Featured Article: Beta cell specific pyruvate dehydrogenase alpha gene deletion results in a reduced islet number and β-cell mass postnatally.
The ability of pancreatic β-cells to undertake glucose-stimulated insulin secretion (GSIS) depends on the generation of adenosine triphosphate (ATP) within the mitochondria from pyruvate, a major rate-limiting enzyme being pyruvate dehydrogenase (PDH) complex (PDC). However, glucose metabolism also controls β-cell mass. To examine the role of PDC in the regulation of pancreatic β-cell development and maturation, we generated β-cell-targeted PDHα subunit knock-out male mice (β-PDHKO) and compared these with control males (β-PDHCT) from birth until 6-8 weeks age. Pancreas morphology, transcription factor expression, pancreatic insulin content, and circulating glucose and insulin values were compared. Compared to β-PDHCT male mice, β-PDHKO animals had significantly reduced pancreatic insulin content from birth, a lower serum insulin content from day 15, and relative hyperglycemia from day 30. Isolated islets from β-PDHKO mice demonstrated a reduced GSIS. The number of islets per pancreatic area, mean islet area, and the proportion of islet cells that were β-cells were all reduced in β-PDHKO animals. Similarly the number of insulin-immunopositive, extra-islet small endocrine cell clusters, a possible source of β-cell progenitors, was lower in β-PDHKO mice. Analysis of pancreatic expression of transcription factors responsible for β-cell lineage commitment, proliferation, and maturation, Pdx1, Neurogenin3, and NeuroD1 showed that mRNA abundance was reduced in the β-PDHKO. This demonstrates that PDC is not only required for insulin expression and glucose-stimulated secretion, but also directly influences β-cell growth and maturity, and positions glucose metabolism as a direct regulator of β-cell mass and plasticity.
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo 14214, NY mspatel@buffalo.edu.
Mulchand S
MS
Patel
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo 14214, NY.
Malathi
M
Srinivasan
Lawson Research Institute, St. Joseph's Health Centre, London, Ontario N6A 4V2, Canada.
Brenda
B
Strutt
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo 14214, NY.
Saleh
S
Mahmood
Lawson Research Institute, St. Joseph's Health Centre, London, Ontario N6A 4V2, Canada Department of Medicine, Physiology, and Paediatrics, University of Western Ontario, London, Ontario N6A 3K7, Canada.
David J
DJ
Hill

               Pdx1 expression; Pyruvate dehydrogenase complex deficiency; insulin secretion; β-cell mass; β-cell maturity