Insulin downregulates SIRT1 and AMPK activation and is associated with changes in liver fat, but not in inflammation and mitochondrial oxidative capacity, in streptozotocin-diabetic rat

Rocco Barazzoni, Michela Zanetti, Mauro Sturnega, Marco Stebel, Annamaria Semolic, Alessia Pirulli, Pierandrea Vinci, Lorena Zentilin, Mauro Giacca, Luigi Cattin, Gianfranco Guarnieri
Clinical Nutrition 2011, 30 (3): 384-90

BACKGROUND & AIMS: Involvement of insulin in diabetes-associated liver triglyceride deposition and its potential pathways remain incompletely defined. SIRT1 may negatively modulate lipogenesis and liver triglyceride accumulation, involving AMP-activated protein kinase (AMPK) activation. In streptozotocin-diabetic rats, we hypothesized that insulin negatively modulates liver SIRT1 and activates AMPK-inhibited lipogenic mediators leading to triglyceride accumulation. The impact of insulin deprivation (INS-) and replacement (INS+) on liver inflammation and mitochondrial oxidative capacity (also potentially regulating triglyceride deposition) was also measured.

METHODS: Streptozotocin-diabetic rats under chronic (8-week) INS- and INS+.

RESULTS: Compared to INS- (P < 0.05), INS+ had low liver SIRT1 with low AMPK activating phosphorylation, low inactivating phosphorylation of its lipogenic target acetyl-CoA carboxylase and high tissue triglycerides. INS- (P < 0.05 vs Control) had liver inflammation and high mitochondrial oxidative capacity, but neither was modulated by INS+. Pair-feeding showed no influence of spontaneous overeating on insulin-induced changes.

CONCLUSIONS: Insulin replacement downregulates SIRT1 and AMPK activation in vivo in streptozotocin-diabetic rat liver, likely contributing to insulin-induced liver triglyceride accumulation. Under the current experimental conditions, insulin-deprived diabetes is associated with liver inflammation and high mitochondrial oxidative capacity, that are not affected by insulin replacement and are therefore unlikely to contribute to tissue triglyceride changes in this model.


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