The Mechanistic basis of how Dulaglutide (Trulicity) once-weekly injection mitigates complications of diabetes and obesity: Dulaglutide (trade name: Trulicity), 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, 19/August/2019, 1.53 pm

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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 Dulaglutide (Trulicity) once-weekly injection mitigates complications of diabetes and obesity: Dulaglutide (trade name: Trulicity), 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, 19/August/2019, 1.53 pm


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:

A study, published from the McMaster University and Hamilton Health Sciences, Ontario, Canada and others, has revealed the role of Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND):...” This study was published, in the 9 June 2019 issue of of the prestigious journal Lancet (Impact factor: 53+)by Profs. Hertzel C Gerstein, MD, M.Sc., FRCPC (Director of the Division of Endocrinology & Metabolism, Director of the Diabetes Care and Research Program and Deputy Director of the Population Health Research Institute), Helen M Colhoun, MD, Gilles R Dagenais, MD, Rafael Diaz, MD, Mark Lakshmanan, MD, Prem Pais, MD and others.  This study suggests that an once-weekly infusion of Dulaglutide, a Glucagon-like peptide-1  (GLP-1) receptor agonist and  FDA-approved drug (2014), aids in the management of diabetic patients, with either previous cardiovascular disease or cardiovascular risk factors.However, the precise mechanism of action of the Dulaglutide (Trulicity) remains largely unclear.

The study presented here substantiates and supports the aforementioned study’s’ claim, and others, by providing detailed mechanistic insights into how  Dulaglutide (Trulicity-0.75 mg to 1.5 mg), developed by Eli Lilly and Company, may protect against and aid in remission of Diabetes.

Dulaglutide (Trulicity)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 Dulaglutide (Trulicity) 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, Dulaglutide (Trulicity) 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 Dulaglutide (Trulicity) 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 Dulaglutide (Trulicity) 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, Dulaglutide (Trulicity), either alone or in combination with other drugs, may be used to cure diabetes mellitus and avoid complications of obesity.

Given: (a) the mechanistic basis, and it matches perfectly with established scientific facts (figure 4), as to how Dulaglutide (Trulicity) aids in diabetic remission & in avoiding complications of diabetes/obesity;  and b) the advantage of injecting Dulaglutide (Trulicity) only once in a week, unlike other anti-diabetic medications available in the market today, medical practitioners/diabetologists may consider recommending Dulaglutide (Trulicity) 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 Dulaglutide (Trulicity) increase the expression of FGF19 or FGF1/2?

Amount: $ 1, 500#

# Research cooperation

For purchase and payment details, you may reach us at info@genomediscovery.org


References:

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

Citation: Boominathan, L.,  The Mechanistic basis of how Dulaglutide (Trulicity) once-weekly injection mitigates complications of diabetes and obesity: Dulaglutide (trade name: Trulicity), 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, 19/August/2019, 1.53 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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