curcumin and Hyperglycemia

Diabetes mellitus is a chronic disease, typified by hyperglycemia resulting from failures in complex multifactorial metabolic functions, that requires life-long medication. Prolonged uncontrolled hyperglycemia leads to micro- and macro-vascular complications. Although antidiabetic drugs are prescribed as the first-line treatment, many of them lose efficacy over time or have severe side effects. There is a lack of in-depth study on the patents filed concerning the use of natural compounds to manage diabetes. Thus, this patent analysis provides a comprehensive report on the antidiabetic therapeutic activity of 6 phytocompounds when taken alone or in combinations. Four patent databases were searched, and 17,649 patents filed between 2001 and 2021 were retrieved. Of these, 139 patents for antidiabetic therapeutic aids that included berberine, curcumin, gingerol, gymnemic acid, gymnemagenin and mangiferin were analyzed. The results showed that these compounds alone or in combinations, targeting acetyl-coenzyme A carboxylase 2, serine/threonine protein kinase, α-amylase, α-glucosidase, lipooxygenase, phosphorylase, peroxisome proliferator-activated receptor-γ (PPARγ), protein tyrosine phosphatase 1B, PPARγ co-activator-1α, phosphoinositide 3-kinase and protein phosphatase 1 regulatory subunit 3C, could regulate glucose metabolism which are validated by pharmacological rationale. Synergism, or combination therapy, including different phytocompounds and plant extracts, has been studied extensively and found effective, whereas the efficacy of commercial drugs in combination with phytocompounds has not been studied in detail. Curcumin, gymnemic acid and mangiferin were found to be effective against diabetes-related complications. Please cite this article as: DasNandy A, Virge R, Hegde HV, Chattopadhyay D. A review of patent literature on the regulation of glucose metabolism by six phytocompounds in the management of diabetes mellitus and its complications. J Integr Med. 2023; 21(3): 226-235.

Topics: Curcumin; Diabetes Mellitus; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Phosphatidylinositol 3-Kinases; PPAR gamma

Considered to be one of the most important non-contagious systemic diseases worldwide, diabetes mellitus is still a topical issue on the health agenda with the problems it causes. Exposure to long-term hyperglycemia causes diabetic complications (diabetic neuropathy, nephropathy and retinopathy). The optic nerve can suffer damage by both diabetic retinopathy and neuropathy during diabetes, both because it is formed by axons of retinal ganglion cells and these axons belong to the central nervous system. The issue of hyperglycemia on the optic nerve have been described as diabetic papillopathy, posterior ischemic optic neuropathy, nonarteritic anterior ischemic optic neuropathy and optic atrophy in clinical studies. Experimental studies indicated axon-myelin degeneration in addition to microvascular and ultrastructural changes caused by the hyperglycemia-induced optic nerve damage. Although there are several proposed biochemical mechanisms to cause these damages, oxidative stress emerges as an important factor among them. Oxidative stress leads to pathological state on the nerve cells by affecting the DNA, protein and lipids at different levels. These are causing deterioration on nerve conduction velocity, myelin sheath and nerve structure, neurotrophic support system, glial cells and nerve function. Curcumin, as an important antioxidant, can be an ideal prophylactic agent to eliminate damages on optic nerve. Curcumin helps to regulate the balance of antioxidant and reactive oxygen species by targeting various molecules (NF-κB, STAT3, MAPK, Mfn2, Nrf2, pro-inflammatory cytokines). In addition, it shows healing or preventive effects on myelin sheath damage via regulating ferritin protein in oligodendrocytes. It is also effective in preventing neurovascular damage.

Topics: Animals; Curcumin; Humans; Hyperglycemia; Optic Nerve; Optic Nerve Injuries; Oxidative Stress

Type 2 diabetes mellitus (T2DM) is a growing metabolic disease characterized by insulin resistance and hyperglycemia. Current preventative and treatment strategies for T2DM and insulin resistance lack in efficacy resulting in the need for new approaches to prevent and manage/treat the disease better. In recent years, epidemiological studies have suggested that diets rich in fruits and vegetables have beneficial health effects including protection against insulin resistance and T2DM. Curcumin, a polyphenol found in turmeric, and curcuminoids have been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, neuroprotective, immunomodulatory and antidiabetic properties. The current review (I of II) summarizes the existing in vitro studies examining the antidiabetic effects of curcumin, while a second (II of II) review summarizes evidence from existing in vivo animal studies and clinical trials focusing on curcumin's antidiabetic properties.

Topics: Animals; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance

Curcuma caesia has shown positive results in treating number of diseases, but till date no work was reported on its activity in diabetic neuropathy. So, the present review aims at exploring several hypothesis which can be proposed to explain further its utility in diabetic neuropathy by its antioxidant property, anti-inflammatory, CNS depressant effect, antibacterial and antifungal property. For finding the accurate and exact detail, a thorough review of all the available research and review article was done. A number of book chapters and encyclopaedias were taken into consideration to find out the origin, botany and genetics. The databases were searched using different keywords like antioxidant, inflammation, turmeric, diabetic neuropathy.. After getting data on pathogenesis of diabetic neuropathy, it has been found out that its role as antioxidant will reduce the level of oxidative stress which is the main reason for the occurrence of the present complication. Apart this, the anti-inflammatory activity will further prevent the inflammation of neurons and antibacterial effect will inhibit the spread of infection. Combining all the factors together, the plant can be utilized in the treatment of diabetic neuropathy.. Curcuma caesia can be proved as a useful approach in the treatment of diabetic neuropathy.

Topics: Antioxidants; Curcuma; Curcumin; Diabetic Nephropathies; Humans; Hyperglycemia; Inflammation Mediators; Microglia; Oxidative Stress; Plant Extracts

Diabetes mellitus is characterised by hyperglycaemia, lipidaemia and oxidative stress and predisposes affected individuals to long-term complications afflicting the eyes, skin, kidneys, nerves and blood vessels. Increased protein glycation and the subsequent build-up of tissue advanced glycation endproducts (AGEs) contribute towards the pathogenesis of diabetic complications. Protein glycation is accompanied by generation of free radicals through autoxidation of glucose and glycated proteins and via interaction of AGEs with their cell surface receptors (referred to as RAGE). Glycationderived free radicals can damage proteins, lipids and nucleic acids and contribute towards oxidative stress in diabetes. There is interest in compounds with anti-glycation activity as they may offer therapeutic potential in delaying or preventing the onset of diabetic complications. Although many different compounds are under study, only a few have successfully entered clinical trials but none have yet been approved for clinical use. Whilst the search for new synthetic inhibitors of glycation continues, little attention has been paid to anti-glycation compounds from natural sources. In the last few decades the traditional system of medicine has become a topic of global interest. Various studies have indicated that dietary supplementation with combined anti-glycation and antioxidant nutrients may be a safe and simple complement to traditional therapies targeting diabetic complications. Data for forty two plants/constituents studied for anti-glycation activity is presented in this review and some commonly used medicinal plants that possess anti-glycation activity are discussed in detail including their active ingredients, mechanism of action and therapeutic potential.

Topics: Antioxidants; Curcumin; Diabetes Complications; Diabetes Mellitus; Female; Garlic; Glycation End Products, Advanced; Glycosylation; Humans; Hyperglycemia; Hyperlipidemias; Maillard Reaction; Male; Oxidative Stress

Hyperglycemia causes the autoxidation of glucose, glycation of proteins, and the activation of polyol metabolism. These changes accelerate generation of reactive oxygen species (ROS) and increases in oxidative chemical modification of lipids, DNA, and proteins in various tissues. Oxidative stress may play an important role in the development of complications in diabetes such as lens cataracts, nephropathy, and neuropathy. Glycation reactions, especially Maillard reactions, occur in vivo as well as in vitro and are associated with the chronic complications of diabetes mellitus and aging and age-related diseases by increases in oxidative chemical modification of lipids, DNA, and proteins. In particular, long-lived proteins such as lens crystallines, collagens, and hemoglobin may react with reducing sugars to form advanced glycation end products (AGEs). Recently, we found a novel type of AGE, named MRX, and we found that MRX is a good biomarker for detecting oxidative stress produced during Maillard reaction. We also examined in detail the role of lipid peroxidation reaction in hyperglycemia and found that hexanoyl modification formed by the reaction of oxidized lipids and proteins must be important for oxidative stress. Detailed analyses of the formation mechanism of hexanoyl lysine (HEL) moiety in proteins were conducted, and excretion of HEL into urine was quantified by using LC/MS/MS. Macrophages and neutrophils play an important role in oxidative stress during hyperglycemia, and we determined that oxidatively modified tyrosines are a good biomarker for formation of oxidative stress at an early stage. Immunochemical analyses by application of monoclonal antibodies specific to lipid hydroperoxide-modified proteins produced by polyunsaturated fatty acids including docosahexaenoic acid (DHA) in oxidative stress caused by hyperglycemia were conducted, and the relationship between glycation and lipid peroxidation reactions both by chemical and immunochemical approaches are discussed. Recently, we put much more focus on dietary antioxidants for prevention of diabetic complications. Curcuminoids, the main yellow pigments in Curcuma longa (turmeric), have been used widely and for a long time in the treatment of sprain and inflammation in indigenous medicine. Curcumin is the main component of turmeric, and two minor components are also present as the curcuminoids. Curcuminoids possess antioxidant activity. Protective effects of curcumin (U1) and one of its major

Topics: Animals; Antioxidants; Curcumin; Food Analysis; Glycation End Products, Advanced; Humans; Hyperglycemia; Lipid Peroxidation; Oxidation-Reduction; Oxidative Stress; Tyrosine

Curcumin is a biologically active phytochemical ingredient found in turmeric. It has several pharmacologic effects that might benefit patients with polycystic ovary syndrome (PCOS).. We hypothesized curcumin to be effective in improving blood sugar levels, insulin resistance and hyperandrogenism in individuals with PCOS.. In a randomized double-blind placebo-controlled trial, individuals with PCOS were treated with curcumin (500 mg three times daily) or placebo for 12 weeks. Primary outcome measures were fasting plasma glucose (FPG), fasting insulin (FI), sex hormone levels, and hirsutism (Ferriman-Gallwey [mFG] score). Secondary outcomes included anthropometric measurements.. Of 72 randomized individuals, 67 completed the trial. The two groups were comparable at baseline. At the end of the study, FPG and Dehydroepiandrosterone levels had decreased significantly in the intervention group compared to control (difference of change (post-pre) between intervention and placebo groups: -4.11 mg/dL; 95% CI: -8.35, -0.35 mg/dL; p = 0.033 and -26.53 microg/dL; 95% CI: -47.99, -4.34 µg/dL; p = 0.035, respectively). We also observed a statistically non-significant increase (p = 0.082) in Estradiol levels in the intervention group compared to control. No serious adverse events were reported throughout the trial.. Curcumin might be a safe and useful supplement to ameliorate PCOS-associated hyperandrogenemia and hyperglycemia. However, longer trials investigating different dosages in longer durations are needed to underpin these findings.

Topics: Adolescent; Adult; Androgens; Blood Glucose; Curcumin; Dehydroepiandrosterone; Dietary Supplements; Double-Blind Method; Female; Hirsutism; Humans; Hyperglycemia; Insulin; Insulin Resistance; Middle Aged; Placebos; Polycystic Ovary Syndrome; Treatment Outcome; Young Adult

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(d,l-lactide-

Topics: Animals; Anti-Inflammatory Agents; Cataract; Curcumin; Diabetes Mellitus, Experimental; Hyperglycemia; Insulin; Insulin, Long-Acting; Ion Channels; Mice; Nanoparticles; Retinal Diseases; Rodentia

Natural compounds have tremendous potential to regulate glucose metabolism, but conventional methods for studying their bioactivities are usually labor intensive. Here, hypoglycemic properties in 22 selected food-derived compounds were examined using molecular docking. The results indicated that curcumin is an inhibitor of both α-glucosidase and dipeptidyl-peptidase 4 (DPP-4), which are important for glycemic control. These effects of curcumin were also confirmed by enzymatic determination in vitro. Furthermore, curcumin significantly improved diet-induced hyperglycemia (e.g., fasting plasma glucose levels and glycogen storage in muscle or liver) in mice. This might be attributed to its inhibitory effects on the activities of α-glucosidase and DPP-4 in vivo. Curcumin also upregulated the expression of genes (e.g., glucagon-like peptide 1) related to DPP-4 activity in the small intestine. In conclusion, curcumin is a potential ingredient of functional foods used for diet-induced hyperglycemia management. PRACTICAL APPLICATIONS: Curcumin has been widely used as a colorant in the food industry. Moreover, a growing number of studies have described its diverse biological functions, such as anti-inflammatory, anti-oxidant, and anti-angiogenic activities. Thus, curcumin is regarded as a potential ingredient in functional foods. Our results highlighted the hyperglycemic effect of curcumin, suggesting that curcumin may be included in food products for hyperglycemic patients.

Topics: alpha-Glucosidases; Animals; Curcumin; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Mice; Molecular Docking Simulation

Type 2 diabetes mellitus (T2DM) is known as a complex genetic disease characterized by genetic and environmental factors. The imbalanced intestinal flora and intestinal mucosal barrier are considered to be related to T2DM. Curcumin has been proved to affect the progression of T2DM. T2DM animal was established by low-dose streptozotocin intraperitoneal injection combined with high-fat diet (HFD) feeding. Hematoxylin and eosin (HE) staining and transfer electron microscopy (TEM) were used to observe morphological changes of intestinal tissues of T2DM rats. Insulin and glucose tolerance tests were performed to investigate the influence of curcumin on blood glucose. Curcumin significantly improved the intestinal integrity, hyperglycemia and insulin resistance in diabetic rats. The metabolic endotoxemia induced by HFD in diabetic rats was inhibited remarkably. Curcumin reversed gut microbiota dysbiosis in diabetic rats caused by HFD. We demonstrated that curcumin could protect intestinal mucosal barrier, improve insulin resistance and reduce blood glucose in diabetic rats. This study might provide experimental evidence for the prevention and treatment in T2DM.

Topics: Animals; Bacteroidetes; Bifidobacterium; Curcumin; Diabetes Mellitus, Type 2; Diet, High-Fat; Endotoxemia; Firmicutes; Gastrointestinal Microbiome; Gene Ontology; Hyperglycemia; Insulin Resistance; Intestines; Lipopolysaccharides; Metabolomics; Mice; NF-kappa B; Rats; Signal Transduction; Tight Junction Proteins; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Increasing evidence suggests that diabetes also targets lung tissues resulting in structural and physiological abnormalities. The present study evaluated the impact of pristine C60 fullerene (C60) against diabetes-induced lung damage for the first time. The objective was to evaluate the impacts of Curcumin (Cur), C60 and C60 fullerene+Curcumin (C60 + Cur) combination on oxidative stress (MDA, GSH, CAT, GST, Retinol, α-tocopherol), apoptosis (Caspase-3, Bcl-2), cholesterol and fatty acid profile (16:0,18:0,18:1,18:2, 22:4, 22:6) against changes in the lung tissue of diabetic rats. Streptozotocin (STZ) was used for inducing diabetes with Cur, C60 and C60 + Cur combination administered for eight weeks to treat diabetic and control rats. Increased oxidative stress, apoptosis and significant changes in cell structure were observed in the lung tissues of diabetic rats. The combination of Cur, C60 and C60 + Cur reduced oxidative stress in the lung tissue of diabetic rats while increasing the antioxidant defense capacity of the tissue, exhibiting tissue protective properties against apoptosis. The diabetic rats displayed favorable properties against lipotoxicity-induced tissue damage due to the increase in the fatty acid and cholesterol levels in lung tissue. It was observed that Cur, C60 and C60 + Cur combination displays protective effects against hyperglycemia induced oxidative damage to lung tissue. Oxidative stress, prevention of lipid and cholesterol accumulation, and weakening of lung apoptosis may be associated with these effects.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Fullerenes; Humans; Hyperglycemia; Lung; Male; Molecular Structure; Rats; Rats, Wistar

There is a growing interest in the correlation between antioxidants and periodontal disease. In this study, we aimed to investigate the effect of oxidative stress and the impact of two antioxidants, curcumin and rutin, respectively, in the etiopathology of experimentally induced periodontitis in diabetic rats.. Fifty Wistar albino rats were randomly divided into five groups and were induced with diabetes mellitus and periodontitis: (1) (CONTROL)-control group, (2) (DPP)-experimentally induced diabetes mellitus and periodontitis, (3) (DPC)-experimentally induced diabetes mellitus and periodontitis treated with curcumin (C), (4) (DPR)-experimentally induced diabetes mellitus and periodontitis treated with rutin (R) and (5) (DPCR)-experimentally induced diabetes mellitus and periodontitis treated with C and R. We evaluated malondialdehyde (MDA) as a biomarker of oxidative stress and reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG and catalase (CAT) as biomarkers of the antioxidant capacity in blood harvested from the animals we tested. The MDA levels and CAT activities were also evaluated in the gingival tissue.. The control group effect was statistically significantly different from any other groups, regardless of whether or not the treatment was applied. There was also a significant difference between the untreated group and the three treatment groups for variables MDA, GSH, GSSG, GSH/GSSG and CAT. There was no significant difference in the mean effect for the MDA, GSH, GSSG, GSH/GSSG and CAT variables in the treated groups of rats with curcumin, rutin and the combination of curcumin and rutin.. The oral administration of curcumin and rutin, single or combined, could reduce the oxidative stress and enhance the antioxidant status in hyperglycemic periodontitis rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Curcumin; Diabetes Mellitus, Experimental; Hyperglycemia; Male; Oxidative Stress; Periodontitis; Rats; Rats, Wistar; Rutin

Curcumin is the main secondary metabolite of

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Curcuma; Curcumin; Diet, High-Fat; Humans; Hyperglycemia; Hyperlipidemias; Lipids; Liver; Plant Extracts; Rats; Streptozocin; Superoxide Dismutase; Triglycerides

The present study aims to examine the protective effects of C60 fullerene (C60), Curcumin (CUR; Curcuma longa), C60 + CUR combination against oxidative stress, apoptosis, and changes in cellular level in kidney tissue of diabetic rats. Treatment practices were administered separately to groups for 8 weeks following the approval of diabetes induction. It was observed that the treatment groups had increased antioxidant potential, decreased oxidative stress levels, decreased cholesterol, alpha tocopherol, retinol levels along with improved important changes in fatty acid metabolism compared with the diabetic group. C60, CUR, and C60 + CUR were also determined to act in the direction of reducing kidney damage by activating apoptotic pathways. It can be concluded based on these findings that C60, CUR, and especially C60 + CUR combination has beneficial properties in maintaining kidney tissue and function by effectively preventing oxidative stress, apoptotic changes, and changes at the cellular level in kidney tissue under hyperglycemia conditions. PRACTICAL APPLICATIONS: C60 and CUR have various biological activities which can be indicated as antioxidant, anti-inflammatory, anticancer, neuroprotective, and hepatoprotective. It has been reported that C60 and CUR protect the cells against oxidative injury brought about by reactive oxygen species (ROS). Data acquired from the present study puts forth that C60 and C60 + CUR may be promising agents to prevent damage induced by hyperglycemic conditions in kidney tissue.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Fullerenes; Hyperglycemia; Kidney; Nanoparticles; Rats; Streptozocin

Curcumin has anti-inflammatory and antioxidant activities.. This study aimed to investigate the effects of curcumin on the histological changes and functional recovery following spinal cord injury (SCI).. One hundred twenty-eight Sprague-Dawley rats were distributed into a sham, SCI only, SCI-hyperglycemia, and SCI-hyperglycemia-curcumin (200 mg/kg/day, i.p.) groups.. SCI was induced using a clip at T9-10 and hyperglycemia was induced by streptozotocin (60-70 mg/kg, i.v.). Plasma malondialdehyde levels and superoxide dismutase activity was measured to determine oxidative stress. The activity of macrophages in the spinal cord after SCI was stained by the anti-CD68 antibody (ED-1). The tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels were measured by enzyme-linked immunosorbent assay and Western blot was used to verify the levels of mitogen-activated protein kinases and STAT3. The glial fibrillary acidic protein expression was evaluated by immunofluorescence analysis. Functional recovery was assessed according to the Basso, Beattie, and Bresnahan scale and histologic outcome was evaluated by the lesion volume and spared tissue area.. Superoxide dismutase activity increased, the malondialdehyde level decreased, and ED-1 macrophage marker level decreased in the SCI-hyperglycemia-curcumin group than in the SCI-hyperglycemia group at 2 weeks after SCI (p<.01). The SCI-hyperglycemia-curcumin group showed a statistically significant reduction in IL-6, IL-8, and TNF-α levels compared with the SCI-hyperglycemia group after SCI. The phosphorylated-extracellular signal-regulated kinase, phosphorylated-JNK, and phospho-p38 levels were significantly lower in the SCI-hypoglycemia-curcumin group than in the SCI-hypoglycemia group. The SCI-hyperglycemia-curcumin group showed a decrease in glial fibrillary acidic protein expression after SCI compared with the SCI-hyperglycemia group. The SCI-hyperglycemia-curcumin group showed a lower lesion volume, higher spared tissue, and better functional recovery than the SCI-hyperglycemia group.. Curcumin may have a potential neuroprotective effect in SCI with hyperglycemia.. Curcumin decreased the inflammatory response and decreased astrogliosis and improved the functional recovery and histologic outcomes in SCI with hyperglycemia.

Topics: Animals; Anti-Inflammatory Agents; Curcumin; Glial Fibrillary Acidic Protein; Hyperglycemia; Interleukin-6; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

The polyphenols resveratrol (RSV) and curcumin (Cur) are phytoalexines and natural antibiotics with numerous pharmacological functions and metabolic impacts. Recent evidences show a broad control of gut microbiota by polyphenols which could influence glycemic regulation. The aim of this work is to estimate the respective effect of RSV and Cur alone or in association on the control of glycemia and on gut microbiota. A 5-week chronic treatment of hyperglycemic mice with RSV and/or Cur resulted in a differential effect on glucose tolerance test and modified gut microbiome. We precisely identified groups of bacteria representing a specific signature of the glycemic effect of RSV. Inferred metagenomic analysis and metabolic pathway prediction showed that the sulfur and branched-chain amino-acid (BCAA) metabolic activities are tightly correlated with the efficacy of RSV for the control of glycaemia. The impact on BCAA metabolism was further validated by serum metabolomics analysis. Altogether, we show that polyphenols specifically impact gut microbiota and corresponding metabolic functions which could be responsible for their therapeutic role.

Topics: Amino Acids, Branched-Chain; Animals; Blood; Curcumin; Diet, High-Fat; Drug Therapy, Combination; Gastrointestinal Microbiome; Hyperglycemia; Male; Mice, Inbred C57BL; Prediabetic State; Resveratrol

The relationship between diabetes mellitus and pancreatic cancer is complex. Diabetes has been postulated to be both an independent risk factor and a consequence of pancreatic cancer. Our previous study confirmed that curcumin plays a vital role in inhibiting the epithelial-mesenchymal transition of pancreatic cancer cells. However, whether curcumin attenuates hyperglycemia-induced cancer invasive and migratory abilities and the underlying mechanisms are not yet well understood. As high glucose is able to induce the expression of epidermal growth factor (EGF), which is intimately related with tumor progression, the aim of this study was to evaluate whether curcumin could influence the high glucose-induced EGF/EGFR pathway and the biological activity of pancreatic cancer cells. Human pancreatic cancer BxPC-3 cells were exposed to high glucose or EGF, with or without curcumin, LY 294002 (an Akt inhibitor) or PD 98059 (an ERK inhibitor). MTT, Transwell invasion and wound healing assays were used to detect the proliferation, invasion and migration potential of cancer cells. The activation of p-EGFR, p-ERK and p-Akt was determined by western blot analysis. The expression levels of uPA and E-cadherin were examined using qRT-PCR and western blot analysis. The results showed that high glucose could not only promote the proliferation, invasion and migration of pancreatic cancer cells, but also induce the expression of EGF and activation of EGFR, ERK and Akt. These effects of high glucose were counter-balanced by curcumin. EGF-induced proliferative, invasive and migratory abilities of BxPC-3 cells were abrogated by curcumin, LY 294002 and PD 98059. In addition, EGF-modulated activation of EGFR, ERK and Akt, as well as the expression of uPA and E-cadherin were inhibited by curcumin. Taken together, the present study indicates that curcumin suppresses hyperglycemia-driven EGF-induced invasion and migration of pancreatic cancer cells by inhibiting the EGF/EGFR signaling pathway and its downstream signaling molecules including ERK and Akt. Curcumin is a potential anticancer agent for pancreatic cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromones; Curcumin; Epidermal Growth Factor; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Glucose; Humans; Hyperglycemia; Morpholines; Neoplasm Invasiveness; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

This study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.. High-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).. Curcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.. Curcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.

Topics: Acetyl Coenzyme A; Adenylate Kinase; Animals; Curcumin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 4; Diet, High-Fat; Enzyme Activation; Feeding Behavior; Gluconeogenesis; Glucose; Hepatocytes; Hyperglycemia; Lipid Metabolism; Liver; Male; Mice, Inbred ICR; Pyruvate Carboxylase; Pyruvate Dehydrogenase Complex

L3, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aims to explore the efficacy of L3 on diabetic atherosclerosis and the related mechanism. The effect of L3 was studied on glucose and lipid metabolism, antioxidant status, atherosclerosis-related indexes and pathological changes of main organs in the mice model of diabetes induced by streptozotocin and high-fat diet. The results showed that L3 treatment could meliorate dyslipidemia and hyperglycemia, reduce oxidative stress, enhance the activity of antioxidases, increase the nitric oxide level in plasma and aortic arch, decrease the production of reactive oxygen species in pancreas and lectin-like oxidized low-density lipoprotein receptor-1 expression in aortic arch, and meliorate the fatty and atherosclerotic degeneration in aortic arch, thereby preventing the development of diabetes and its complications. These results suggested that L3 can alleviate the diabetic atherosclerosis by multiple effects. This study provided scientific basis for the further research and clinical application of L3.

Topics: Animals; Aorta; Atherosclerosis; Curcumin; Diabetes Mellitus, Experimental; Diet, High-Fat; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Liver; Mice; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Pancreas; Reactive Oxygen Species; Scavenger Receptors, Class E

Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Lepr(db/db) on the Kaliss background).. In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity.. These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance.

Topics: 3T3-L1 Cells; Animals; Body Composition; Cell Survival; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Glycated Hemoglobin; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Oligopeptides; Pentacyclic Triterpenes; Polyphenols; Proteasome Inhibitors; Receptors, Leptin; Triterpenes

Dehydrozingerone (DHZ) exerts beneficial effects on human health; however, its mechanism of action remains unclear. Here, we found that DHZ suppressed high-fat diet-induced weight gain, lipid accumulation and hyperglycaemia in C57BL/6 mice and increased AMP-activated protein kinase (AMPK) phosphorylation and stimulated glucose uptake in C2C12 skeletal muscle cells. DHZ activated p38 mitogen-activated protein kinase (MAPK) signalling in an AMPK-dependent manner. Inhibiting AMPK or p38 MAPK blocked DHZ-induced glucose uptake. DHZ increased GLUT4 (major transporter for glucose uptake) expression in skeletal muscle. Glucose clearance and insulin-induced glucose uptake increased in DHZ-fed animals, suggesting that DHZ increases systemic insulin sensitivity in vivo. Thus, the beneficial health effects of DHZ could possibly be explained by its ability to activate the AMPK pathway in skeletal muscle.

Topics: AMP-Activated Protein Kinases; Animals; Biological Transport; Blood Glucose; Cells, Cultured; Curcumin; Deoxyglucose; Diet, High-Fat; Enzyme Activation; Glucose; Glucose Transporter Type 4; Hyperglycemia; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Obesity; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; RNA Interference; RNA, Small Interfering; Styrenes

Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD-STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin-pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in α2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased α2-adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of β-adrenergic receptors when compared with control. Pretreatment significantly increased β-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in α2-adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through β-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced β-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion.

Topics: Adrenergic Agents; Animals; Blood Glucose; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Gene Expression; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Pancreas; Phytotherapy; Plant Extracts; Prediabetic State; Rats, Wistar; Receptors, Adrenergic, alpha-2; Receptors, Adrenergic, beta; Signal Transduction; Streptozocin

A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.

Topics: Animals; Atherosclerosis; Cholesterol; Curcumin; Diet, High-Fat; Diet, Western; Dietary Fats; Disease Models, Animal; Gene Expression; Glucose Intolerance; Hyperglycemia; Intestinal Mucosa; Intestines; Kidney; Lipopolysaccharides; Macrophages; Mice; Mice, Knockout; Nephrectomy; Polymyxins; Receptors, LDL; Renal Insufficiency

Curcuma oil (C. oil) isolated from turmeric (Curcuma longa L.) has been shown to have neuro-protective, anti-cancer, antioxidant and anti-hyperlipidaemic effects in experimental animal models. However, its effect in insulin resistant animals remains unclear. The present study was carried out to investigate the disease modifying potential and underlying mechanisms of the C. oil in animal models of diet induced insulin resistance and associated thrombotic complications.. Male Golden Syrian hamsters on high fructose diet (HFr) for 12 wk were treated orally with vehicle, fenofibrate (30 mg/kg) or C. oil (300 mg/kg) in the last four weeks. Wistar rats fed HFr for 12 wk were treated orally with C. oil (300 mg/kg) in the last two weeks. To examine the protective effect of C. oil, blood glucose, serum insulin, platelet aggregation, thrombosis and inflammatory markers were assessed in these animals.. Animals fed with HFr diet for 12 wk demonstrated hyperlipidaemia, hyperglycaemia, hyperinsulinaemia, alteration in insulin sensitivity indices, increased lipid peroxidation, inflammation, endothelial dysfunction, platelet free radical generation, tyrosine phosphorylation, aggregation, adhesion and intravascular thrombosis. Curcuma oil treatment for the last four weeks in hamsters ameliorated HFr-induced hyperlipidaemia, hyperglycaemia, insulin resistance, oxidative stress, inflammation, endothelial dysfunction, platelet activation, and thrombosis. In HFr fed hamsters, the effect of C. oil at 300 mg/kg [ ] was comparable with the standard drug fenofibrate. Curcuma oil treatment in the last two weeks in rats ameliorated HFr-induced hyperglycaemia and hyperinsulinaemia by modulating hepatic expression of sterol regulatory element binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1)α and PGC-1β genes known to be involved in lipid and glucose metabolism.. High fructose feeding to rats and hamsters led to the development of insulin resistance, hyperglycaemia, endothelial dysfunction and oxidative stress. C. oil prevented development of thrombotic complications associated with insulin resistance perhaps by modulating genes involved in lipid and glucose metabolism. Further studies are required to confirm these findings.

Topics: Animals; Blood Glucose; Cricetinae; Curcuma; Diet, High-Fat; Gene Expression Regulation; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipid Peroxidation; Liver; Mesocricetus; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Plant Extracts; Platelet Aggregation; Rats; Sterol Regulatory Element Binding Protein 1; Thrombosis; Transcription Factors

Nitrosative and oxidative stress play a key role in obesity and diabetes-related mitochondrial dysfunction. The objective was to investigate the effect of curcumin treatment on state 3 and 4 oxygen consumption, nitric oxide (NO) synthesis, ATPase activity and lipid oxidation in mitochondria isolated from liver and kidneys of diabetic db/db mice.. Hyperglycaemia increased oxygen consumption and decreased NO synthesis in liver mitochondria isolated from diabetic mice relative to the control mice. In kidney mitochondria, hyperglycaemia increased state 3 oxygen consumption and thiobarbituric acid-reactive substances (TBARS) levels in diabetic mice relative to control mice. Interestingly, treating db/db mice with curcumin improved or restored these parameters to normal levels; also curcumin increased liver mitochondrial ATPase activity in db/db mice relative to untreated db/db mice.. These findings suggest that hyperglycaemia modifies oxygen consumption rate, NO synthesis and increases TBARS levels in mitochondria from the liver and kidneys of diabetic mice, whereas curcumin may have a protective role against these alterations.

Topics: Adenosine Triphosphatases; Animals; Body Weight; Cell Respiration; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Disease Models, Animal; Genotype; Hyperglycemia; Kidney; Lipid Peroxidation; Liver; Male; Mice; Mitochondria; Mitochondria, Liver; Nitric Oxide; Oxidative Stress; Oxygen Consumption; Selective Breeding

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Fibrosis; Glutathione Peroxidase; Heart Ventricles; Hemodynamics; Hyperglycemia; Lipid Peroxidation; Male; Myocytes, Cardiac; Oxidative Stress; Protein Kinase Inhibitors; Protein Kinases; Rats; Rats, Sprague-Dawley

Curcumin has been reported to lower plasma lipids and glucose in diabetic rats, and to decrease body weight in obese rats, which may partly be due to increased fatty acid oxidation and utilization in skeletal muscle.. Diabetic rats induced by high-fat diet plus streptozotocin (STZ, 30 mg/kg BW) were fed a diet containing 50, 150, or 250 mg/kg BW curcumin for 7 wk. Curcumin dose-dependently decreased plasma lipids and glucose and the dose 150 mg/kg BW appeared to be adequate to produce a significant effect. Curcumin supplementation reduced glucose and insulin tolerance measured as areas under the curve. L6 myotubes were treated with palmitate (0.25 mmol/L) in the presence of different levels of curcumin for 24 h in our in vitro experiment. Curcumin at 10 μmol/L was adequate to cause a significant increase in 2-deoxy-[(3)H]d-glucose uptake by L6 myotubes. Curcumin up-regulated expression of phosphorylated AMP-activated protein kinase (AMPK), CD36, and carnitine palmitoyl transferase 1, but down-regulated expression of pyruvate dehydrogenase 4 and phosphorylated glycogen synthase (GS) in both in vivo and in vitro studies. Moreover, curcumin increased phosphorylated acetyl COA carboxylase in L6 myotubes. The effects of curcumin on these enzymes except for GS were suppressed by AMPK inhibitor, Compound C. LKB1, an upstream kinase of AMPK, was activated by curcumin and inhibited by radicicol, an LKB1 destabilizer.. Curcumin improves muscular insulin resistance by increasing oxidation of fatty acid and glucose, which is, at least in part, mediated through LKB1-AMPK pathway.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Biological Transport; Cell Line; Curcumin; Deoxyglucose; Diabetes Mellitus, Experimental; Dietary Fats; Dietary Supplements; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Muscle, Skeletal; Palmitic Acid; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Random Allocation; Rats; Rats, Wistar; Signal Transduction

Diabetes is featured by elevated levels of blood glucose, i.e. hyperglycemia, which might be a risk factor for hepatic fibrogenesis in patients with non-alcoholic steatohepatitis. Hepatic stellate cells (HSCs) are the major effectors during hepatic fibrogenesis. This study was designed to evaluate impacts of high levels of glucose on HSC activation, assess roles of the phytochemical curcumin in attenuating the glucose impacts, and elucidate underlying mechanisms. In this report, levels of intracellular glucose were measured. Contents and gene expression of glucose transporter-2 (GLUT2) in cell fractions were examined. Levels of cellular glutathione and oxidative stress were analyzed. We observed that high levels of glucose induced cell proliferation, type I collagen production and expression of genes relevant to HSC activation, and elevated intracellular glucose levels in cultured HSCs. Curcumin eliminated the stimulatory impacts. Curcumin abrogated the membrane translocation of GLUT2 by interrupting the p38 MAPK signaling pathway. In addition, curcumin suppressed glut2 expression by stimulating the activity of peroxisome proliferator-activated receptor-gamma (PPARγ) and de novo synthesis of glutathione. In conclusion, hyperglycemia stimulated HSC activation in vitro by increasing intracellular glucose, which was eliminated by curcumin by blocking the membrane translocation of GLUT2 and suppressing glut2 expression. The latter was mediated by activating PPARγ and attenuating oxidative stress. Our results presented evidence to impacts of hyperglycemia on stimulating HSC activation and hepatic fibrogenesis, and provided novel insights into the mechanisms by which curcumin eliminated the hyperglycemia-caused HSC activation and potential therapeutic strategies for treatment of diabetes-associated hepatic fibrogenesis.

Topics: Animals; Cell Membrane; Cell Proliferation; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucose; Glucose Transporter Type 2; Glutamate-Cysteine Ligase; Glutathione; Hepatic Stellate Cells; Hyperglycemia; Intracellular Space; Lipid Peroxidation; Male; MAP Kinase Signaling System; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; PPAR gamma; Protein Subunits; Protein Transport; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Time Factors

Oxidative stress has been strongly implicated in the pathogenesis of diabetic encephalopathy (DE). Numerous studies have demonstrated a close relationship between oxidative stress and AMPK activation in various disorders, including diabetes-related brain disorders. Since curcumin has powerful antioxidant properties, this study investigated its effects on hyperglycaemia-mediated oxidative stress and AMPK activation in rats with DE. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ-55 mg/kg BW). The diabetic rats were then orally administered curcumin (100 mg/kg BW) or vehicle for 8 weeks. The cerebra of the diabetic rats displayed upregulated protein expression of AdipoR1, p-AMPKα1, Tak1, GLUT4, NADPH oxidase sub-units, caspase-12 and 3-NT and increased lipid peroxidation in comparison with the controls and all of these effects were significantly attenuated with curcumin treatment, except for the increase in AdipoR1 expressions. These results provide a new insight into the beneficial effects of curcumin on hyperglycaemia-mediated DE, which are produced through the down-regulation of AMPK-mediated gluconeogenesis associated with its anti-oxidant property.

Topics: AMP-Activated Protein Kinases; Animals; Brain Diseases; Cerebrum; Curcumin; Diabetes Complications; Diabetes Mellitus, Experimental; Enzyme Activation; Hyperglycemia; Oxidative Stress; Rats; Reactive Oxygen Species; Streptozocin

To localize and demonstrate the effect of curcumin on vascular endothelial growth factor in diabetic mice kidney induced by streptozotocin.. Diabetic mice were induced by streptozotocin (60 mg/kg BW). Male mice were divided into three groups, control mice, diabetic mice (DM) and diabetic mice treated with curcumin (DMC) (200 mg/kg BW). At 4 and 8 weeks, animals were sacrificed and kidneys were processed by immunohistochemistry technique.. At the end of 4 and 8 week experiments, glomeruli were slightly enlarged and showed diffuse thickening of the glomerular capillary walls in diabetic mice. Administration with curcumin presented the better improvement and recovery of cells and tissues compared with diabetic mice. Immunohistochemical staining for vascular endothelial growth factor (VEGF) demonstrated that VEGF was mainly detected in the podocytes and renal tubules. There was an increase in VEGF expression in diabetic mice as compared to control. Treatment with curcumin significantly inhibited the expression of VEGF in the kidney tissue of diabetic mice in both 4 and 8 weeks. Comparing the diabetic mice between 4 and 8 week experiments, the expression of VEGF in the podocytes and renal tubules at 8 week were significantly stronger than at 4 week which represented time-dependent change. Nevertheless, the intensity of VEGF was not different in DMC mice when it was compared between 4 and 8 weeks.. VEGF immunoreactivity of the podocytes and the renal tubules at 4 and 8 weeks in DM mice showed strong intensity more than in control mice. However, the intensity of VEGF in DMC mice was less when it was compared with DM mice. Moreover, VEGF was a key modulator of angiogenesis and a potent mitogen for endothelial cells. These results demonstrated the potential use of antiangiogenic curcumin as a novel therapeutic agent in diabetic mellitus and maintain normal structure of the kidney.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Curcumin; Diabetes Mellitus, Experimental; Hyperglycemia; Immunohistochemistry; Kidney; Male; Mice; Streptozocin; Vascular Endothelial Growth Factors

Diabetic retinopathy is one of the most devastating microvascular complications of long standing type 1 and type 2 diabetes. Neovascularization stimulated by hyperglycemia-mediated induction of vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis. Various small molecules have been investigated for their ability to inhibit angiogenesis. In this study, we evaluated whether curcumin and its dietary source turmeric can inhibit VEGF expression in strepotzotocin (STZ)-induced diabetic rat retina. Diabetes was induced in 3-month-old male WNIN rats by a single intraperitoneal injection of STZ. After induction, one group of diabetic rats were fed only the AIN-93 diet and the rest of the groups were fed with AIN-93 diet containing 0.002% or 0.01% curcumin or 0.5% turmeric for a period of 8 weeks. The control rats received sham injection and fed on the AIN-93 diet. At the end of 8 weeks animals were sacrificed and retina was dissected. The VEGF expression was analyzed by both real time PCR and immunoblotting. There was an increase in VEGF expression in diabetic retina as compared to control retina at both transcript and protein level. Notably, feeding of curcumin and turmeric to diabetic rats inhibited expression of VEGF. This study highlights the importance of biologically active compounds derived from dietary agents that could be explored further for the prevention and/or treatment of diabetic retinopathy.

Topics: Animals; Curcumin; Diabetic Retinopathy; Gene Expression Regulation; Hyperglycemia; Male; Rats; Retina; Streptozocin; Vascular Endothelial Growth Factor A

This study was aimed to evaluate the combined effect of curcumin with vitamin C supplementation on hyperglycemic and dyslipidemia conditions and endothelial cell dysfunction induced in diabetic rats. Wistar Furth rats were used and divided into four groups: control (single injection of 0.9% sterile saline), STZ (streptozotocin, Sigma, 55 mg/kg.BW, i.v.), STZ-vitC (1 g/l ascorbic acid mixed in drinking water), STZ-cur (daily oral treatment of 300 mg/kg.BW curcumin; Cayman Chemical Co., USA), and STZ-cur+vitC (1 g/l ascorbic acid mixed in drinking water and oral treatment of 300 mg/kg.BW curcumin). On 8th week after STZ-injection, the microcirculation in the iris tissue was observed using intravital fluorescence videomicroscopy, and also leukocyte adhesion in the venule was examined for each group. Blood glucose (BG), lipid profiles, glycosylated hemoglobin (HbA1c) were measured in blood samples collected at the end of each experiment. The contents of liver malondialdehyde (MDA) were also quantified for each group. Feeding curcumin (STZ-cur) could decrease BG, HbA1c, dyslipidemia, and MDA significantly, compared to STZ. In cases of feedings curcumin with vitamin C, these results were more effective in all aspects, including leukocyte adhesion. In conclusion, curcumin might increase the effect of vitamin C in protecting the function of endothelial cells through its anti-oxidant with hypoglycemic and hypolipidemic actions.

Topics: Animals; Ascorbic Acid; Blood Glucose; Curcumin; Diabetes Complications; Diabetes Mellitus, Experimental; Dyslipidemias; Endothelium, Vascular; Hyperglycemia; Iris; Laser-Doppler Flowmetry; Leukocyte Rolling; Lipoproteins; Male; Microcirculation; Microscopy, Video; Rats; Rats, Inbred WF

Clinical research has confirmed the efficacy of several photo-chemicals in modulating oxidative stress associated with diabetes mellitus. Here we investigate the effect of tetrahydrocurcumin (THC), an active metabolite of curcumin, on antioxidant status in streptozotocin-nicotinamide-induced diabetes in rats. A single dose of streptozotocin (65 mg kg(-1) bwt) resulted in decreased insulin, hyperglycemia, increased lipid peroxidation (thiobarbituric reactive substances, lipid hydroperoxides), and decreased antioxidant levels (vitamin C, vitamin E, reduced glutathione and ceruloplasmin). The oral administration of THC (80 mg kg(-1) bwt) for 45 days to diabetic rats significantly increased plasma insulin and plasma antioxidants and significantly decreased lipid peroxidation. The positive effects of THC were better that those achieved with curcumin. The results of the study indicate that in addition to its antidiabetic effect in type 2 diabetic rats, THC has an antioxidant effect.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Blood Glucose; Ceruloplasmin; Curcumin; Diabetes Mellitus, Experimental; Glutathione; Hyperglycemia; Insulin; Lipid Peroxidation; Male; Niacinamide; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Vitamin E

The purpose of this study was to investigate the effect of curcumin and its source, turmeric, on streptozotocin-induced diabetic cataract in rats.. Wistar-NIN rats were selected and diabetes was induced by streptozotocin (35 mg/kg body weight, intraperitoneally) and divided into four groups (group II-V). The control (group I) rats received only vehicle. Group I and II animals received an unsupplemented AIN-93 diet, and those in groups III, IV, and V received 0.002% and 0.01% curcumin and 0.5% turmeric, respectively, in an AIN-93 diet for a period of 8 weeks. Cataract progression due to hyperglycemia was monitored by slit lamp biomicroscope and classified into four stages. At the end of 8 weeks, the animals were killed and the biochemical pathways involved in the pathogenesis of cataract such as oxidative stress, polyol pathway, alterations in protein content and crystallin profile in the lens were investigated, to understand the possible mechanism of action of curcumin and turmeric. Blood glucose and insulin levels were also determined.. Although, both curcumin and turmeric did not prevent streptozotocin-induced hyperglycemia, as assessed by blood glucose and insulin levels, slit lamp microscope observations indicated that these supplements delayed the progression and maturation of cataract. The present studies suggest that curcumin and turmeric treatment appear to have countered the hyperglycemia-induced oxidative stress, because there was a reversal of changes with respect to lipid peroxidation, reduced glutathione, protein carbonyl content and activities of antioxidant enzymes in a significant manner. Also, treatment with turmeric or curcumin appears to have minimized osmotic stress, as assessed by polyol pathway enzymes. Most important, aggregation and insolubilization of lens proteins due to hyperglycemia was prevented by turmeric and curcumin. Turmeric was more effective than its corresponding levels of curcumin.. The results indicate that turmeric and curcumin are effective against the development of diabetic cataract in rats. Further, these results imply that ingredients in the study's dietary sources, such as turmeric, may be explored for anticataractogenic agents that prevent or delay the development of cataract.

Topics: Animals; Blood Glucose; Body Weight; Cataract; Chromatography, Gel; Crystallins; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Diet; Disease Progression; Eating; Electrophoresis, Polyacrylamide Gel; Glutathione; Hyperglycemia; Insulin; Lipid Peroxidation; Male; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

A decline in the chaperone-like activity of eye lens alpha-crystallin in diabetic conditions has been reported. In this study, we investigated whether curcumin, a dietary antioxidant, can manipulate the chaperone-like activity of alpha-crystallin in diabetic rat lens.. A group of rats received ip injection of streptozotocin (STZ; 35 mg/kg body weight in buffer) to induce hyperglycemia, while another group of rats received only buffer as vehicle and served as control. STZ-treated rats were assigned to 3 groups and fed either no curcumin or 0.002% or 0.01% curcumin, respectively. Cataract progression due to hyperglycemia was monitored with a slit lamp biomicroscope. At the end of 8 weeks animals were sacrificed and lenses were collected. alphaH- and alphaL-crystallins from a set of pooled lenses in each group were isolated by gel filtration. Chaperone activity, hydrophobicity, and secondary and tertiary structure of alphaH- and alphaL-crystallins were assessed by light scattering/spectroscopic methods.. A decrease in chaperone-like activity of alphaH- and alphaL-crystallins was observed in STZ-treated diabetic rats. The declined chaperone-like activity due to hyperglycemia was associated with reduced hydrophobicity and altered secondary and tertiary structure of alphaH- and alphaL-crystallins. Interestingly, alphaH- and alphaL-crystallins isolated from curcumin fed diabetic rat lenses had shown improved chaperone-like activity as compared to alphaH- and alphaL-crystallins from untreated diabetic rat lens. Feeding of curcumin prevented the alterations in hydrophobicity and structural changes due to STZ-induced hyperglycemia. Modulation of functional and structural properties by curcumin was found to be greater with the alphaL-crystallin than alphaH-crystallin. Loss of chaperone activity of alpha-crystallin, particularly alphaL-crystallin, in diabetic rat lens could be attributed at least partly to increased oxidative stress. Being an antioxidant, curcumin feeding has prevented the loss of alpha-crystallin chaperone activity and delayed the progression and maturation of diabetic cataract.. We demonstrate that curcumin, at the levels close to dietary consumption, prevented the loss of chaperone-like activity of alpha-crystallin vis-a-vis cataractogenesis due to diabetes in rat lens.

Topics: alpha-Crystallins; Animals; Antioxidants; Blood Glucose; Body Weight; Cataract; Chromatography, Gel; Circular Dichroism; Curcumin; Diabetes Mellitus, Experimental; Diet; Hyperglycemia; Lens, Crystalline; Male; Molecular Chaperones; Rats; Spectrometry, Fluorescence

Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose- and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKCbeta2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKCbeta inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-kappaB and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis.

Topics: Acetylcysteine; Adult; Aged; Anti-Infective Agents; Antioxidants; Arteriosclerosis; Cells, Cultured; Curcumin; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Flavonoids; Foam Cells; Gene Expression Regulation; Glucose; Glycation End Products, Advanced; Humans; Hyperglycemia; Macrophages; Male; MAP Kinase Signaling System; Mesylates; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Nitriles; Phosphorylation; Protein Kinase C; Protein Kinase C beta; Protein Processing, Post-Translational; Pyrroles; Receptors, LDL; RNA, Messenger; Signal Transduction; Sulfones; Transcription Factor AP-1; Tumor Necrosis Factor-alpha