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: Mechanistic insights into how Semaglutide functions as an anti-obesity/diabetic drug : Semaglutide-based therapy for TIIDM and obesity-associated metabolic deficits: Semaglutide (trade name:Victoza, Saxenda), a glucagon-like peptide-1 agonist used in the treatment of diabetes, 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, 19/February/2021, 10.43 pm
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 15/September/2017 at 5.14 am; 5/May/2018 at 7.09 am and in others) that how Liraglutide may improve insulin sensitivity and protect against obesity and diabetes ( https://genomediscovery.org/2017/11/molecular-therapy-for-tiidm-and-obesity-associated-metabolic-deficits-victozasaxenda-a-drug-used-in-the-treatment-of-tiidm-and-obesity-increases-lipocalin-2-lcn2-expression-activates/; & https://genomediscovery.org/2019/05/mechanistic-insights-into-how-liraglutide-may-aid-in-the-treatment-of-diabetes-liraglutide-brand-name-victoza-saxenda-others-an-acylated-glucagon-like-peptide-1-glp-1-agon/)
Evidently, a very recent study from the Department of Pediatrics, Yale University, New Haven, CT; Pediatric Endocrinology, Angeles Hospital of Puebla, Puebla City, Mexico; Novo Nordisk, Søborg, Denmark; the Diabetes and Endocrinology Unit, Department of Paediatrics, Cairo University, Cairo; Novo Nordisk, Plainsboro, NJ; Institute of Cancer and Genomic Sciences, University of Birmingham,and Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom and others shows that “Liraglutide in Children and Adolescents with Type 2 Diabetes.” This study was published, in the 28 April 2019 issue of of the prestigious journal N Engl J Med. (NEJM) (Impact factor: 79.258+), by Profs. Timothy Barrett, William V Tamborlane and others. This study suggests that Liraglutide, in conjunction with Metformin, is efficacious in improving glycemic control in children and adolescents with type II diabetes. However, the precise mechanism of action of this drug remains largely unclear.
Next, a very recent study from the Division of Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago, USA and others shows that “Once-Weekly Semaglutide in Adults with Overweight or Obesity.” This study was published, in the 10 February 2021 issue of the prestigious journal N Engl J Med. (NEJM) (Impact factor: 79.258+), by Prof. Robert F Kushner and others. This study suggests that Semalgutide (2.4 mg once weekly) plus lifestyle intervention results in reduction in body weight. However, the precise mechanism of action through which how semaglutide reduces weight gain remains unknown.
The study presented here substantiates the above authors claim, by providing a detailed mechanistic insight into how Liraglutide and Semaglutide aid in attenuating insulin resistance, in the treatment of obesity-associated diabetes, and in promoting weight loss.
Simaglutide, by increasing the expression of its target gene, it could increase the expression of LCN2 (Lipocalin 2). Thereby, it could: (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 Semaglutide and Liraglutide could decrease blood glucose levels and prevent obesity, medical practitioners/diabetologists may consider treating diabetes mellitus, Obesity-associated metabolic deficits/abnormalities, and promote weight loss (Figures 3 & 4).
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 Semaglutide increase the expression of LCN2 and MC4R, while down regulate the expression of TXNIP?
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Citation: Boominathan, L., Mechanistic insights into how Semaglutide functions as an anti-obesity/diabetic drug : Semaglutide-based therapy for TIIDM and obesity-associated metabolic deficits: Semaglutide (trade name:Victoza, Saxenda), a glucagon-like peptide-1 agonist used in the treatment of diabetes, 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, 19/February/2021, 10.43 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org
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