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Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes
Matthew R Brown1, Heather Holmes1, Kuntol Rakshit1
1Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
The Journal of Clinical Investigation
|October 8, 2021
Summary
Increased expression of SLC4A4/NBCe1 in pancreatic beta cells contributes to type 2 diabetes mellitus (T2DM) by impairing glucose homeostasis. Reducing SLC4A4/NBCe1 protects against T2DM and beta cell failure.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Pancreatic beta cell dysfunction is central to type 2 diabetes mellitus (T2DM), leading to impaired insulin secretion.
- SLC4A4, encoding the NBCe1 transporter, is misexpressed in T2DM beta cells, impacting intracellular pH and function.
Purpose of the Study:
- To investigate the role of SLC4A4/NBCe1 misexpression in T2DM beta cell dysfunction.
- To determine if targeting SLC4A4/NBCe1 can ameliorate T2DM-associated metabolic impairments.
Main Methods:
- Confirmed SLC4A4/NBCe1 upregulation in T2DM patient beta cells.
- Generated and analyzed beta cell-specific Slc4a4/NBCe1 knockout (KO) mice.
- Assessed glucose tolerance, beta cell function, mitochondrial activity, and gene expression.
Main Results:
- SLC4A4/NBCe1 induction in T2DM beta cells correlated with loss of identity, alkalinization, and dysfunction.
- Slc4a4/NBCe1-KO mice showed protection against diet-induced metabolic stress and beta cell failure.
- KO mice exhibited improved glucose tolerance, enhanced beta cell function, augmented mitochondrial function, and preserved gene expression.
Conclusions:
- Increased SLC4A4/NBCe1 expression in T2DM beta cells contributes to beta cell failure.
- SLC4A4/NBCe1 represents a potential therapeutic target for T2DM.
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