Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Rosselot, Carolina; Alvarsson, Alexandra; Wang, Peng; Li, Yansui; Beliard, Kara; Lu, Geming; Li, Rosemary; Liu, Hongtao; Gillespie, Virginia; Tzavaras, Nikolaos; Kumar, Kunal; DeVita, Robert J.; Stewart, Andrew F.; Stanley, Sarah A.; Garcı́a-Ocaña, Adolfo

doi:10.1101/2020.07.24.220244

Cited by 5 publications

(2 citation statements)

References 55 publications

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“…Recently, several groups have demonstrated that small molecule drugs that inhibit the kinase DYRK1A ( d ual t y rosine– r egulated k inase 1A) are able to induce adult human β cells to proliferate, to increase in numbers, and to enhance their differentiation and function ( 7 – 17 ). Even higher rates of proliferation can be achieved by combining DYRK1A inhibitors with peptide agonists of the GLP1 receptor such the GLP1 7–36 peptide, or more stable synthetic analogs, such as exendin-4, liraglutide, semaglutide, and others, all in current widespread use in T2D ( 10 , 12 ). The combination of a DYRK1A inhibitor, harmine, together with exendin-4, increases human β cell mass in immunodeficient mice transplanted with human islets by 700% over 3 months of treatment, while also reversing diabetes ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…Even higher rates of proliferation can be achieved by combining DYRK1A inhibitors with peptide agonists of the GLP1 receptor such the GLP1 7–36 peptide, or more stable synthetic analogs, such as exendin-4, liraglutide, semaglutide, and others, all in current widespread use in T2D ( 10 , 12 ). The combination of a DYRK1A inhibitor, harmine, together with exendin-4, increases human β cell mass in immunodeficient mice transplanted with human islets by 700% over 3 months of treatment, while also reversing diabetes ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

Wang¹,

Karaköse²,

Argmann³

et al. 2022

Journal of Clinical Investigation

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Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

Wang¹,

Karaköse²,

Argmann³

et al. 2022

Journal of Clinical Investigation

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A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets

Patel¹,

Parmar²,

Rathwa³

et al. 2022

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors

Karakose,

Wang,

Wang

et al. 2023

Preprint

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Diabetes ultimately results from an inadequate number of functional, insulin-producing human beta cells. Although current attempts to replenish the remaining beta cell pool in people with diabetes are encouraging, scalability and cost limit access for the millions of people with diabetes. The small molecule DYRK1A inhibitor class of beta cell regenerative drugs, either alone or in combination with GLP1 receptor agonists or TGF beta superfamily inhibitors, are capable of inducing beta cell replication in vitro and increasing beta cell mass in vivo. Despite these advances, the precise mechanisms of action of DYRK1A inhibitors remain incompletely understood. To address the mechanisms more deeply, we performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or in combination with a GLP1 receptor agonist or a TGF beta superfamily inhibitor. We identify a cluster of Cycling Alpha Cells as the cells most responsive to DYRK1A inhibition. Velocity and pseudotime lineage trajectory analyses suggest that Cycling Alpha Cells serve as the primary target cell type for of DYRK1A inhibitors, and may serve as precursor cells that transdifferentiate into functional human beta cells in response to the DYRK1A inhibition. In addition to providing a novel mechanism of action for DYRK1A inhibitors, our findings suggest that efforts to target regenerative drugs to human beta cells may be mis-directed: the proper target may be Cycling Alpha Cells.

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Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Cited by 5 publications

References 55 publications

Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets

Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors

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