GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration
Authors: Esra Karakose
Roberto Sanchez
Bernard Thorens
Patrick E MacDonald
Adolfo Garcia-Ocaña
Dieter Egli
Andrew F Stewart
Ethan Swartz
Yansui Li
Donald K Scott
Hongtao Liu
Courtney Ackeifi
Peng Wang
Dirk Homann
Cecilia Berrouet
Jessica Wilson
Robert DeVita
Kunal Kumar
Jocelyn E Manning Fox
Bryan J González
Journal: Science Translational Medicine (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: GLP1R agonist; DYRK1A inhibitor; human β cell proliferation; insulin secretion; cAMP
Affiliations: Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada., Naomi Berrie Diabetes Center and Columbia Stem Cell Center, Columbia University, New York, NY 10032, USA., Department of Pharmacological Sciences, and Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland., Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. .

Abstract:  Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist-DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist-DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity. 

Retracted: No

PubPeer comments:
 Previously, authors shown that Harmine, a DYRK1A inhibitor, induces cell proliferation in human and rodent beta cells by inducing Myc, a well-known proto-oncogene (Nat Med. 2015 Apr; 21(4): 383u2013388). In this paper as well as in the subsequent papers on this topic by this group including in the paper published in Science Translational Medicine, authors observed a greater induction of proliferation in non-beta cells than in the beta cells. In their Science Translational Medicine paper, they show induction of proliferation in CK19+ cells (Sci Transl Med. 2020 Feb 12; 12 (530), Figure S3 E and F). CK19 is a marker for pancreatic tumors (pancreatic ductal adenocarcinoma) of insulin-negative cells. Therefore, the induction of proliferation in C19+ cells indicates carcinogenic potential of Harmine. In spite of this finding, authors claim that Harmine will be an anti-diabetic drug that will increase beta cell proliferation and that in turn will increase beta cell mass in Type 1 and 2 diabetic patients. , 
 Shown below is another example for non-selective induction of proliferation by Harmine and 2-2C (a Harmine analog synthesized by this group) in mice. Note that in Harmine and 2-2c u2013treated mice, non-beta cells show higher rate of proliferation than the beta cells (J Med Chem. 2020 Jan 31 [Epub ahead of print]). ![file] , 
 In the article published in Science Translation Medicine, authors claim that there was no pathological manifestations observed in tissues from 7 day Harmine treated mice examined by pathologist blinded to experimental treatments. However, a Type 1 diabetic kid would need to take the beta cell proliferator drug throughout his her life to replenish the beta cells that are continuously die due to immunological attack. So can Harmine and harmalogs, drugs with known potential to induce tumor, be taken as an anti-diabetic drug? Sci Transl Med. 2020 Feb 12; 12 (530) Figure 8: These were not blind analyses. Additionally, it would be impossible for anyone including the authors to accurately graft 500IEQ as they claim in the article. If the grafted human islets were bigger in size in H1+Ex0.5 group compared to the other 500IEQ recipient groups (Saline, Ex0.5 and H1), that would also produce results shown on hyperglycemia (Fig.8 A, B, D and E) and serum insulin levels (Fig.8C). , 
 In the article published Nature Medicine (Nat Med. 2015 Apr; 21(4): 383u2013388), they showed that the treatment with Harmine increased beta cell mass in partially pancreatectomized mice. In a follow-up paper published in Cell Metabolism (Cell Metab. 2019 Mar 5; 29 (3):638-652), they showed Harmine was ineffective but treatment with Harmine+ GW788388 (TGF beta receptor inhibitor) increases beta cell mass in partially pancreatectomized mice. First point to note here is that they could not reproduce their own findings. Secondly, when Harmine cannot improve beta cell mass in mice whose beta cells proliferate at a much higher rate compared to very reluctantly proliferating human beta cells, how Harmine can be used in humans to enhance beta cell mass expansion? Finally, authors are forgetting that the increase in beta cell mass were observed following simultaneous suppression of a tumor suppressor, TGF beta, by GW788388 and activation Myc, a proto-oncogene, by Harmine. So, can this be a real strategy to treat diabetes? ![file] , 
 I am quite curious as to why harmine (known PAINS) was used instead of a more selective DYRK1A inhibitor? , 
 #5 Great point. Harmine is not a useful pharmacological tool. It is u2018activeu2019 against several hundred pharmacological targets in the low micromolar nanomolar potency range. Data is in PubChem. At best it is a u2018staurosporineu2019 type chemical probe. At worst it is a PAINS-type compound like resveratrol or curcumin. , 
 Is Harmine safe for human use? Cells in our body develop mutations but these cells are detected and cleared by our immune surveillance system. However, progression to tumor from a mutant cells mainly happens due to overexpression of a proto-oncogene like Myc, which leads to uncontrollable cell proliferation. So, when a non-selective cell proliferator and Myc inducer compound like Harmine is administered to humans, it could make any mutant cell to escape the immune surveillance system and form tumors. Additionally, Harmine will increase the cancer risk in diabetics due to their predisposition to cancer. Also authorsu2019 claim that Myc expression induced by Harmine in beta cells at physiologically relevant levels similar to that seen in proliferating beta cells. How did they made this comparison when less than 0.5% of beta cells proliferate in a day? What is level of Myc expression in proliferating non-beta cells? Since they saw higher rate of proliferation in non-beta cells than beta cells, Myc expression might be at pathological level. ,