Combinatorial therapy for autoimmune diabetes  (TIDM):   A pharmaceutical mixture encompassing Dulaglutide (trade name: Trulicity), a Glucagon-like peptide-1  (GLP-1) receptor agonist, and Verapamil (brand name: Calanm, Isoptin and others), an anti-hypertensive drug,  increases PD-L1 expression, increases 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, 23/August/2019, 11.38 pm

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Introduction: What they say

A study from the International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, “L. Sacco” Department of Biomedical and Clinical Sciences, University of Milan, Milan 20157, Italy; and Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA shows that “PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.” This research paper was published, in the 15 November 2017 issue of the journal “Science Translational Medicine” [One of the best research journals in Science with an I.F of 15 plus], by Prof. Fiorina P and Nasr MB and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Combinatorial therapy for autoimmune diabetes  (TIDM):   A pharmaceutical mixture encompassing Dulaglutide (trade name: Trulicity), a Glucagon-like peptide-1  (GLP-1) receptor agonist, and Verapamil (brand name: Calanm, Isoptin and others), an anti-hypertensive drug,  increases PD-L1 expression, increases 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


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) Type 1 Diabetes (T1DM) constitutes about 5-10% (11 to 12 million) of all diabetic cases; (3) the incidence of T1DM is exponentially increasing year after year by 3%; (4) Diabetes is going to be one of the top 10 causes of death by 2030; (5) the life-long painful injection/drug treatment is required to treat DM; (6) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, while treatment for T1DM costs about $15 billion dollars per annum, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM;(ii) a side-effect-free natural product-based drug that does not harm or deplete adult stem cells; and (iii) a way to cure, not just treat, diabetes.


What is known?

Prof. Fiorina’s research team has recently shown that:(1) programmed death ligand 1 (PD-L1), the immune checkpoint regulator, is expressed poorly in hematopoietic stem and progenitor cells (HSPCs) of Type-1 diabetic (T1D) patients; (2) PD-L1 inhibits activated T-cells and thereby promotes immune tolerance; (3) the expression of PD-L1 is controlled by a network of miRNAs; (4) attenuating the expression of one of the miRNAs that target PD-L1 restores the expression of PD-L1 in HSPCs; (5) increasing the expression of PD-L1 in HSPCs, either genetically or pharmacologically, inhibits autoimmune response and reverses autoimmune diabetes; and (6) PD-L1 is expressed poorly in human HSPCs of T1D patients, suggesting that increasing the expression of PD-L1 in T1D patients may reverse and cure T1D.


From research findings to Therapeutic opportunity:

A number of studies suggest that Dulaglutide (also known as Trulicity-0.75 mg to 1.5 mg), developed by Eli Lilly and Company, attenuate hyperglycemia and may aid in the treatment of type II Diabetes.

This study suggests, for the first time, with detailed mechanistic insights, that a pharmaceutical mixture encompassing Dulaglutide and Verapamil can cure autoimmune diabetes (TIDM-Type I diabetes).

A pharmaceutical mixture encompassing Dulaglutide and Verapamil, by increasing the expression of its target gene, it may increase the expression of PD-L1, while decreasing the expression of TXNIP. Thereby, it may: (1) increase Regulatory T-cells(Tregs) function; and hematopoietic stem and progenitor cells (HSPCs); (2) decrease immune activation; (3) increase pancreatic-β-cell proliferation and regeneration; (4) increase the expression of genes that promote insulin sensitivity and insulin secretion;(4) decrease metabolic stress; and (5) promote glucose homeostasis (Fig.1).

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Dulaglutide and Verapamil inhibits the development of autoimmune diabetes (T1DM).  Artesunate, by increasing the expression of its target genes, it may increase the expression of PD-L1, insulin, and other anti-diabetic genes, while decreasing the expression of TXNIP.  Thereby, it may prevent immune activation and attenuate the development of T1DM.

Figure 2. A pharmaceutical mixture encompassing Dulaglutide and Verapamil functions as an anti-hyperglycemic agent (in autoimmune diabetes), by up regulating the expression of PD-L1 and other anti-diabetic genes, and by down regulating the expression of TXNIP.

Figure 3. While it has been that pharmacological activation of PD-L1 attenuates autoimmune diabetes, this study suggests for the first time that a pharmaceutical mixture encompassing Dulaglutide and Verapamil promotes beta-cell regeneration and proliferation and prevents autoimmune diabetes through up regulation of PD-L1 and down regulation of TXNIP.

Thus, pharmacological formulations encompassing “Dulaglutide and Verapamil or their analogues, either alone or in combination with other drugs,” may be used to treat TIDM (Figs.2-4).

Given: (a) the mechanistic basis, and it matches perfectly with established scientific facts (figure 1), as to how a pharmacological mixture encompassing Dulaglutide (Trulicity) and Verapamil (Calan) may aid in diabetic remission & in avoiding complications of type I diabetes;  and b) the advantage of injecting Dulaglutide (Trulicity) plus Verapamil only once in a week, unlike other anti-diabetic medications available in the market today, medical practitioners/diabetologists may consider recommending Dulaglutide (Trulicity) plus Verapamil (Calan) to the type I diabetic patients or putting this promising finding into a clinical trial.


Details of the research findings:

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

Undisclosed information: How does Dulaglutide and Verapamil increase the expression of PD-L1?

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

Amount: $750#

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References:

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

Citation: Boominathan, L.,  Combinatorial therapy for autoimmune diabetes  (TIDM):   A pharmaceutical mixture encompassing Dulaglutide (trade name: Trulicity), a Glucagon-like peptide-1  (GLP-1) receptor agonist, and Verapamil (brand name: Calan, Isoptin and others), an anti-hypertensive drug,  increases PD-L1 expression, increases 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, 23/August/2019, 11.38 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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