Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion
Open accessAbstract
It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that β-cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 β-cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (KATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor α-cyano-β-(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.
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The MPC is a target of thiazolidinediones and a regulator of insulin secretion.
“In fact, the MPC has emerged as an unanticipated target of thiazolidinediones (Colca et al., 2013; Divakaruni et al., 2013), a class of insulin sensitizing drugs, and as a regulator of insulin secretion (Patterson et al., 2014; Vigueira et al., 2014);”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Patterson et al., 2014
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Self-citation
- Authors
- Patterson, J. N., Cousteils, K., Lou, J. W., Manning Fox, J. E., MacDonald, P. E., & Joseph, J. W.
- Affiliations
- University of Waterloo (CA)
- University of Alberta (CA)
- Corresponding author
- Joseph, Jamie W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 289
- Issue
- 19
- Pages
- 13335-13346
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4036342
- OpenAlex
- W2045887831
- Cited by
- 98
- References
- 56
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 18 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 12 · 2015: 9 · 2014: 4
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP 86638)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial pyruvate carrier, pyruvate metabolism, glucose-stimulated insulin secretion, pancreatic beta cells, MPC1, MPC2, ATP-sensitive potassium channels, ATP/ADP ratio, NADPH/NADP+ ratio, glucose homeostasis, impaired glucose tolerance, UK5099, islets
- MeSH terms
- Insulin Secretion, Acrylates, Adenosine Diphosphate, Adenosine Triphosphate, Animals, Female, Glucose, Humans, Insulin, Male, Mitochondria, NADP, Rats, Sprague-Dawley, Pyruvic Acid, Mitochondrial Proteins, Anion Transport Proteins, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, Cell Line, Tumor, Insulin-Secreting Cells, Rats, Gene Knockdown Techniques
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