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Updated: Jun 21, 2025
Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres
Published on: November 5, 2016
Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system
Carolina Rosselot1, Yansui Li1, Peng Wang1
1Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.
Insights
A new study shows combining a DYRK1A inhibitor with GLP1 receptor agonists significantly increases human beta cell mass in vivo. This combination therapy reverses diabetes by enhancing beta cell proliferation, function, and survival.
Area of Science:
- Endocrinology
- Regenerative Medicine
- Pharmacology
Background:
- Diabetes affects over 537 million people globally, characterized by reduced insulin-producing beta cells.
- Current diabetes medications do not increase human beta cell numbers.
- Dual tyrosine-regulated kinase 1A (DYRK1A) inhibitors and glucagon-like peptide 1 receptor agonists (GLP1RAs) show potential for beta cell regeneration.
Purpose of the Study:
- To investigate if DYRK1A inhibitors combined with GLP1RAs increase human beta cell mass in vivo.
- To assess the impact of this combination therapy on human beta cell survival and diabetes reversal.
- To evaluate the preclinical safety profile of this therapeutic combination.
Main Methods:
- Utilized an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol.
- Employed mouse kidneys with human islet grafts to model the in vivo environment.
- Administered a DYRK1A inhibitor in combination with exendin-4 (a GLP1RA).
Main Results:
- The combination therapy increased human beta cell mass by four- to sevenfold over 3 months in both diabetic and nondiabetic mice.
- Diabetes was reversed in treated mice without altering human alpha cell mass.
- Mechanisms included enhanced beta cell proliferation, function, and survival, with VGF mediating part of the survival benefit.
Conclusions:
- The combination of a DYRK1A inhibitor and GLP1RA demonstrates significant therapeutic potential for increasing human beta cell mass in vivo.
- This approach offers a promising strategy for diabetes treatment, showing efficacy in reversing diabetes and a favorable preclinical safety profile.
- The findings support further clinical investigation of DYRK1A inhibitors and GLP1RAs for managing diabetes.
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