1. Introduction
Natural products have received considerable attention for the management of diabetes and its complications [1–3] which have reached epidemic levels worldwide [4]. The spice turmeric, which is derived from the root of the plant Curcuma longa, has been described as a treatment for diabetes in Ayurvedic [5] and traditional Chinese medicine for thousands of years (Figure 1).
[figure omitted; refer to PDF]The most active component of turmeric, curcumin, has caught scientific attention as a potential therapeutic agent in experimental diabetes and for the treatment of the complications of diabetes patients [7], primarily because it is effective in reducing glycemia and hyperlipidemia in rodent models and is relatively inexpensive and safe [8–10]. The structure of curcumin (Figure 1(c)), shown to be a diferuloylmethane, was resolved by Lampe and Milobedeska in 1910 [11]. We retrieved more than 200 publications with the search term “curcumin and diabetes” from the MEDLINE database in 2013. The first paper that described an effect of curcumin related to diabetes described a blood glucose lowering effect of the drug in one diabetic individual only and was published in 1972 [12]. Curcumin has been since extensively studied in experimental animal models of diabetes and in a few clinical trials of type 2 diabetic patients to treat their complications [13]. This review seeks to briefly summarize the ample scientific literatures regarding curcumin as a potential treatment for diabetes and its associated complications. Particular attention will be given to the anti-inflammatory and antioxidant properties of curcumin.
2. Effect of Curcumin on Glycemia in Animal Model of Diabetes
Since Srinivasan discovered that curcumin has an effect on glycemia in one patient, a lot of papers have been published to discuss the ability of curcumin in controlling blood glucose in various rodent models (Table 1).
Table 1
Diabetic animal models employed in studying the effect of curcumin on glycemia.
Animal | Induction of diabetes |
Curcumin |
Course of |
Reference |
---|---|---|---|---|
Wistar rats | i.f. of STZ, 55 mg/kg·BW | Oral, 60 mg/kg·BW | 14 days | [17, 18] |
Wistar rats | i.p. of STZ, 55 mg/kg·BW; HFD | Oral, 150 mg/kg·BW | 42 days | [19] |
SD rats | HFD | Oral, 80 mg/kg·BW | 15 and 60 days | [26] |
SD rats | i.p. of STZ, 55 mg/kg·BW | Oral, 100 mg/kg·BW | 28 days; 56 days | [21, 23] |
Wistar rats | Injection of STZ, 45 mg/kg·BW | 0.5% curcumin in diet | 16 weeks | [27] |
Wistar rats | i.p. of STZ, 55 mg/kg·BW | Oral, 300 mg/kg·BW | 56 days | [20] |
Wistar rats | i.p. of alloxan monohydrate |
Oral, 80 mg/kg·BW | 21 days | [15] |
Swiss mice | i.p. of STZ |
i.p., 10 mM | 28 days | [32] |
C57BL/6J mice | HFD | Oral, 50 mg/kg·BW | 15 days | [33] |
C57BL/6J mice: ob/ob mice | HFD | 0.5% curcumin in diet | 42 days | [29] |
db/db mice | Not Applicable | 0.02% curcumin in diet | 42 days | [30] |
i.f.: intrafemoral injection, i.p.: intraperitoneally injection.
The most used animal in studying the effect of curcumin is the rat. Various diabetic rat models were employed to probe the effect of curcumin on glycemia. In alloxan-induced diabetes rats, streptozotocin- (STZ-) induced rats models, and STZ-nicotinamide-induced rats models [14], oral administration of various dosages of curcumin (80 mg/kg·body weight (BW) for 21 days [15] and 45 days [16]; 60 mg/kg·BW for 14 days [17]; 90 mg/kg·BW for 15 days [18]; 150 mg/kg·BW for 49 days [19]; 300 mg/kg·BW for 56 days [20]; 100 mg/kg·BW) for 4 weeks [21], 7 weeks [22], and 8 weeks [23] were able to prevent body weight loss, reduce the levels of glucose, hemoglobin (Hb), and glycosylated hemoglobin (HbA1C) in blood [15], and improve insulin sensitivity [16]. In addition, oral administration of turmeric aqueous extract (300 mg/kg·BW) [24] or curcumin (30 mg/kg·BW) for 56 days [25] resulted in a significant reduction in blood glucose in STZ-induced diabetes model in rats. In high fat diet (HFD) induced insulin resistance and type 2 diabetes models in rats, oral administration of curcumin (80 mg/kg·BW) for 15 and 60 days, respectively, showed an antihyperglycemic effect and improved insulin sensitivity [26]. Dietary curcumin (0.5% in diet) was also effective in ameliorating the increased levels of fasting blood glucose, urine sugar, and urine volume in STZ-induced diabetic rats [27].
Diabetic mice models were also employed to show the effect of curcumin on glycemia. In type 2 diabetic KK-A(y) mice, dietary turmeric extract (0.5% in diet, ethanol and/or hexane extraction) for 4 weeks significantly reduced the blood glucose levels [28]. In diet-induced obesity mice and ob/ob male mice, dietary curcumin (3%) for 6 weeks significantly improves glycemic status (blood glucose, glucose tolerance, and HbA1c) and insulin sensitivity [29]. In C57BL/KsJ db/db mice, dietary curcumin (0.2%) for 6 weeks was beneficial in improving glucose homeostasis and insulin resistance [30]. Curcumin (15 mg/kg·BW) for 30 days alone also suppressed elevated level of blood glucose in sodium arsenite treated rats [31]. In STZ-induced Swiss diabetic mice, intraperitoneal administration of curcumin (10 mM; 100 μL/mouse) for 28 days significantly reversed hyperglycemia, glucose intolerance, and hypoinsulinemia [32]. In HFD induced obesity and insulin resistance mice, oral administration of curcumin (50 mg/kg·BW) for 15 days was effective in improving glucose intolerance [33].
The possible mechanisms of the effect of curcumin on glycemia in diabetes models may be explained as follows. First, curcumin could attenuate tumor necrosis factor-
Further, curcumin supplemented with vitamin C [20], yoghurt [36], and bone marrow transplantation [32] was effective in reducing the levels of blood glucose, Hb, and HbA1C in STZ diabetes models.
However, several researchers claimed that curcumin has no significant effect on blood glucose. Nishizono found that the intragastric administration of curcumin (200 mg/kg·BW) has no effect on serum concentration of glucose, insulin, and triacylglycerols in STZ- and HFD-induced diabetic Sprague Dawley rats for 14 days [37]. Majithiya also claimed that oral administration of curcumin from 4 weeks to 24 weeks (200 mg/kg·BW) has no significant effect on blood glucose and pressure in STZ diabetic rats [38]. The reason for yielding conflicting results from different groups may be due to different induction diabetes rodent models or different administration of curcumin.
3. Curcumin and Diabetes-Associated Liver Disorders
Diabetic patients often suffer from fatty liver disease and other liver disorders [39]. Babu and Srinivasan [40] found that STZ-induced diabetic rats fed dietary curcumin for 8 weeks excreted less albumin, urea, creatine, and inorganic phosphorus. Curcumin also reduced liver weight and lipid peroxidation products in the plasma and urine. In this study the beneficial effects of curcumin occurred independently of changes in glycemia or body weight. A further study by this group [41] suggested that hepatic cholesterol-7a-hydroxylase mediates the hypolipidemic action of curcumin in STZ diabetic rats. The effect of curcumin on lipidemia was also demonstrated by other groups [16, 20, 25, 36].
In sodium arsenite induced liver disorder rats, oral administration of curcumin can decrease total lipid, cholesterol, triglyceride (TG), and low density lipoprotein-cholesterol (LDL-c) [31].
Improved lipidemia by curcumin may be attributed to the induction of PPAR-
AMP-activated protein kinase (AMPK) is a strong energy regulator that controls whole-body glucose homeostasis in the liver and other key tissues in type 2 diabetes [44]. AMPK could stimulate glucose uptake and mediate suppression of hepatic gluconeogenesis. G6Pase and PEPCK are key enzymes involved in hepatic gluconeogenesis in the liver. Increased expression of G6Pase and PEPCK may have deleterious effects in diet-induced insulin resistance and type 2 diabetes [45]. Kim et al. [46] showed that curcumin inhibited PEPCK and G6Pase activities in H4IIE rat hepatoma and Hep3B human hepatoma cells. They further demonstrated that curcumin could increase phosphorylation of AMPK [47] and its downstream target acetyl-CoA carboxylase (ACC) [9] in H4IIE and Hep3B cells.
Hyperleptinemia associated with type 2 diabetes could cause hepatic fibrosis, which activates hepatic stellate cells (HSCs). As a sensor of cellular energy homeostasis, AMPK also stimulates fatty acid oxidation and regulates lipogenesis. Curcumin-mediated activation of AMPK could inactivate HSCs because of reduced stimulation by leptin [48], insulin, hyperglycemia [49], advanced glycation endproducts (AGEs) [50], and oxidized low-density lipoprotein (ox-LDL) [51]. The driving mechanisms behind hypolipidemia may be understood as follows. First, curcumin could disrupt insulin signaling and attenuate oxidative stress [52]. Second, curcumin could suppress membrane translocation and GLUT2-mediated gene expression. Third, curcumin was also able to increase expression of the AGE receptor [50], and reduce expression of lectin-like oxidized LDL receptor-1 (LOX-1) [51]. In addition, interruption of Wnt signaling [53] and stimulation of PPAR-
Curcumin prevented liver fat accumulation in HFD rats. The anti-inflammatory and antilipolytic properties of curcumin may account for these results, as evident by reduced levels of TNF-
In clinical trials, oral administration of low-dose curcumin (45 mg/day) for 2 months showed a trend of reduction in total cholesterol level and LDL cholesterol level in 63 acute coronary syndrome patients [59].
4. Curcumin and Adipose Tissue Dysfunction
Adipose tissue plays an important role in controlling wholebody glucose homeostasis [60]. Development of type 2 diabetes may involve deregulation of adiponectin secretion. Recent studies revealed that curcumin stimulated human adipocyte differentiation [7] and suppressed macrophage accumulation or activation in adipose tissue [61] by regulating adiponectin secretion [29, 62]. The mechanism may be due to suppression of NF-
5. Curcumin and Diabetic Neuropathy
Diabetic neuropathy is neuropathic disorders that are associated with DM. These conditions are thought to result from diabetic microvascular injury, elevated AGEs, and activated protein kinase C (PKC) [69]. Curcumin has been actively involved in modulating the diabetic neuropathic disorders by the following lines of evidence. Curcumin effectively suppressed the development of diabetic cataracts in rat models of STZ-induced diabetes by reversing changes in lipid peroxidation, reduced glutathione, protein carbonyl content, and activities of antioxidant enzymes, which is beneficial to normalize expression of
Premanand et al. [75] showed that curcumin induces apoptosis of human retinal endothelial cells (HREC) by inhibiting vascular endothelial growth factor (VEGF) expression, intracellular reactive oxygen species (ROS) generation, and VEGF-mediated PKC-
In addition, curcumin has been show to attenuate diabetes-induced cognitive deficits, as measured by the Morris water maze test [81], and cholinergic dysfunction involving acetylcholinesterase activity and cholinergic receptors [17, 82] through regulation of GLUT3, dopamine (D1, D2) receptors, CREB, phospholipase C [83], and insulin receptors [84]. These changes may be in part due to decreased glutamate-mediated excitotoxicity by curcumin, which alters the neurochemical parameters (NMDA and AMPA receptors) [85] in the cerebral cortices of diabetic rats. Curcumin reduced expression of single-minded 2 (Sim2) [86], which is involved in hyperglycemia-induced neuronal injury and impairment of learning and memory. Curcumin-mediated suppression of
6. Curcumin and Diabetic Nephropathy
Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, progressive decline in the glomerular filtration rate, and elevated arterial blood pressure [93]. Currently, diabetic nephropathy is the leading cause of chronic kidney disease [94] and one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes. There are multiple mechanisms by which curcumin may ameliorate renal damage. Curcumin increases blood urea nitrogen [21, 95] and promotes clearance of creatine and urea [16, 96]. In addition, curcumin decreases levels of albuminuria [36, 76] and enzymuria, including levels of N-acetyl-D-glucosaminidase, lactate dehydrogenase (LDH), aspartate aminotransferase, alanine aminotransferase, and alkaline and acid phosphatases. Curcumin can also restore renal integrity by normalizing glutathione, SODC, glucose-6-phosphate dehydrogenase, LDH, aldose reductase, SDH, transaminases, ATPases, and membrane PUFA/SFA ratio [97]. A further study revealed that curcumin induces changes in posttranslational modification of histone H3 and altered expression of HSP-27 and p38 mitogen-activated protein kinase (MAPK) in diabetic kidneys [95]. These changes were mediated through inhibition of p300 and NF-
7. Curcumin and Diabetic Vascular Disease
Vascular disease is a common long-term complication of diabetes. Diabetic vascular disease causes damage to large and small blood vessels throughout the body. Curcumin has been reported to be active against diabetic vascular disease demonstrated by the following list of lines of evidence. First, curcumin modulated PKC-
8. Curcumin and Other Diabetes-Associated Complications
The effects of curcumin on other diabetes-associated complications have been demonstrated by several studies. First, several groups demonstrated that curcumin was effective against diabetes-induced musculoskeletal diseases. Hie et al. [127] showed that curcumin suppressed diabetes-stimulated bone resorption by reducing tartrate-resistant acid phosphatase and cathepsin K, which was associated with inhibition of expression of c-fos and c-jun expression. The ability of curcumin to increase glucose uptake into skeletal muscle was mediated by improving the expressions of GLUT4 through the PLC-PI3K pathway [128] and insulin resistance in muscular tissue through the LKB1-AMPK pathway [19]. Curcumin effectively reduced the level of insulin receptor substrate-1 (IRS-1) phosphorylation on Ser307 and increased Akt phosphorylation [129] in skeletal muscle. In addition, curcumin and vitamin D3 reversed expression of
Second, curcumin enhanced erectile function in diabetes-induced erectile dysfunction by increasing intracavernosal pressure (ICP), cGMP levels, HO-1, eNOS, neuronal NOS (nNOS), and Nrf2 with significant reductions in NF-
Finally, in diabetic gastroparesis rats, dietary curcumin for 6 weeks significantly improved gastric emptying rates as well as decreasing the levels of MDA and increasing SOD activity. The potential mechanism involved antioxidant action and enhancing expression of stem cell factor (SCF)/c-kit [132]. SCF/c-Kit signaling is important for recovering of the reducing interstitial cells of Cajal in diabetic gastroparesis in both humans and model animals [133, 134]. In B-lymphoma cells, curcumin-induced growth inhibition was mediated by reduced Akt activation and subsequent inhibition of spleen tyrosine kinase (Syk) [135].
9. Effect of Curcumin on Pancreatic
The effect of curcumin on pancreatic cells has been extensively studied. First, curcumin increased islet viability and delayed islet ROS production, which is mediated through inhibiting poly ADP-ribose polymerase-1 activation (STZ-induced islet damage) [136] and normalizing cytokine (TNF
10. Curcumin and Its Anti-Inflammatory Actions
Inflammation is now recognized as one of the main contributors to diabetes and may be ameliorated by diminishing the underlying causes [149]. The beneficial effect of curcumin on diabetes may be due to its ability to spice up the immune system [150]. Margina et al. showed that curcumin restored transmembrane potential and stiffened membrane fluidity, limiting the release of proinflammatory factors, such as MCP-1 from endothelial and immune cells in human umbilical vein endothelial cells and Jurkat T lymphoblasts in the presence of high glucose or increased concentrations of AGEs [151]. These effects were more obvious during the late stages of diabetes.
Sharma et al. [152] showed that curcumin suppressed the activities of T- and B-lymphocytes and macrophages by inhibiting proliferation, antibody production (IgG1 and IgG2a), and lymphokine secretion (IL-4, IL-1, IL-6, and TNF-
Curcumin treatment significantly inhibited degradation of I
Curcumin improved peripheral insulin resistance in insulin-resistant ob/ob mice with steatosis by reducing NF-
In high-fat diet-induced obese and leptin-deficient ob/ob mice, dietary curcumin ameliorated metabolic derangements by reversing many of inflammatory parameters, including reduced macrophage infiltration of white adipose tissue, increased adipose tissue adiponectin production, decreased hepatic NF-
11. Curcumin and Its Antioxidant Actions
Increasing evidence demonstrates that increased levels of circulating ROS are involved in diabetes. Hyperglycemia causes autoxidation of glucose, glycation of proteins, and activation of polyol metabolism. These changes accelerate ROS generation and increase oxidative chemical modification of lipids, DNA, and proteins in various tissues [134]. Curcumin caused antioxidant effects through several mechanisms. First, curcumin dose-dependently abolished phorbol-12, myristate-13, acetate, and thapsigargin-induced ROS generation by inhibiting Ca2+ entry and PKC activity [156].
Second, curcumin blocked ROS formation, which led to cellular apoptosis by blocking subsequent apoptotic changes (DNA fragmentation, caspase-3 activation, cleavage of PARP, mitochondrial cytochrome c release, and JNK activation) in methylglyoxal-stimulated ESC-B5 cells, blastocysts, and human hepatoma G2 cells [157, 158].
Third, oral administration of photoirradiated curcumin resulted in near-normalization of antioxidant enzymatic activities and levels of lipid peroxidation markers, including circulatory lipid peroxidation, vitamin C, vitamin E, and SODC [141, 159].
Fourth, curcumin controlled oxidative stress by inhibiting increases in TBARS and protein carbonyls and reversing altered antioxidant enzyme activities in diabetic rats [34].
However, Majithiya and Balaraman [38] claimed that curcumin treatment had no significant effect on SODC and reduced glutathione levels. Curcumin treatment attenuated the phenylephrine-induced increase in contraction during the early stages of disease. However, this treatment had no significant effects during the medium and late stages. The reason why curcumin was unable to prevent oxidative stress is because of the excessive production of free radicals during the late stages.
12. Curcuminoids
Curcuminoids exhibit biological activities similar to those of curcumin [160] (Table 2). Curcuminoids derived from turmeric extract show significantly suppressed increasement in blood glucose levels by PPAR-
Table 2
The applications of curcuminoids in treating diabetes and its associated disorders.
Curcuminoids | Structures | Antidiabetic function | Reference |
---|---|---|---|
NCD | PCT/ |
Decreasing lipid peroxides; attenuating mitochondria dysfunction | [164] |
|
|||
Demethoxycurcumin (DMC) |
|
Induction of HO; elevating levels of glutamyl cysteine ligase and NAD(P)H:quinone oxidoreductase; inactivating pancreatic a-amylase | [166, 167] |
Bisdemethoxycurcumin (BDMC) |
|
||
|
|||
Tetrahydrocurcumin (THC) |
|
Scavenging ROS; modulating hepatic metabolism enzyme and antioxidant enzyme; decreasing level of glycoprotein; normalizing erythrocyte membrane bounding enzyme and renal abnormalities. | [14, 16, 35, 168–178] |
|
|||
Bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione |
|
Deceasing ALP, LDH, TGA, FFA, and tissue phospholipids; elevating levels of SOD, CAT, and GPx. | [179–181] |
Bis-o-hydroxycinnamoyl methane | Scavenging ROS and protecting the pancreatic |
||
|
|||
Bis(curcumino)oxovanadium complex |
|
Decreasing blood glucose levels and serum lipids; restoring blood pressure and vascular reactivity | [182] |
|
|||
C66 |
|
Reducing production of TNF- |
[183, 184] |
B06 |
|
Pugazhenthi et al. [166] showed that the further purification yields of curcumin, demethoxy curcumin (DMC), and bisdemethoxy curcumin (BDMC) induced expression of HO-1 through PI3K/Akt signaling in MIN6 cells. Real-time reverse transcription polymerase chain reaction also showed that DMC and BDMC elevated levels of glutamyl cysteine ligase (synthesis of glutathione) and NAD(P)H:quinone oxidoreductase (detoxifies quinines). Additional studies revealed that the induction was dependent on the presence of antioxidant response element (ARE) sites and the transcription factor that binds to ARE. Further, BDMC inactivated human pancreatic
Osawa and Kato [168] showed that tetrahydrocurcumin (THC) scavenged ROS and increased glutathione concentrations in 25% galactose-fed SD rats with diabetic cataracts and in the cultured rat lens. Further studies revealed that THC normalized blood glucose by increasing plasma insulin, preventing lipid peroxidation (TBARS and hydroperoxides), and modulating levels of hepatic metabolic enzymes (hexokinase, glucose-6-phosphate dehydrogenase, fructose-1,6-bisphosphatase, and SDH) and antioxidant enzymes (SODC, GPx, glutathione-S-transferase, and reduced glutathione) in the liver, muscle, and brain of STZ-induced diabetic rats [14, 169]. THC also exhibited similar effects in STZ-nicotinamide-induced diabetic rats [170–173]. A further study by this laboratory showed that THC decreased the level of glycoprotein (hexose, hexosamine, fucose, and sialic acid) in diabetic rats [174]. In addition, THC normalized erythrocyte membrane-bounding enzymes [35], insulin receptor [175], renal abnormalities (urea, uric acid, and creatine) [16], and tail tendon collagen (accumulation and cross-linking of collagen) [176]. Further, combined treatment with THC and chlorogenic acid augmented enzymatic antioxidants and decreased lipid peroxidation [177] and blood glucose levels [178] in STZ-nicotinamide induced diabetic rats.
Reddy et al. [179, 180] discovered that bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione, a BDMC analog, effectively decreased toxic effects and hyperlipidemia in STZ-nicotine induced diabetic rats. Bis-o-hydroxycinnamoylmethane, an analogue of the naturally occurring curcuminoid BDMC, exhibited antidiabetic properties by scavenging ROS production and protecting the pancreatic
Majithiya et al. [182] showed that the bis (curcumino) oxovanadium showed antidiabetic and hypolipidemic effects by decreasing blood glucose levels and serum lipids and restoring blood pressure and vascular reactivity to normal in STZ diabetic rats.
C66 and B06, two new synthetic analogues of curcumin, reduced production of TNF-
New formulation of curcumin has also been developed to improve its bioavailability. NCB-02, which is a standardized preparation of curcuminoids, had a favorable effect on endothelial dysfunction through anti-inflammatory and antioxidant mechanisms in a clinical trial [185].
13. Conclusion
Recent research has provided the scientific basis for “traditional” curcumin and confirmed the important role of curcumin in the prevention and treatment of diabetes and its associated disorders. Curcumin could favorably affect most of the leading aspects of diabetes, including insulin resistance, hyperglycemia, hyperlipidemia, and islet apoptosis and necrosis (Figure 2). In addition, curcumin could prevent the deleterious complications of diabetes. Despite the potential tremendous benefits of this multifaceted nature product, results from clinical trials of curcumin are only available in using curcumin to treat diabetic nephropathy, microangiopathy and retinopathy so far. Studies are badly needed to be done in humans to confirm the potential of curcumin in limitation of diabetes and other associated disorders. Further, multiple approaches are also needed to overcome limited solubility and poor bioavailability of curcumin. These include synthesis of curcuminoids and development of novel formulations of curcumin, such as nanoparticles, liposomal encapsulation, emulsions, and sustained released tablets. Enhanced bioavailability and convinced clinical trial results of curcumin are likely to bring this promising natural product to the forefront of therapeutic agents for diabetes by generating a “super curcumin” in the near future.
[figure omitted; refer to PDF]Conflict of Interests
The authors declare that they have no conflicting of interests.
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Abstract
Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a “super curcumin” through improvement of the bioavailability to bring this promising natural product to the forefront of diabetes therapeutics.
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Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Diabetes Research Center, Beijing University of Chinese Medicine, Beijing 100029, China
2 Fraser Lab for Diabetes Research, McGill University Health Center, Montreal, Canada H3A 1A1,