Rhein Protects Pancreatic β-Cells From Dynamin-Related Protein-1–Mediated Mitochondrial Fission and Cell Apoptosis Under Hyperglycemia
Jing Liu
Zhaohong Chen
Yujing Zhang
Mingchao Zhang
Xiaodong Zhu
Yun Fan
Shaolin Shi
Ke Zen
kzen@nju
Zhihong Liu
Rhein, an anthraquinone compound isolated from rhubarb, has been shown to improve glucose metabolism disorders in diabetic mice. The mechanism underlying the protective effect of rhein, however, remains unknown. Here, we demonstrate that rhein can protect the pancreatic b-cells against hyperglycemia-induced cell apoptosis through stabilizing mitochondrial morphology. Oral administration of rhein for 8 or 16 weeks in db/db mice significantly reduced fasting blood glucose (FBG) level and improved glucose tolerance. Cell apoptosis assay using both pancreatic sections and cultured pancreatic b-cells indicated that rhein strongly inhibited b-cell apoptosis. Morphological study showed that rhein was mainly localized at b-cell mitochondria and rhein could preserve mitochondrial ultrastructure by abolishing hyperglycemiainduced mitochondrial fission protein dynamin-related protein 1 (Drp1) expression. Western blot and functional analysis confirmed that rhein protected the pancreatic b-cells against hyperglycemiainduced apoptosis via suppressing mitochondrial Drp1 level. Finally, mechanistic study further suggested that decreased Drp1 level by rhein might be due to its effect on reducing cellular reactive oxygen species. Taken together, our study demonstrates for the first time that rhein can serve as a novel therapeutic agent for hyperglycemia treatment and rhein protects pancreatic b-cells from apoptosis by blocking the hyperglycemia-induced Drp1 expression. Diabetes 62:3927-3935, 2013
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Racid) is an anthraquinone compound isolated
hein (4,5-dihydroxyanthraquinone-2-carboxylic
from rhubarb that has been used for more than
2,000 years in China to treat constipation,
gastrointestinal hemorrhage, and ulcers (1). In our previous
work, we found that rhein could improve glucose
metabolism disorders in diabetic mice, and its effect on reducing
blood glucose level was even stronger than rosiglitazone
and benazepril (2,3). Moreover, rhein also inhibited
apoptosis of islet cells and protected islet function (4). Using
mouse nonalcoholic fatty liver disease as an animal model
associated with obesity, insulin resistance, and
inflammatory disorders, Sheng et al. (5) reported that rhein could
ameliorate fatty liver disease in diet-induced obese mice
via negative energy balance, hepatic lipogenous regulation,
and immunomodulation. Recent antihyperglycemic study
by Chatterjee et al. (6) suggests that rhein, as well as other
natural inhibitors such as aloins and capparisine, may be
a foundation for a better antidiabetic therapy. However,
the mechanism underlying these protective effects of rhein
remains unclear.
Increasing evidence suggests that b-cell failure is the
mainstay of the pathogenesis of type 2 diabetes (7).
Although the precise mechanisms underlying the b-cell
dysfunction in type 2 diabetes are not fully understood,
hyperglycemia has been shown as a major factor to
cause the b-cell apoptosis. Once hyperglycemia develops,
the pancreatic b-cell is exposed to increased metabolic
flux and associated cellular stress, leading to impairment
of b-cell function and survival, a process called
glucotoxicity (8,9). In type 2 diabetes, hyperglycemia is commonly
associated with deregulation of lipid metabolism and
elevation of free fatty acids, which also contribute to b-cell
dysfunction (8,10). Moreover, high levels of glucose can
also amplify lipotoxicity (10). The thiazolidinedione
peroxisome proliferatoractivated receptor-g activator drugs,
rosiglitazone and pioglitazone, have been widely used to
suppress insulin resistance in type 2 diabetic patients (11).
Although rhein shows a similar or even better effect on
reducing mouse blood glucose level than rosiglitazone, the
underlying mechanism remains unclear. It has been known
that mitochondrial fission and fusion modulators,
dynaminrelated protein 1 (Drp1) (12), optic atrophy protein 1 (Opa1)
(13), prohibitin (14), and mitofusin (15), collectively control
the dynamic balance of mitochondria fission and fusion
processes and consequent mitochondria functions.
Previous studies have demonstrated that Drp1 plays an
important role in promoting hyperglycemia-induced apoptosis
of b-cells and neurons (12,16,17). Drp1 expression was
increased drastically in islet b-cells under hyperglycemia
conditions. Estaquier and Arnoult (18) further
demonstrated that inhibiting Drp1-mediated mitochondrial fission
could selectively prevent the release of cytochrome c, a
mediator of apoptosis, from mitochondria. In contrast to the
mitochondria fission modulators, which are upregulated
or activated by stress factors such as high concentration
of glucose (HG), mitochondria fusion modulators are
generally reduced when cells are challenged with
proapoptotic insults. Recent studies by Kushnareva et al. (19)
and Leboucher et al. (15) showed that stress-induced
loss of Opa1 and mitofusin can faci (...truncated)