that not to be such a good plan. Now ARBs are off patent there has been a suggestion to use them in favour to ACEs due to the lower side effect profile. Rather than increase my amlodipine I might ask for losartan as well if my BP keeps increasing (thyroid is yet another factor, both low and high and mine is not completely nailed yet.

    Bugger, I put the reply on the wrong thread, should have been here about the calcium and magnesium. I blame the Alzheimers . . .

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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by Long birder on Tue Jul 17 2018, 08:09

    My problems stem from Conn's, Chris. In my case I believe the poor first stage insulin causing Reactive Hypoglycemia, is caused as Jerome Conn MD, over fifty years knew, is the inability of the islet cells to function effectively because they can't retain potassium due to excessive aldosterone. He knew this because 60% of his patients with aldosterone adenomas had carbohydrate intolerance. 80% of them were cured by tumour removal.

    My body cannot get rid of sodium and leaks potassium.It caused LVH.
    It is the reason I have to be paced.
    And 30 years htn.
    ARB's only work for me after going very low sodium and blocking a lot of aldosterone receptors.  Otherwise I have zero renin.
    I aim for just lifting renin and controlling the RAAS with 25mg of Losartan.
    D.

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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by Long birder on Tue Jul 17 2018, 11:38

    BTW Valsartan in the States has been listed as contaminated with carcinogens.

    For a long time I didn't know Amlodipine was causing me joint pain. In fact one doctor sent me for another bone scan because he thought my prostate cancer had spread.  So I got an unnecessary input source of gamma radiation (6 hour half life).
    I knew I was ok because after much earlier radiotherapy my PSA was miniscule.
    When I stopped the CCB for some reason some years later my 'arthritus' switched off immediately.
    I tried it again and it came back. Needless to say I wouldn't take a CCB.

    HTN needs investigating properly, GP's can't do the tests to find the causes and it all gets labelled 'essential'. Some of the tests need an endo to sanction.

    Plenty of studies to show the 'Prils and ARBs and potassium sparing diuretics can reverse LVH if one is young enough.

    It's a bit late for me to have my adrenal tumour out and hope for a reversal of r.h., BP, and heart issues.
    D.
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    Re: Human clinical trial reveals verapamil as an effective Type 1 diabetes therapy

    Post by chris c on Wed Jul 18 2018, 23:24

    Yes it's all very interesting and disappointing that sodium gets the blame for what the insulin did - in most cases, I believe a small proportion of hypertension improves with sodium restriction but more improves with the addition of potassium and the vast majority improves on low carb.

    I suspect my reactive hypoglycemia stems from a lack of GLP-1 which fails to switch the Phase 1 insulin on, my Phase 2 is still good after all these years, and of course better without the insulin resistance. Many paths to the same destination, sodium/potassium balance, calcium/magnesium and very likely a lack of other micronutrients along with the gross overdose of carbs and Omega 6s.

    I have to wonder if Conn's would be found more often if people actually bothered to look for it.

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