Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass.
OBJECTIVE
C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about beta-cell failure in these mice.


METHODS
DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced beta-cell mass or function and studied islet metabolism and signaling.


RESULTS
HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced beta-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca(2+) was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets.


CONCLUSIONS
beta-Cell failure in HDR mice is not due to reduced beta-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca(2+) and lipid signaling, as well as free cholesterol deposition.
Peyot
Marie-Line
ML
Montreal Diabetes Research Center and CRCHUM, Montreal, QC, Canada. marie-line.peyot@crchum.qc.ca.
Pepin
Emilie
E
Lamontagne
Julien
J
Latour
Martin G
MG
Zarrouki
Bader
B
Lussier
Roxane
R
Pineda
Marco
M
Jetton
Thomas L
TL
Madiraju
S R Murthy
SR
Joly
Erik
E
Prentki
Marc
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D004032:Diet; D004041:Dietary Fats / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D011384:Proinsulin / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015430:Weight Gain / Q000502:physiology*
D004041:Dietary Fats; D007328:Insulin; D000255:Adenosine Triphosphate; D011384:Proinsulin; D005947:Glucose