Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Nolan, Christopher; Leahy, Jack L.; Delghingaro-Augusto, Viviane; Moibi, Jacob A.; Soni, Krishnakant G.; Peyot, Marie‐Line; Fortier, Mélanie; Guay, Claudiane; Lamontagne, Julien; Barbeau, Annie; Przybytkowski, Ewa; Joly, Etienne; Masiello, Pellegrino; Wang, Shaopu; Mitchell, Grant A.; Prentki, Marc

doi:10.1007/s00125-006-0305-5

Cited by 117 publications

(130 citation statements)

References 47 publications

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“…We have proposed that lipid metabolism and signalling are involved in beta cell compensation in ZF rat islets due to enhanced GL/FA cycling [29]. Thus, it was of interest to determine whether defects in islet lipid metabolism, short of causing steatosis, could be involved in beta cell failure in ZF-Px rats.…”

Section: Discussionmentioning

confidence: 99%

“…Islet fatty acid oxidation and esterification These were determined as in [29] and as detailed in the ESM.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that this degree of Px had no impact on glycaemia in non-obese Sprague-Dawley rats [27]. ZF rats are normally able to fully compensate for insulin resistance through large enhancements in beta cell mass [28] and function [26,29]. The latter involves increased glucose utilisation and oxidation along with elevated anaplerosis and pyruvate cycling pathways [26].…”

Section: Introductionmentioning

confidence: 99%

“…The latter involves increased glucose utilisation and oxidation along with elevated anaplerosis and pyruvate cycling pathways [26]. We recently reported that GSIS is markedly augmented by NEFA in ZF rat islets [29] and that this coincides with enhanced glycerolipid/fatty acid (GL/ FA) cycling [29].…”

Section: Introductionmentioning

confidence: 99%

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Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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Aims/hypothesis The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. Methods Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. Results ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. Conclusions/interpretation Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Islet fatty acid oxidation and esterification These were determined as in [29] and as detailed in the ESM.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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“…To test this possibility, we incubated adipocytes with orlistat, a general lipase inhibitor (36). As shown in Fig.…”

Section: Agents That Increase Camp Stimulate Both Lipolysis and Ampk mentioning

confidence: 99%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

220

206

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AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis. AMP-activated protein kinase (AMPK)2 is a sensor of cellular energy state that responds to metabolic stresses and other regulatory signals. The mechanism of activation of AMPK is a complex phenomenon and is still not fully understood, although it is recognized that it involves phosphorylation of the critical Thr-172 residue of its ␣ catalytic subunit by upstream kinases such as LKB1, Ca 2ϩ -calmodulin-dependent protein kinase kinase, and possibly Tak1, a member of the mitogenactivated protein kinase kinase kinase family (1-5). AMPK is also regulated by AMP allosterically and the current view is that this both increases AMPK activity directly and makes it a poorer substrate for phosphatases (6).The role and regulation of AMPK in muscle, liver, and various cultured cells have been extensively studied. It is now well established that energy depletion because of starvation, hypoxia, and exercise increases the intracellular AMP:ATP ratio and secondarily AMPK activity (7). Upon its activation, a major role of AMPK is to replete cellular energy stores by stimulating processes that generate ATP, such as fatty acid oxidation, and inhibiting ATP-consuming pathways (e.g. lipogenesis, triglyceride synthesis, and gluconeogenesis) that are not acutel...

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Current literature in diabetes

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Diabetes Metabolism Res

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Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

Cited by 117 publications

References 47 publications

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Current literature in diabetes

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