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Published on: January 23, 2018
Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion
Rebecca L Pongratz1, Richard G Kibbey, Gerald I Shulman
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
The Journal of Biological Chemistry
|November 15, 2006
Summary
A pyruvate-malate cycle is crucial for insulin secretion. The cytosolic malic enzyme 1 (ME1) isoform is vital for glucose and amino acid-stimulated insulin release, while the mitochondrial ME2 isoform impacts amino acid-stimulated secretion.
Area of Science:
- Metabolic Regulation
- Cellular Physiology
- Endocrinology
Background:
- Islet beta-cells utilize metabolic pathways to regulate insulin secretion.
- Pyruvate carboxylase (PC) flux correlates with insulin secretion rates, suggesting a role for pyruvate metabolism.
Purpose of the Study:
- To investigate the functional relevance of malic enzyme isoforms and pyruvate-malate cycles in insulin secretion.
- To determine the specific roles of cytosolic ME1 and mitochondrial ME2 in glucose- and amino acid-stimulated insulin release.
Main Methods:
- Quantification of malic enzyme isoform expression in INS-1 cells and rat islets.
- Selective knockdown of ME1 and ME2 using small interfering RNA (siRNA).
- Measurement of insulin secretion in response to glucose and amino acids.
- Metabolic modeling using [U-(13)C]glucose and isotopic analysis of glutamate.
Main Results:
- Cytosolic ME1 was the most abundant malic enzyme isoform.
- ME1 knockdown significantly reduced both glucose- and amino acid-stimulated insulin secretion.
- ME2 knockdown did not affect glucose-stimulated secretion but reduced amino acid-stimulated secretion.
- Metabolic modeling revealed distinct pyruvate pools and differential effects of ME1 and ME2 knockdown on PC flux.
Conclusions:
- Two distinct pyruvate cycles, mediated by ME1 and ME2, are physiologically relevant to insulin secretion.
- ME1 generates cytosolic NADPH and is essential for both glucose and amino acid responses.
- ME2 responds to amino acids and supports Krebs cycle flux when glucose is limited.
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