Rhein Protects Pancreatic β-Cells From Dynamin-Related Protein-1–Mediated Mitochondrial Fission and Cell Apoptosis Under Hyperglycemia

Liu, Jing; Chen, Zhaohong; Zhang, Yujing; Zhang, Mingchao; Zhu, Xiaodong; Fan, Yun; Shi, Shaolin; Zen, Ke; Liu, Zhihong

doi:10.2337/db13-0251

Cited by 63 publications

(36 citation statements)

References 48 publications

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“…Recent studies suggest that Drp1 recruitment involves posttranslational modifications including sumoylation, S-nitrosylation, ubiquitination, and phosphorylation (16,17). Interestingly, Drp1 activation under glucolipotoxic conditions in pancreatic b-cells leads to abnormalities in mitochondrial structure and function, followed by activation of proapoptotic signaling cascades (18)(19)(20)(21). It has recently been reported that manipulation of mitochondrial morphology by overexpressing dominantnegative Drp1 with erased GTPase activity decreases GSIS in INS-1E insulinoma cells, and this was attributed to increased mitochondrial proton leak (22).…”

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confidence: 99%

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

et al. 2017

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In pancreatic b-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient b-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic b-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.The development of type 2 diabetes is associated with mitochondrial dysfunction in pancreatic b-cells. b-Cells have developed highly coordinated mechanisms that link glucose sensing with metabolic signaling cascades that direct the secretion of sufficient insulin to maintain glucose homeostasis (1). The mechanism underlying glucose-stimulated insulin secretion (GSIS) from b-cells involves glucose uptake by specific glucose transporters followed by glucose catabolism through glycolysis yielding pyruvate, which in turn is further catabolized via the tricarboxylic acid cycle. Both glycolysis and tricarboxylic acid cycle turnover generate reducing power that is used by the mitochondrial respiratory chain to produce ATP through oxidative phosphorylation. The resultant increase in the cytosolic ATP/ADP ratio closes ATP-sensitive K + (K ATP ) channels, thus depolarizing the plasma membrane. Depolarization triggers opening of voltagegated Ca 2+ channels, and the influx of Ca 2+ ions consequently leads to exocytosis of insulin-containing granules from b-cells (2). This sequence of events illustrates that b-cell mitochondria exert strong control over GSIS (3), as mitochondrial energy-transducing processes dictate how fast and efficiently glucose is converted to ATP. Mitochondrial dysfunction impairs glucose-insulin secretion coupling and ultimately promotes b-cell apoptosis and death, one of the key features of type 2 diabetes (4).Mitochondria are dynamic organelles that are constantly remodeled through the opposing action of fission and fusion proteins (5). Until recently, the influence of mitochondrial dynamics over energy transduction has been underappreciated. The continuous changes in mitochondrial morphology are controlle...

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confidence: 99%

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

et al. 2017

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“…It is well known that chronic hyperglycemia induces overproduction of reactive oxygen species 17 , which have a very short half-life, and react rapidly with DNA, protein and lipids, thereby resulting in oxidative damage 18 . Mitochondrial dysfunction is induced by high glucose and free fatty acids in various type cells 19,20 . Mitochondria are the major site of reactive oxygen species production within the cell 21 .…”

Section: Discussionmentioning

confidence: 99%

Circulating cell‐free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus

Liu

Zou

Tang

et al. 2015

J of Diabetes Invest

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Aims/IntroductionCirculating cell‐free mitochondrial deoxyribonucleic acid (ccf‐mtDNA) is presumably derived from injured tissues or cells in the body and has been suggested to be potential biomarker in several diseases. The present study explored whether mtDNA could be used as a biomarker to evaluate disease in coronary heart disease (CHD) patients with or without diabetes mellitus (DM).Materials and MethodsA total of 50 CHD patients with type 2 diabetes, 50 CHD patients without type 2 diabetes, and 50 age‐ and sex‐matched patients without CHD and DM (non‐CHD‐DM) were recruited. Ccf‐mtDNA levels were assessed by measuring the nicotinamide adenine dinucleotide dehydrogenase 1 gene using quantitative real‐time polymerase chain reaction. Receiver operating characteristic curve analysis of plasma mtDNA in CHD with or without DM was also determined. Multivariate logistic regression analyses were carried out to determine the correlation between the mtDNA levels and traditional CHD risk factors.ResultsThe plasma ccf‐mtDNA levels were significantly elevated in CHD patients with DM compared with those without and non‐CHD‐DM. The area under the receiver operating characteristic curves of mtDNA in CHD patients with DM vs non‐CHD‐DM was 0.907%. Correlation analyses of the mtDNA levels and traditional CHD risk factors showed that the mtDNA levels were significantly correlated with fasting blood glucose in CHD patients with DM.ConclusionsCcf‐mtDNA levels can be used as a biomarker in CHD patients with DM.

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“…This value was constant and concentration-independent, and agrees with previously published data reporting a protein binding of 93.46% in rats (Liu et al, 2013). Subsequently, unbound plasma levels were predicted based on this average value and determination of total concentrations.…”

Section: Resultsmentioning

confidence: 73%

Effect of glycyrrhizic acid on rhein renal penetration: a microdialysis study in rats

Wei

Guan

et al. 2015

Xenobiotica

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1. Rhein (RH), a primary active component isolated from rhubarb, is effective in protecting against the progression of diabetic nephropathy (DN) progression. Glycyrrhizic acid (GA), an active constituent of liquorice, is also considered to be a protective agent against DN. Here, we evaluated the effect of GA on the renal penetration of RH in rats. 2. Plasma and renal pharmacokinetics were profiled to estimate kidney penetration. After rats were anesthetized, the carotid artery was used for blood collection and a microdialysis probe was inserted into the kidney cortex to collect dialysate samples. 3. When co-administered with GA, the Vss and CL values of RH in plasma increased by 25% and 34%, respectively. The Cmax in kidney dialysates significantly increased 1.3-fold (p<0.05). There was no change in AUC0-∞ in kidney dialysates, but a significant decrease (2×fold) in the plasma was observed. The AUC0-∞kidney/AUC0-∞plasma ratio of RH, representing kidney penetration, increased by 1.4-fold in the group pre-treated with GA compared to the RH alone group. 4. These results demonstrate that GA increases the renal penetration of RH efficiently and may exert a synergistic effect, although the molecular mechanism of interaction requires further investigation.

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Rhein Protects Pancreatic β-Cells From Dynamin-Related Protein-1–Mediated Mitochondrial Fission and Cell Apoptosis Under Hyperglycemia

Cited by 63 publications

References 48 publications

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

Circulating cell‐free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus

Effect of glycyrrhizic acid on rhein renal penetration: a microdialysis study in rats

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