β-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced β …

ML Peyot, E Pepin, J Lamontagne, MG Latour… - Diabetes, 2010 - Am Diabetes Assoc
ML Peyot, E Pepin, J Lamontagne, MG Latour, B Zarrouki, R Lussier, M Pineda, TL Jetton…
Diabetes, 2010Am Diabetes Assoc
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 β-cell failure in these mice. RESEARCH DESIGN AND 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
β-cell mass or function and studied islet metabolism and signaling. RESULTS HDR mice …
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 β-cell failure in these mice.
RESEARCH DESIGN AND 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 β-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 β-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 Ca2+ 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
β-Cell failure in HDR mice is not due to reduced β-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca2+ and lipid signaling, as well as free cholesterol deposition.
Am Diabetes Assoc