Introduction: What they say
A study from the Department of Physiology-Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York, USA shows that “MC4R-dependent suppression of appetite by bone-derived lipocalin 2.” This research paper was published, in the 8 March 2017 issue of the journal “Nature” [One of the best research journals in General Science with an I.F of 43 plus], by Dr. Stavroula Kousteni and Mosialou and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Curing diabetes with commonly available blood pressure drug Verapamil: Verapamil-based therapy for TIIDM and obesity-associated metabolic deficits: Verapamil (trade name: Calan, Isoptin, and others), a calcium channel blocker used in the treatment of high blood pressure, angina and others, increases Lipocalin 2 (LCN2) expression, activates an MC4R-dependent anorexigenic pathway, decreases TXNIP expression, suppresses appetite and weight gain, increases insulin secretion, improves glucose tolerance, promotes glucose homeostasis, improves obesity-associated metabolic deficits and prevents progression to TIIDM, via down-regulation of its target gene
From significance of the study to public health relevance:
Given that: (1) more than 387 million people worldwide are affected by Diabetes mellitus (DM); (2) diabetic disease results in a number of health complications, including diabetic cardiomyopathy (DCM), diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy; (3) one third of people with diabetes suffer from diabetic kidney disease (DKD); and one third of them will develop kidney failure; (4) Obesity plays a central role in the development of TIIDM; (5) Diabetes is going to be one of the top 10 causes of death by 2030; (6) the life-long painful injection/drug treatment is required to treat DM; (7) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM; (ii) a cheaper alternative to the existing expensive weight-loss drugs; (iii) a side-effect-free natural product-based drug; and (iv) a way to cure, not just treat, diabetes.
What is known?
Dr. Stavroula Kousteni’s research team has recently shown, using loss-and gain-of-function experiments, that Lipocalin 2 (LCN2): (1) induces insulin release; (2) improves glucose tolerance; and (3) augments insulin sensitivity. Further, they have shown that LCN2: (1) binds and activates the melanocortin 4 receptor (MC4R) in the neurons of the hypothalamus; (2) activates an MC4R-dependent appetite-suppressing pathway; (3) suppresses appetite and body weight gain; (4) levels are low in TIIDM patients and they are inversely correlated with body weight gain and blood A1c levels; and (5) levels are higher in patients with lower body weight gain and blood A1c levels, suggesting that increasing the expression of LCN2 may alleviate metabolic deficits in diabetic patients.
From research findings to Therapeutic opportunity:
I had suggested earlier (on 25/December/2017 at 1.46 am; 14/July/2018 at 4.21 pm and in others) that how Verapamil may improve insulin sensitivity and protect against obesity and diabetes (https://genomediscovery.org/2017/12/molecular-therapy-for-middle-aged-tiidm-patients-verapamil-an-anti-hyperglycemic-medication-decreases-dna-ppk-expression-suppresses-phosphorylation-of-hsp90a-increases-ampk-activity-augment/; https://genomediscovery.org/2018/07/a-commonly-prescribed-blood-pressure-drug-comes-to-the-rescue-of-autoimmune-diabetes-tidm-verapamil-trade-name-calan-isoptin-and-others-a-drug-used-in-the-treatment-of-high-bl/)
Molecular therapy for middle aged TIIDM patients: Verapamil, an anti-hyperglycemic medication, decreases DNA-PPK expression, suppresses phosphorylation of HSP90a, increases AMPK activity, augments mitochondrial biogenesis and energy metabolism, promotes weight loss and exercise endurance and alleviates TIIDM via down regulation of its target gene, 25/December/2017, 1.46 am
A commonly prescribed blood-pressure drug comes to the rescue of autoimmune diabetes (TIDM): Verapamil (trade name: Calan, Isoptin, and others), a calcium channel blocker used in the treatment of high blood pressure, angina, supraventricular tachycardia, migraines, increases the expression of PD-L1, augments Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and reverses TIDM, via up regulation of its target gene, 14/July/2018, 4.21 pm
Subsequently, a study from the Comprehensive Diabetes Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA and others shows that “Verapamil and beta cell function in adults with recent-onset type 1 diabetes.” This study was published, in the 9 July 2018 issue of of the prestigious journal Nature Medicine (Impact factor: 33+), by Prof. Anath Shalev (Director of Comprehensive Diabetes Center) and her research team. This study suggests that Verapamil (trade name: Calan, Isoptin, and others), a calcium channel blocker used in the treatment of high blood pressure, angina, supraventricular tachycardia, migraines and others, improves glycemic control in people with type I diabetes. However, the precise mechanism of action of this drug remains largely unclear.
The study presented here, and our our earlier studies, substantiates their present claim, by providing a detailed mechanistic insights into how Verapamil may not only aid in the treatment of type I diabetes, but also aid in the treatment of weight loss and obesity-associated TIIDM.
This study suggests that anti-hypertensive drug Verapamil may aid in the treatment of type II diabetes mellitus. Verapamil, by increasing the expression of its target gene, it may increase the expression of LCN2 (Lipocalin 2). Thereby, it may: (1) induce insulin release; (2) increase the expression of components of the Insulin-PI3K pathway; (3) promote glucose tolerance; (4) improve insulin sensitivity; (5) activate the MC4R (Melanocortin-4-receptor-MC4R)-dependent appetite-suppressing pathway in hypothalamus; (6) decrease Thioredoxin-interacting protein (TXNIP) expression; (7) suppress appetite; and weight gain; (8) improve metabolic deficits; and (9) promote glucose homeostasis (Fig.1).
Given the detailed mechanistic basis as to how anti-hypertensive drug verapamil may decrease blood glucose levels, medical practitioners/diabetologists may consider putting this interesting finding into a clinical trial or adopting this as a mode of curative therapy for diabetes mellitus and Obesity-associated metabolic deficits/abnormalities (Figure 2).
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.
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Undisclosed mechanistic information: How does Verapamil increase the expression of LCN2 and MC4R and down regulate the expression of TXNIP?
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Citation: Boominathan, L., Curing diabetes with commonly available blood pressure drug Verapamil: Verapamil-based therapy for TIIDM and obesity-associated metabolic deficits: Verapamil (trade name: Calan, Isoptin, and others), a calcium channel blocker used in the treatment of high blood pressure, angina and others, increases Lipocalin 2 (LCN2) expression, activates an MC4R-dependent anorexigenic pathway, decreases TXNIP expression, suppresses appetite and weight gain, increases insulin secretion, improves glucose tolerance, promotes glucose homeostasis, improves obesity-associated metabolic deficits and prevents progression to TIIDM, via down-regulation of its target gene, 04/June/2019, 7.48 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org
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