The Mechanistic basis of how Liraglutide mitigates complications of diabetes and obesity:  Liraglutide (trade name: Victoza, Saxenda), a Glucagon-like peptide-1  (GLP-1) receptor agonist,  augments the expression of FGF19 and FGF1,  attenuates hepatic glucose production, decreases hepatic acetyl CoA content, brings down the levels of plasma ACTH, and corticosterone, augments insulin sensitivity, promotes weight loss and alleviates diabetes mellitus, via down regulation of its target gene, 24/August/2019, 12.27 am

Natural product-based anti-ageing and Lifespan extension therapy: A pharmaceutical mixture encompassing Curcumin and Dasatinib (CAD)  increases CHIP levels, increases monoubiquitylation of insulin receptor (INSR), decreases INSR protein levels and enhances lifespan, via down regulation of its target gene, 24/August/2019, 12.05 am
August 23, 2019
New Mechanistic and functional insights into how Vildagliptin mitigates complications of diabetes and obesity:  Vildagliptin/LAF237 (brand names: Galvus/Vildagluse/Gliptus), a DPP4 (dipeptidyl peptidase 4 ) inhibitor,  augments the expression of FGF19 and FGF1,  attenuates hepatic glucose production, decreases hepatic acetyl CoA content, brings down the levels of plasma ACTH, and corticosterone, augments insulin sensitivity, promotes weight loss and alleviates diabetes mellitus, via down regulation of its target gene, 25/August/2019, 11.49 pm
August 25, 2019
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Introduction: What they say 

A study from Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA shows that Central injection of FGF1 induces sustained remission of diabetic hyperglycemia in rodents. This research paper was published, in the 23 May 2016 issue of the journal “Nature Medicine” [One of the best research journals in General Medicine with an I.F of 29.886 plus], by Prof. Schwartz MW and Scarlett JM and others.

Another study from Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA; and Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA shows that “FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis. This research paper was published, in the 28 April 2015 issue of the journal “Nature communications” [One of the best research journals in General science research with an I.F of 11.329 plus], by Prof. Shulman GI and Perry RJ and others.

Yet another study from Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA shows that “Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.” This research paper was published, in the 16 July 2014 issue of the journal “Nature” [One of the best research journals in General science with an I.F of 43 plus], by Prof. Evans RM and Suh JM and others


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  The Mechanistic basis of how Liraglutide mitigates complications of diabetes and obesity:  Liraglutide (trade name: Victoza, Saxenda), a Glucagon-like peptide-1  (GLP-1) receptor agonist,  augments the expression of FGF19 and FGF1,  attenuates hepatic glucose production, decreases hepatic acetyl CoA content, brings down the levels of plasma ACTH, and corticosterone, augments insulin sensitivity, promotes weight loss and alleviates diabetes mellitus, via down regulation of its target gene, 24/August/2019, 12.27 am


From significance of the study to public health relevance:

Given that: (1) more than 422 million people worldwide are affected by Diabetes mellitus (DM); (2) Diabetes is going to be one of the top 10 causes of death by 2030; (3) the life-long painful injection/drug treatment is required to treat DM; (3) 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?

Prof. Shulman GI’s research team has shown that injection of FGF19 or FGF1: (1) decreases hepatic glucose production and hepatic acetyl CoA content by 60%; (2) promote  whole-body lipolysis; (3) lowers plasma ACTH, and corticosterone concentrations; and (4) has no glucose-lowering effect when it is countered with intra-arterial infusion of corticosterone, suggesting that increasing the expression of FGF19 or FGF1 in diabetic patients may decrease insulin resistance, and alleviate TIDM.


From research findings to Therapeutic opportunity:

I has suggested earlier (on 14/November/2017 at 5.14 am and in others) that how Victoza/Saxenda/Liraglutide (a GLP-1 analogue)  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/; and https://genomediscovery.org/2019/05/mechanistic-insights-into-how-liraglutide-aids-in-control-of-body-weight-energy-homeostasis-and-tiidm-liraglutide-brand-name-victoza-saxenda-and-others-a-drug-used-in-the-t/ ).

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 PhD., William Tamborlane MD.,  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. 

The study presented here substantiates and supports the aforementioned study’s’ claim, and others, by providing detailed mechanistic insights into how Liraglutidedeveloped by Novo Nordisk, may aid in the management of Diabetes.

Liraglutide (Victoza, Saxenda)by decreasing the expression of its target genes, it increases the expression of FGF19 or FGF1/2. Thereby, it may: (1) inhibit hepatic glucose production; (2) decrease hepatic acetyl CoA content; (3) increase insulin sensitivity, beta-cell self-renewal, and regeneration; (4) augment lipolysis and weight loss; (5) protect against diet-induced obesity; (6) aid in the  management of diabetes;  (7) protect against the development of diabetes (Fig.1).

Figure 1. Mechanistic insights into how Liraglutide aids in remission of diabetes. It increases the expression of FGF19, FGF1/2 and insulin,  augments insulin sensitivity, increases beta-cell regeneration and promotes weight loss.

Figure 2. Dulaglutide (Trulicity), by increasing the expression of FGF19 and FGF1/2, it promotes beta-cell regeneration, insulin sensitivity, lipolysis and weight loss.

Figure 3. The core mechanism of action of Dulaglutide (Trulicity).  Dulaglutide (Trulicity) promotes the expression of FGF19 and FGF1/2, increases insulin expression, promotes insulin sensitivity, augments beta-cell regeneration and weight loss, and promotes diabetic remission.

Figure 4. While it had been shown that genetic ablation or pharmacological intervention augments the expression of FGF19 and FGF1/2 and attenuates the development of diabetes, the study presented here suggests, for the first time, that, Liraglutide increases the expression of FGF19 and FGF1/2 , promotes insulin sensitivity and weight loss. And, thereby, not only protects against diabetes, but also promotes diabetic remission.

Figure 5. While it had been shown that Liraglutide aids in the management of diabetic patients,  with either previous cardiovascular disease or cardiovascular risk factors, the study presented here suggests, for the first time, that  Liraglutide  increases the expression of FGF19 and FGF1/2 , promotes insulin sensitivity and weight loss. And, thereby, it not only aids in the management of diabetes, but may also promote diabetic remission in the long term.

Thus, Liraglutide, either alone or in combination with other drugs, may be used to cure diabetes mellitus and avoid complications of obesity.

Given the mechanistic basis, and it matches perfectly with established scientific facts (figure 4), as to how Liraglutide aids in diabetic remission & in avoiding complications of diabetes/obesity, medical practitioners/diabetologists may consider recommending Liraglutide to the needy diabetic or obese patients or putting this promising finding, with a strong mechanistic basis,  as mentioned earlier, which matches with the established anti-diabetic mechanisms revealed recently, into a clinical trial.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How does Liraglutide increase the expression of FGF19 or FGF1/2?

Amount: $ 1, 500#

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References:

Web: http://genomediscovery.org or http://newbioideas.com

Citation: Boominathan, L.,  The Mechanistic basis of how Liraglutide mitigates complications of diabetes and obesity:  Liraglutide (trade name: Victoza, Saxenda), a Glucagon-like peptide-1  (GLP-1) receptor agonist,  augments the expression of FGF19 and FGF1,  attenuates hepatic glucose production, decreases hepatic acetyl CoA content, brings down the levels of plasma ACTH, and corticosterone, augments insulin sensitivity, promotes weight loss and alleviates diabetes mellitus, via down regulation of its target gene, 24/August/2019, 12.27 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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