Lack of preservation of insulin gene expression by a glucagon-like peptide 1 agonist or a dipeptidyl peptidase 4 inhibitor in an in vivo model of glucolipotoxicity.
Prolonged exposure of pancreatic beta-cells to elevated levels of glucose and fatty acids adversely affects insulin secretion and gene expression.


OBJECTIVE
To examine whether the GLP-1 agonist exenatide or the inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase 4 (DPP-4) sitagliptin rescue insulin gene expression in rats infused for 72h with glucose+Intralipid, independently from their glucose-lowering action.


METHODS
Wistar rats were infused alternatively with glucose or Intralipid for cycles of 4h each for a total of 72h. The animals received exenatide (5microg/kg/day IV) or sitagliptin (5mg/kg/day IV) continuously starting 4 days prior to and continuing throughout the 3-day infusion period.


RESULTS
Plasma glucose, fatty acids, insulin and C-peptide levels were unaffected by exenatide or sitagliptin treatment during the infusion period. Insulin mRNA levels increased in response to the glucose infusion, but this increase was abolished in islets from rats receiving glucose+Intralipid. Neither exenatide nor sitagliptin administration rescued insulin mRNA in glucose+Intralipid infused rats.


CONCLUSIONS
Neither a GLP-1 agonist nor a DPP-4 inhibitor, at doses that do not alter blood glucose levels, prevented the inhibition of insulin gene expression in this in vivo model of glucolipotoxicity.
Fontés
Ghislaine
G
Montréal Diabetes Research Center, CRCHUM, University of Montreal, QC, Canada. ghislaine.fontes@crchum.qc.ca <ghislaine.fontes@crchum.qc.ca>
Hagman
Derek K
DK
Latour
Martin G
MG
Semache
Meriem
M
Poitout
Vincent
V
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D005217:Fat Emulsions, Intravenous; D015870:Gene Expression / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000378:metabolism; D005947:Glucose; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D006949:Hyperlipidemias / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005217:Fat Emulsions, Intravenous; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D010455:Peptides; D011719:Pyrazines; D012333:RNA, Messenger; D014230:Triazoles; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4; D005947:Glucose; D000068900:Sitagliptin Phosphate