TY - JOUR
T1 - Silencing of cytosolic or mitochondrial isoforms of malic enzyme has no effect on glucose-stimulated insulin secretion from rodent islets
AU - Ronnebaum, Sarah M.
AU - Jensen, Mette V.
AU - Hohmeier, Hans E.
AU - Burgess, Shawn C.
AU - Zhou, Yun Ping
AU - Qian, Su
AU - MacNeil, Douglas
AU - Howard, Andrew
AU - Thornberry, Nancy
AU - Ilkayeva, Olga
AU - Lu, Danhong
AU - Sherry, A. Dean
AU - Newgard, Christopher B.
PY - 2008/10/24
Y1 - 2008/10/24
N2 - We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, it has recently been shown by other laboratories that NADP-dependent cytosolic malic enzyme (MEc), but not NAD-dependent mitochondrial malic enzyme (MEm), regulates GSIS. In the current study, we show that small interfering RNA-mediated suppression of either MEm or MEc results in decreased GSIS in both 832/13 cells and a new and more glucose-and incretin-responsive INS-1-derived cell line, 832/3. The effect of MEm to suppress GSIS in these cell lines was linked to a substantial decrease in cell growth, whereas MEc suppression resulted in decreased NADPH, shown previously to be correlated with GSIS. However, adenovirus-mediated delivery of small interfering RNAs specific to MEc and MEm to isolated rat islets, while leading to effective suppression of the targets transcripts, had no effect on GSIS. Furthermore, islets isolated from MEc-null MOD1-/- mice exhibit normal glucose- and potassium-stimulated insulin secretion. These results indicate that pyruvate-malate cycling does not control GSIS in primary rodent islets.
AB - We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, it has recently been shown by other laboratories that NADP-dependent cytosolic malic enzyme (MEc), but not NAD-dependent mitochondrial malic enzyme (MEm), regulates GSIS. In the current study, we show that small interfering RNA-mediated suppression of either MEm or MEc results in decreased GSIS in both 832/13 cells and a new and more glucose-and incretin-responsive INS-1-derived cell line, 832/3. The effect of MEm to suppress GSIS in these cell lines was linked to a substantial decrease in cell growth, whereas MEc suppression resulted in decreased NADPH, shown previously to be correlated with GSIS. However, adenovirus-mediated delivery of small interfering RNAs specific to MEc and MEm to isolated rat islets, while leading to effective suppression of the targets transcripts, had no effect on GSIS. Furthermore, islets isolated from MEc-null MOD1-/- mice exhibit normal glucose- and potassium-stimulated insulin secretion. These results indicate that pyruvate-malate cycling does not control GSIS in primary rodent islets.
UR - http://www.scopus.com/inward/record.url?scp=57349189962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57349189962&partnerID=8YFLogxK
U2 - 10.1074/jbc.M804665200
DO - 10.1074/jbc.M804665200
M3 - Article
C2 - 18755687
AN - SCOPUS:57349189962
SN - 0021-9258
VL - 283
SP - 28909
EP - 28917
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -