Abstract
Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes.
Highlights
Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic b-cells
Our results show that the mouse double minute 2 (MDM2)–p53 axis is essential for mitochondrial oxidative metabolism and subsequent GSIS in b-cells by regulating the mitochondrial enzyme pyruvate carboxylase (PC)
Consistent with the in vivo observations, our ex vivo analysis in isolated islets showed that total, first and second phases of GSIS were sharply diminished by b-cell-specific ablation of MDM2, whereas insulin secretion induced by potassium chloride (KCl) was similar between MDM2-deficient islets and WT controls (Fig. 1g,h and Supplementary Fig. 3)
Summary
Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic b-cells. Glucose-stimulated insulin secretion (GSIS) is tightly controlled by a complex metabolic process involving mitochondrial oxidative metabolism in pancreatic b-cells[1,2]. Dysregulation of this process contributes to the development of diabetes[3]. The byproducts such as NADPH, a-ketoglutarate and GTP generated during mitochondrial pyruvate cycling in the TCA cycle act as amplifying factors for second-phase insulin secretion[4] These metabolic pathways are coordinated by various mitochondrial enzymes, such as malic enzymes, pyruvate dehydrogenase kinase and pyruvate carboxylase (PC)[4], yet their molecular regulation and precise roles in the pathogenesis of b-cell dysfunction in diabetes remain largely unknown. We explore the feasibility to reverse impaired GSIS in type 2 diabetic mice by pharmacological intervention of the MDM2–p53 signalling axis
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