Glucotoxicity and α cell dysfunction: involvement of the PI3K/Akt pathway in glucose-induced insulin resistance in rat islets and clonal αTC1-6 cells.
OBJECTIVE
The objective of this study was to assess how long-term exposure to high glucose affects the α cell function and whether the increased glucagon secretion is mediated via insulin resistance.


METHODS
We established a β cell-depleted rat model to obtain pure primary α cells. Furthermore, isolated rat islets and TC1-6 cells (a clonal α cell line) were exposed to high glucose (25 or 30 mmol/L) and low glucose (5.5 mmol/L) for up to 5 days to evaluate the influence of chronic glucose toxicity on glucagon secretion and glucagon gene expression. Moreover, we added insulin and/or Wortmannin to examine if the inhibitory effect of insulin on glucagon secretion was impaired by high glucose via the phosphatidylinositol 3 kinase/PKB protein kinase B pathway.


RESULTS
Both glucagon secretion and glucagon gene expression were increased in response to 5 days exposure to high glucose. While a moderate insulin concentration slightly inhibits glucagon secretion from rat islets and α TC1-6 cells at high glucose, a pronounced increase in glucagon secretion was observed at low glucose. We found that the insulin-mediated activity of the phosphatidylinositol 3 kinase/PKB protein kinase B pathway in the α cell was markedly impaired by chronic exposure to high glucose.


CONCLUSIONS
The hypersecretion of glucagon induced by glucotoxicity may be secondary to insulin resistance of the α cell induced by impaired activity of the insulin signaling pathway.
Endocrinology and Cardiac Disease Clinical Center, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China. shenxx09@yahoo.cn
Xiao-Xia
XX
Shen
Hong-Liang
HL
Li
Lin
L
Pan
Jing
J
Hong
Juan
J
Xiao
Kjeld
K
Hermansen
Per Bendix
PB
Jeppesen
Guang-Wei
GW
Li
D000818:Animals; D002478:Cells, Cultured; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D007328:Insulin; D005934:Glucagon; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose