Pancreatic islet beta-cells transiently metabolize pyruvate

Area of Science:

• Cellular Metabolism
• Endocrinology
• Biophysics

Background:

• Pancreatic beta-cells regulate blood glucose via insulin secretion.
• NAD(P)H redox state is a key indicator of cellular metabolic activity.
• Understanding substrate-specific metabolic pathways is crucial for insulin secretion mechanisms.

Purpose of the Study:

• To investigate the distinct roles of glucose and pyruvate in stimulating pancreatic beta-cell metabolism and insulin secretion.
• To elucidate the contribution of cytoplasmic and mitochondrial NAD(P)H dynamics.
• To determine the involvement of pyruvate transport and the malate-aspartate shuttle in substrate-stimulated responses.

Main Methods:

• Quantitative two-photon NAD(P)H imaging of pancreatic islets.
• Measurement of insulin secretion in response to glucose and pyruvate.
• Pharmacological inhibition of mitochondrial pyruvate transporter and malate-aspartate shuttle.

Main Results:

• Glucose robustly increased both NAD(P)H levels and insulin secretion.
• Pyruvate elicited a weaker, transient NAD(P)H response and minimal insulin secretion.
• Mitochondrial NAD(P)H and insulin secretion upon glucose stimulation were independent of pyruvate transport but dependent on NAD(P)H shuttling.
• Inhibition of the malate-aspartate shuttle unexpectedly enabled pyruvate-stimulated insulin secretion.

Conclusions:

• Glycolysis plays a dominant role in glucose-stimulated insulin secretion.
• A novel mechanism for glucose-stimulated insulin secretion involves allosteric inhibition of TCA cycle enzymes and pH-dependent mitochondrial pyruvate transport.
• Pyruvate metabolism contributes differently to beta-cell redox state and insulin release compared to glucose.