Neratinib protects pancreatic beta cells in diabetes
Amin Ardestani1, Sijia Li2, Karthika Annamalai3
1Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany. ardestani.amin@gmail.com.
Abstract:
The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.
Insights
Neratinib, an FDA-approved drug, inhibits mammalian sterile 20-like kinase 1 (MST1), protecting pancreatic beta-cells. This discovery offers a potential new therapy for diabetes by preserving beta-cell function and survival.
Area of Science:
- Endocrinology
- Cell Biology
- Pharmacology
Background:
- Loss of functional insulin-producing beta-cells is central to diabetes pathogenesis.
- Mammalian sterile 20-like kinase 1 (MST1) critically regulates beta-cell death and dysfunction.
- Targeting MST1 presents a therapeutic strategy for beta-cell protection in diabetes.
Purpose of the Study:
- To identify novel inhibitors of MST1.
- To evaluate neratinib as a potential MST1 inhibitor for diabetes therapy.
- To assess neratinib's efficacy in preserving beta-cell function and survival.
Main Methods:
- In vitro studies using human islets and INS-1E cells under diabetogenic conditions.
- Identification of neratinib as an MST1 inhibitor.
- In vivo preclinical studies in mouse models of type 1 (streptozotocin-induced) and type 2 (Leprdb/db) diabetes.
Main Results:
- Neratinib demonstrated potent inhibition of MST1.
- Neratinib improved beta-cell survival in human islets and cell lines.
- In vivo, neratinib reduced hyperglycemia and enhanced beta-cell mass and function in diabetic mouse models.
Conclusions:
- Neratinib is a novel, potent inhibitor of MST1.
- Neratinib exhibits beta-cell protective effects in vitro and in vivo.
- Neratinib represents a promising therapeutic candidate for diabetes treatment.
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