Augmented mitochondrial energy metabolism is an early response to chronic glucose stress in human pancreatic beta cells.

Aims/hypothesis: In islets from individuals with type 2 diabetes and in islets exposed to chronic elevated glucose, mitochondrial energy metabolism is impaired. Here, we studied early metabolic changes and mitochondrial adaptations in human beta cells during chronic glucose stress.

Methods: Respiration and cytosolic ATP changes were measured in human islet cell clusters after culture for 4 days in 11.

Cellular stress is a prerequisite for glucose-induced mitochondrial matrix alkalinization in pancreatic β-cells.

Changes in mitochondrial and cytosolic pH alter the chemical gradient across the inner mitochondrial membrane. The proton chemical gradient contributes to mitochondrial ATP synthesis as well as the uptake and release of metabolites and ions from the organelle. Here mitochondrial pH and ΔpH were studied for the first time in human pancreatic β-cells.

Antibiotics induce mitonuclear protein imbalance but fail to inhibit respiration and nutrient activation in pancreatic β-cells.

Chloramphenicol and several other antibiotics targeting bacterial ribosomes inhibit mitochondrial protein translation. Inhibition of mitochondrial protein synthesis leads to mitonuclear protein imbalance and reduced respiratory rates as confirmed here in HeLa and PC12 cells. Unexpectedly, respiration in INS-1E insulinoma cells and primary human islets was unaltered in the presence of chloramphenicol.

Coordinated activation of mitochondrial respiration and exocytosis mediated by PKC signaling in pancreatic β cells.

Mitochondria play a central role in pancreatic β-cell nutrient sensing by coupling their metabolism to plasma membrane excitability and insulin granule exocytosis. Whether non-nutrient secretagogues stimulate mitochondria as part of the molecular mechanism to promote insulin secretion is not known. Here, we show that PKC signaling, which is employed by many non-nutrient secretagogues, augments mitochondrial respiration in INS-1E (rat insulinoma cell line clone 1E) and human pancreatic β cells.