| First Author | Patel MS | Year | 2014 |
| Journal | Exp Biol Med (Maywood) | Volume | 239 |
| Issue | 8 | Pages | 975-985 |
| PubMed ID | 24845368 | Mgi Jnum | J:238824 |
| Mgi Id | MGI:5824198 | Doi | 10.1177/1535370214531895 |
| Citation | Patel MS, et al. (2014) Featured Article: Beta cell specific pyruvate dehydrogenase alpha gene deletion results in a reduced islet number and beta-cell mass postnatally. Exp Biol Med (Maywood) 239(8):975-985 |
| abstractText | The ability of pancreatic beta-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 beta-cell mass. To examine the role of PDC in the regulation of pancreatic beta-cell development and maturation, we generated beta-cell-targeted PDHalpha subunit knock-out male mice (beta-PDHKO) and compared these with control males (beta-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 beta-PDHCT male mice, beta-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 beta-PDHKO mice demonstrated a reduced GSIS. The number of islets per pancreatic area, mean islet area, and the proportion of islet cells that were beta-cells were all reduced in beta-PDHKO animals. Similarly the number of insulin-immunopositive, extra-islet small endocrine cell clusters, a possible source of beta-cell progenitors, was lower in beta-PDHKO mice. Analysis of pancreatic expression of transcription factors responsible for beta-cell lineage commitment, proliferation, and maturation, Pdx1, Neurogenin3, and NeuroD1 showed that mRNA abundance was reduced in the beta-PDHKO. This demonstrates that PDC is not only required for insulin expression and glucose-stimulated secretion, but also directly influences beta-cell growth and maturity, and positions glucose metabolism as a direct regulator of beta-cell mass and plasticity. |
