Life Extension Magazine®

Issue: Feb 2011


Ceramide enhances cholesterol efflux to apolipoprotein A-I by increasing the cell surface presence of ATP-binding cassette transporter A1.

It is widely accepted that functional ATP-binding cassette transporter A1 (ABCA1) is critical for the formation of nascent high density lipoprotein particles. However, the cholesterol pool(s) and the cellular signaling processes utilized by the ABCA1-mediated pathway remain unclear. Sphingomyelin maintains a preferential interaction with cholesterol in membranes, and its catabolites, especially ceramide, are potent signaling molecules that could play a role in ABCA1 regulation or function. To study the potential role of ceramide in this process, we treated a variety of cell lines with 20 microM C2-ceramide and examined apolipoprotein-mediated cholesterol efflux to lipid-free apoA-I. We found that cell lines expressing ABCA1 displayed 2-3-fold increases in cholesterol efflux to apoA-I. Cell lines not expressing ABCA1 were unaffected by ceramide. We further characterized the cholesterol efflux effect in Chinese hamster ovary cells. Ceramide treatment did not cause significant cytotoxicity or apoptosis and did not affect cholesterol efflux to non-apolipoprotein acceptors. Raising endogenous ceramide levels increased cholesterol efflux to apoA-I. Using a cell surface biotinylation method, we found that the total cellular ABCA1 and that at the plasma membrane were increased with ceramide treatment. Also ceramide enhanced the binding of fluorescently labeled apoA-I to Chinese hamster ovary cells. These data suggest that ceramide may increase the plasma membrane content of ABCA1, leading to increased apoA-I binding and cholesterol efflux.

J Biol Chem. 2003 Oct 10;278(41):40121-7

Adiponectin in insulin resistance: lessons from translational research.

Adiponectin is an adipose tissue-secreted endogenous insulin sensitizer, which plays a key role as a mediator of peroxisome proliferator-activated receptor gamma action. Adiponectin alters glucose metabolism and insulin sensitivity, exhibits antiinflammatory and antiatherogenic properties, and has been linked to several malignancies. Circulating concentrations of adiponectin are determined primarily by genetic factors, nutrition, exercise, and abdominal adiposity. Adiponectin concentrations are lower in subjects with obesity, metabolic syndrome, and cardiovascular disease. Adiponectin knockout mice manifest glucose intolerance, insulin resistance, and hyperlipidemia and tend to develop malignancies especially when on high-fat diets. Animal studies have also shown beneficial effects of adiponectin in rodents in vivo. Circulating concentrations of adiponectin are lower in patients with diabetes, cardiovascular disease, and several malignancies. Studies to date provide promising results for the diagnostic and therapeutic role of adiponectin in obesity, insulin resistance, diabetes, cardiovascular disease, and obesity-associated malignancies.

Am J Clin Nutr. 2010 Jan;91(1):258S-261S

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond.

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders.

J Biomed Sci. 2008 Sep;15(5):565-76

Signal transduction of stress via ceramide.

The sphingomyelin (SM) pathway is a ubiquitous, evolutionarily conserved signalling system analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide, which serves as second messenger in this pathway, is generated from SM by the action of a neutral or acidic SMase, or by de novo synthesis co-ordinated through the enzyme ceramide synthase. A number of direct targets for ceramide action have now been identified, including ceramide-activated protein kinase, ceramide-activated protein phosphatase and protein kinase Czeta, which couple the SM pathway to well defined intracellular signalling cascades. The SM pathway induces differentiation, proliferation or growth arrest, depending on the cell type. Very often, however, the outcome of signalling through this pathway is apoptosis. Mammalian systems respond to diverse stresses with ceramide generation, and recent studies show that yeast manifest a form of this response. Thus ceramide signalling is an older stress response system than the caspase/apoptotic death pathway, and hence these two pathways must have become linked later in evolution. Signalling of the stress response through ceramide appears to play a role in the development of human diseases, including ischaemia/reperfusion injury, insulin resistance and diabetes, atherogenesis, septic shock and ovarian failure. Further, ceramide signalling mediates the therapeutic effects of chemotherapy and radiation in some cells. An understanding of the mechanisms by which ceramide regulates physiological and pathological events in specific cells may provide new targets for pharmacological intervention.

Biochem J. 1998 Nov 1;335 ( Pt 3):465-80

Frictional properties of human forearm and vulvar skin: influence of age and correlation with transepidermal water loss and capacitance.

The dynamic friction coefficient between skin and a Teflon probe and its correlation with age, body weight, height, transepidermal water loss and skin capacitance was studied in vulvar and forearm skin of 44 healthy female volunteers. The friction coefficient of vulvar skin was 0.66 +/- 0.03 (mean +/- SEM) compared to that of forearm skin of 0.48 +/- 0.01. The difference was highly significant (p less than 0.001). Multiple-regression analysis showed that the vulvar skin friction coefficient was significantly correlated with capacitance as an indicator of stratum corneum hydration (p less than 0.01) but not with age, weight, height or transepidermal water loss. It is concluded that the high friction coefficient of vulvar skin may be due to the increased hydration of vulvar skin. Age-related differences seem to exist for transepidermal water loss and friction coefficient in forearm but not in vulvar skin.

Dermatologica. 1990;181(2):88-91

Changes with age in the moisture content of human skin.

A technique to measure the dynamic mechanical properties of human skin in vivo is described. The technique measures the propagation and attenuation of shear waves in skin tissue over a range of frequencies (8-1016 Hz). Results show that both the propagation velocity and attenuation of shear waves in skin are highly dependent upon the water content of the stratum corneum. The technique was used to measure the dynamic mechanical properties of the skin on the back of the left hand for a group of 16 men ranging in age from 24-63 years. The results suggest that aged skin has a lower water content than the skin of younger men.

J Invest Dermatol. 1984 Jan;82(1):97-100

The moisturizing effect of a wheat extract food supplement on women’s skin: a randomized, double-blind placebo-controlled trial.

Ceramides, specific lipid components of the skin, represent 35-40% of the intercellular cement binding cells together and contributing to skin hydration. A wheat extract rich in ceramides and digalactosyl-diglycerides was developed by Hitex in two forms: wheat extract oil (WEO) and wheat extract powder (WEP). In vitro tests and two clinical studies demonstrated promising efficacy results with WEP on skin hydration. To confirm these early results, a double-blind, randomized, placebo-controlled study was carried out on 51 women aged mg of WEO or years with dry to very dry skin who received either 350 20-63 months. Evaluation of skin hydration on legs, arms and face, placebo for 3 assessed at baseline (D0) and at study end (D84) was performed by the dermatologist using dermatological scores (dryness, roughness, erythema), skin hydration measurement (corneometry) and self-assessment scores (Visual Analogue Scale: VAS). Perceived efficacy was noted by participants throughout the study; tolerability and overall acceptability of the study products were evaluated by the dermatologist and the participants at the end of study. Skin hydration was significantly increased between D0 and D84 on the arms (P<0.001) and legs 0.012) in the WEO group compared with placebo. Even if no significant = (P statistical differences between groups were observed for the dermatological evaluation, skin dryness and redness tended to be reduced in the WEO group. Moreover, from D0 to D84, the VAS index had a tendency to increase in favour of 0.084) indicating that participants = WEO for the overall skin hydration (P perceived an improvement. The WEO capsules were perceived by participants as being more effective than placebo on all skin dryness signs. In conclusion, WEO months’ treatment, a capsules were well tolerated and appreciated. After 3 significant increase in skin hydration and an improvement in associated clinical signs were observed in women with dry skin.

Int J Cosmet Sci. 2010 Jul 14

Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications.

Skin colonization with Staphylococcus aureus is a characteristic feature of atopic dermatitis with more than 90% of patients being colonized. Extracellular matrix proteins are important for the adherence of S. aureus to human keratinocytes. The bacterium interferes in the inflammatory process of atopic dermatitis in various ways, among which the ability to release superantigens in a high percentage of clinical isolates is of great importance. As the colonization correlates significantly with the severity of eczema, anti-staphylococcal treatment measurements are widely used. In cases of atopic dermatitis exacerbation with wide-spread weeping lesions, a systemic antibiotic treatment is warranted, with erythromycin no longer being recommended due to an increased resistance rate. In localized superinfected lesions the topical application of an antibiotic-glucocorticoid preparation may offer advantages to the mere steroid application. Based on efficacy and resistance data, fusidic acid is the antibiotic of choice. There is evidence that phototherapy in atopic dermatitis may be even more effective when combined with anti-staphylococcal measurements. In the future new therapeutical options may be available.

Br J Dermatol. 1998 Dec;139 Suppl 53:13-6

Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus.

The stratum corneum of the skin of patients with atopic dermatitis is highly susceptible to colonization by various bacteria, including Staphylococcus aureus. The defense system of the skin against bacterial invasion appears to be significantly disrupted in atopic dermatitis skin, but little is known about the defense mechanism(s) involved. As one sphingolipid metabolite, sphingosine is known to exert a potent antimicrobial effect on S. aureus at physiologic levels, and it may play a significant role in bacterial defense mechanisms of healthy normal skin. Because of the altered ceramide metabolism in atopic dermatitis, the possible alteration of sphingosine metabolism might be associated with the acquired vulnerability to colonization by S. aureus in patients with atopic dermatitis. In this study, we measured the levels of sphingosine in the upper stratum corneum from patients with atopic dermatitis, and then compared that with the colonization levels of bacteria in the same subjects. Levels of sphingosine were significantly downregulated in uninvolved and in involved stratum corneum of patients with atopic dermatitis compared with healthy controls. This decreased level of sphingosine was relevant to the increased numbers of bacteria including S. aureus present in the upper stratum corneum from the same subjects. This suggests the possibility that the increased colonization of bacteria found in patients with atopic dermatitis may result from a deficiency of sphingosine as a natural antimicrobial agent. As for the mechanism involved in the decreased production of sphingosine in atopic dermatitis, analysis of the activities of ceramidases, major sphingosine-producing enzymes, revealed that, whereas the activity of alkaline ceramidase did not differ between patients with atopic dermatitis and healthy controls, the activity of acid ceramidase was significantly reduced in patients with atopic dermatitis and this had obvious relevance to the increased colonization of bacteria in those subjects. Further, there was a close correlation between the level of sphingosines and acid ceramidase (r = 0.65, p < 0.01) or ceramides (r = 0.70, p < 0.01) in the upper stratum corneum from the same patients with atopic dermatitis. Collectively, our results suggest the possibility that vulnerability to bacterial colonization in the skin of patients with atopic dermatitis is associated with reduced levels of a natural antimicrobial agent, sphingosine, which results from decreased levels of ceramides as a substrate and from diminished activities of its metabolic enzyme, acid ceramidase.

J Invest Dermatol. 2002 Aug;119(2):433-9

Bacteria and the skin: clinical practice and therapy update.

Any doctor using antibiotics should be aware of the increasing worldwide problem with multiresistant bacteria, with the majority of hospital-based infections in some countries being caused by these bacteria. Proper use of antibiotics is therefore mandatory for any physician, including for dermatologists, who treat bacterial infections of the skin. Detailed knowledge is needed of when to use topical versus systemic antibiotics, and for how long such treatments should be given. Besides the clinical symptoms of bacterial infections and treatment guidelines, an increased awareness has focused on the possible importance of bacterial toxins, including superantigens, and their contribution to skin inflammation. Rare syndromes such as Kawasaki’s syndrome, toxic epidermal necrolysis or staphylococcal scalded skin syndrome, are well-known diseases elicited by specific bacterial toxins. But many observations give indirect support to the notion that bacteriae can augment the immune inflammation seen in common and important diseases such as psoriasis and atopic dermatitis. This supplement provides up-to-date information about skin bacteriology, information on the possible importance of superantigens for chronic skin diseases, and practical guidelines for the use of both topical and systemic antibiotic therapy, together with a review of the dangers following improper use. This information is important for all doctors, including dermatologists.

Br J Dermatol. 1998 Dec;139 Suppl 53:1-3

Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity.

Epidemiological data suggest that consumption of fruits and vegetables has been associated with a lower incidence of cancer. Cyanidin-3-glucoside (C3G), a compound found in blackberry and other food products, was shown to possess chemopreventive and chemotherapeutic activity in the present study. In cultured JB6 cells, C3G was able to scavenge ultraviolet B-induced *OH and O2-* radicals. In vivo studies indicated that C3G treatment decreased the number of non-malignant and malignant skin tumors per mouse induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7,12-dime-thylbenz[a]anthracene-initiated mouse skin. Pretreatment of JB6 cells with C3G inhibited UVB- and TPA-induced transactivation of NF-kappaB and AP-1 and expression of cyclooxygenase-2 and tumor necrosis factor-alpha. These inhibitory effects appear to be mediated through the inhibition of MAPK activity. C3G also blocked TPA-induced neoplastic transformation in JB6 cells. In addition, C3G inhibited proliferation of a human lung carcinoma cell line, A549. Animal studies showed that C3G reduced the size of A549 tumor xenograft growth and significantly inhibited metastasis in nude mice. Mechanistic studies indicated that C3G inhibited migration and invasion of A549 tumor cells. These finding demonstrate for the first time that a purified compound of anthocyanin inhibits tumor promoter-induced carcinogenesis and tumor metastasis in vivo.

J Biol Chem. 2006 Jun 23;281(25):17359-68

Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis—relationship with tissue anthocyanin levels.

Anthocyanins are dietary flavonoids, which can prevent carcinogen-induced colorectal cancer in rats. Here, the hypotheses were tested that Mirtoselect, an anthocyanin mixture from bilberry, or isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, interfere with intestinal adenoma formation in the Apc(Min) mouse, a genetic model of human familial adenomatous polyposis, and that consumption of C3G or Mirtoselect generates measurable levels of anthocyanins in the murine biophase. Apc(Min) mice ingested C3G or Mirtoselect at 0.03, 0.1 or 0.3% in the diet for 12 weeks, and intestinal adenomas were counted. Plasma, urine and intestinal mucosa were analyzed for presence of anthocyanins by high-pressure liquid chromatography with detection by UV spectrophotometry (520 nm) or tandem mass spectrometry (multiple reaction monitoring). Ingestion of either C3G or Mirtoselect reduced adenoma load dose-dependently. At the highest doses of C3G and Mirtoselect adenoma numbers were decreased by 45% (p < 0.001) or 30% (p < 0.05), respectively, compared to controls. Anthocyanins were found at the analytical detection limit in the plasma and at quantifiable levels in the intestinal mucosa and urine. Anthocyanin glucuronide and methyl metabolites were identified in intestine and urine. Total anthocyanin levels in mice on C3G or Mirtoselect were 43 ng and 8.1 microg/g tissue, respectively, in the intestinal mucosa, and 7.2 and 12.3 microg/ml in the urine. The efficacy of C3G and Mirtoselect in the Apc(Min) mouse renders the further development of anthocyanins as potential human colorectal cancer chemopreventive agents worthwhile.

Int J Cancer. 2006 Nov 1;119(9):2213-20

Cyanidin 3-glucoside protects 3T3-L1 adipocytes against H2O2- or TNF-alpha-induced insulin resistance by inhibiting c-Jun NH2-terminal kinase activation.

Anthocyanins are naturally occurring plant pigments and exhibit an array of pharmacological properties. Our previous study showed that black rice pigment extract rich in anthocyanin prevents and ameliorates high-fructose-induced insulin resistance in rats. In present study, cyanidin 3-glucoside (Cy-3-G), a typical anthocyanin most abundant in black rice was used to examine its protective effect on insulin sensitivity in 3T3-L1 adipocytes exposed to H(2)O(2) (generated by adding glucose oxidase to the medium) or tumor necrosis factor alpha (TNF-alpha). Twelve-hour exposure of 3T3-L1 adipocytes to H(2)O(2) or TNF-alpha resulted in the increase of c-Jun NH(2)-terminal kinase (JNK) activation and insulin receptor substrate 1 (IRS1) serine 307 phosphorylation, concomitantly with the decrease in insulin-stimulated IRS1 tyrosine phosphorylation and cellular glucose uptake. Blocking JNK expression using RNA interference efficiently prevented the H(2)O(2)- or TNF-alpha-induced defects in insulin action. Pretreatment of cells with Cy-3-G reduced the intracellular production of reactive oxygen species, the activation of JNK, and attenuated H(2)O(2)- or TNF-alpha-induced insulin resistance in a dose-dependent manner. In parallel, N-acetyl-cysteine, an antioxidant compound, did not exhibit an attenuation of TNF-alpha-induced insulin resistance. Taken together, these results indicated that Cy-3-G exerts a protective role against H(2)O(2)- or TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes by inhibiting the JNK signal pathway.

Biochem Pharmacol. 2008 Mar 15;75(6):1393-401

Gastroprotective effect of cyanidin 3-glucoside on ethanol-induced gastric lesions in rats.

This study investigated the in vivo protective effect of cyanidin 3-glucoside (C3G) against ethanol-induced gastric lesions in rats. The experimental rats were treated with 80% ethanol after pretreatment with various doses of C3G (4 and 8 mg/kg of body weight), and the control rats received only 80% ethanol. Oral pretreatment with C3G significantly inhibited the formation of ethanol-induced gastric lesions and the elevation of the lipid peroxide level. In addition, pretreatment with C3G significantly increased the level of glutathione and the activities of radical scavenging enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in gastric tissues. These results suggest that the gastroprotective effect of C3G removes the ethanol-induced lipid peroxides and free radicals and that it may offer a potential remedy for the treatment of gastric lesions.

Alcohol. 2008 Dec;42(8):683-7

Isolation and free-radical-scavenging properties of cyanidin 3-O-glycosides from the fruits of Ribes biebersteinii Berl.

The reversed-phase preparative high performance liquid chromatographic purification of the methanol extract of the fruits of Ribes biebersteinii Berl. (Grossulariaceae) afforded five cyanidin glycosides, 3-O-sambubiosyl-5-O-glucosyl cyanidin (1), cyanidin 3-O-sambubioside (2), cyanidin 3-O-glucoside (3), cyanidin 3-O-(2(G)-xylosyl)-rutinoside (4) and cyanidin 3-O-rutinoside (5). They showed considerable free-radical-scavenging properties in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay with the RC(50) values of 9.29 x 10(-6), 9.33 x 10(-6), 8.31 x 10(-6), 8.96 x 10(-6) and 9.55 x 10(-6) mol L(-1), respectively. The structures of these compounds were elucidated by various chemical hydrolyses and spectroscopic means. The total anthocyanin content was 1.9 g per 100 g dried fruits on cyanidin 3-glucoside basis.

Acta Pharm. 2010 Mar 1;60(1):1-11

Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice.

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine expression is one of the most important targets for the prevention of obesity and improvement of insulin sensitivity. In this study, we have demonstrated that anthocyanin (cyanidin 3-glucoside; C3G) which is a pigment widespread in the plant kingdom, ameliorates hyperglycemia and insulin sensitivity due to the reduction of retinol binding protein 4 (RBP4) expression in type 2 diabetic mice. KK-A(y) mice were fed control or control +0.2% of a C3G diet for 5 weeks. Dietary C3G significantly reduced blood glucose concentration and enhanced insulin sensitivity. The adiponectin and its receptors expression were not responsible for this amelioration. C3G significantly upregulated the glucose transporter 4 (Glut4) and downregulated RBP4 in the white adipose tissue, which is accompanied by downregulation of the inflammatory adipocytokines (monocyte chemoattractant protein-1 and tumor necrosis factor-alpha) in the white adipose tissue of the C3G group. These findings indicate that C3G has significant potency in an anti-diabetic effect through the regulation of Glut4-RBP4 system and the related inflammatory adipocytokines.

Biochem Pharmacol. 2007 Dec 3;74(11):1619-27

Direct intestinal absorption of red fruit anthocyanins, cyanidin-3-glucoside and cyanidin-3,5-diglucoside, into rats and humans.

We determined red fruit anthocyanins, cyanidin-3-glucoside (Cy-g) and cyanidin-3,5-diglucoside (Cy-dg), incorporated into plasma and liver of rats and human plasma by UV-HPLC. Fifteen minutes after an oral supplementation of a mixture of 320 mg of Cy-g and 40 mg of Cy-dg/kg of body weight, rats showed an increase to a maximum of 1,563 microg (3,490 nmol) of Cy-g/L and 195 microg (320 nmol) of Cy-dg/L in plasma and 0.067 microg (0.15 nmol) of Cy-g/g and a trace of Cy-dg together with methylated metabolites such as peonidin-3-glucoside in liver. In human plasma, 30 min after intake (2.7 mg of Cy-g and 0.25 mg of Cy-dg/kg of body weight), an average of 11 microg (24 nmol) of Cy-g/L and a trace of Cy-dg were found. Cyanidin as aglycone of Cy-g and Cy-dg was not found in such plasma samples, neither were conjugated and methylated anthocyanins. The results indicated that anthocyanins are incorporated keeping structurally intact glycoside forms, from the digestive tract into the blood circulation system in mammals.

J Agric Food Chem. 1999 Mar;47(3):1083-91

Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine.

The potential of purple corn color (PCC), a natural anthocyanin, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH), receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PCC was given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PCC-treatment-related changes in clinical signs, body weight and food consumption were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by PCC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci by PhIP tended to be decreased by the PCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PCC in the diet, under the present experimental conditions.

Cancer Lett. 2001 Sep 28;171(1):17-25

A comprehensive study of anthocyanin-containing extracts from selected blackberry cultivars: extraction methods, stability, anticancer properties and mechanisms.

The purpose of these studies was to investigate and compare the composition, stability, antioxidant and anticancer properties and mechanisms of anthocyanin-containing blackberry extracts (ACEs) from selected cultivars and using different extraction methods. ACEs were analyzed for total anthocyanin and phenolics content, polymeric color, and total antioxidant capacity (TAC). The influence of water content in the extraction system was evaluated. A 90-day stability study of the extract and a 48-h stability study of the extract in biologically relevant buffers were completed. The cytotoxic effects of ACEs on HT-29, MCF-7, and HL-60 cells were determined. H2O2 production in culture medium was measured and intracellular ROS levels were quantified. As compared to powder-derived ACEs, puree-derived ACEs contained similar amounts of anthocyanins, but greater levels of phenolics, increased TAC, significantly enhanced production of H2O2, and significantly enhanced cytotoxicity in all cell lines. Catalase could not protect cells from ACE-induced cell death. Cyanidin 3-glucoside exerted anticancer effect by acting synergistically or additively with other active components in the extracts. These data suggest that anthocyanins and non-anthocyanin phenolics in ACEs act synergistically or additively in producing anticancer effects. These studies also provide essential information for the development of fruit-derived ACEs as potential Botanical Drug Products.

Food Chem Toxicol. 2009 Apr;47(4):837-47

DNA stability and lipid peroxidation in vitamin E-deficient rats in vivo and colon cells in vitro—modulation by the dietary anthocyanin, cyanidin-3-glycoside.

BACKGROUND: Fruit and vegetable consumption protects against cancer. This is attributed in part to antioxidants such as vitamin E combating oxidative DNA damage. Anthocyanins are found in significant concentrations in the human diet. However, it remains to be established whether they are bioactive in vivo. AIM: To investigate the consequence both of vitamin E deficiency on oxidative damage to DNA and lipids and the cytoprotective effect of nutritionally relevant levels of cyanidin-3-glycoside both in vivo in rats and in vitro in human colonocytes.METHODS: Male Rowett Hooded Lister rats were fed a diet containing less than 0.5 mg/kg vitamin E or a vitamin E supplemented control diet containing 100 mg d alpha-tocopherol acetate/kg. Half of the controls and vitamin E-deficient rats received cyanidin-3-glycoside (100 mg/kg). After 12 weeks endogenous DNA stability in rat lymphocytes (strand breaks and oxidised bases) and response to oxidative stress ex vivo (H2O2; 200 microM) was measured by single cell gel electrophoresis (SCGE). Tissue levels of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-Oxo-dG) were measured by HPLC with EC detection. D alpha-tocopherol and lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) were measured by HPLC. Rat plasma pyruvate kinase and the production of reactive oxygen by phagocytes were detected spectrophotometrically and by flow cytometry respectively. Immortalised human colon epithelial cells (HCEC) were preincubated in vitro with the anthocyanins cyanidin and cyanidin-3-glycoside and the flavonol quercetin (all 50 microM) before exposure to H2O2 (200 microM). DNA damage was measured by SCGE as above. RESULTS: Plasma and liver d alpha-tocopherol declined progressively over 12 weeks in rats made vitamin E deficient. Lipid peroxidation was increased significantly in plasma, liver and red cells. Reactive oxygen levels in phagocytes and plasma pyruvate kinase were increased. Vitamin E deficiency did not affect DNA stability in rat lymphocytes, liver or colon. Cyanidin-3-glycoside did not alter lipid peroxidation or DNA damage in rats. However, it was chemoprotective against DNA damage in human colonocytes.DNA strand breakage was decreased 38.8 +/- 2.2% after pretreatment with anthocyanin.

CONCLUSION: While it is accepted that vitamin E alters lipid oxidation in vivo, its role in maintaining DNA stability remains unclear. Moreover, whereas cyanidin-3-glycoside protects against oxidative DNA damage in vitro, at nutritionally relevant concentrations it is ineffective against oxidative stress in vivo.

Eur J Nutr. 2005 Jun;44(4):195-203

Purple corn color suppresses Ras protein level and inhibits 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in the rat.

Anthocyanins belong to the class of phenolic compounds collectively named flavonoids. Many anthocyanins are reported to have inhibitory effects on carcinogenesis. Purple corn color (PCC), an anthocyanin containing extract of purple corn seeds, is used as a food colorant. The major anthocyanin in PCC is cyanidin 3-O-beta-D-glucoside (C3-G). The present study was conducted to assess the influence of dietary PCC on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats. PCC significantly inhibited DMBA-induced mammary carcinogenesis in human c-Ha-ras proto-oncogene transgenic (Hras128) rats and in their non-transgenic counterparts. PCC and C3-G also inhibited cell viability and induced apoptosis in mammary tumor cells derived from Hras128 rat mammary carcinomas. At the molecular level, PCC and C3-G treatment resulted in a preferential activation of caspase-3 and reduction of Ras protein levels in tumor cells. It is proposed that C3-G could act as a chemopreventive and possibly chemotherapeutic agent for cancers with mutations in ras. Secondly, the in vitro-in vivo system used in this study can be utilized for screening for cancer preventive compounds that act via Ras down-regulation.

Cancer Sci. 2008 Sep;99(9):1841-6

Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2’-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/micrograms of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.

Ann Neurol. 1993 Oct;34(4):609-16

Mitochondria in the diabetic heart.

Diabetes mellitus increases the risk of developing cardiovascular diseases such as coronary artery disease and heart failure. Studies have shown that the heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Although the cause of this increased heart failure risk is multifactorial, increasing evidence suggests that derangements in cardiac energy metabolism play an important role. In particular, abnormalities in cardiomyocyte mitochondrial energetics appear to contribute substantially to the development of cardiac dysfunction in diabetes. This review will summarize these abnormalities in mitochondrial function and discuss potential underlying mechanisms.

Cardiovasc Res. 2010 Nov 1;88(2):229-40

Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure.

Mitochondria contribute to cardiac dysfunction and myocyte injury via a loss of metabolic capacity and by the production and release of toxic products. This article discusses aspects of mitochondrial structure and metabolism that are pertinent to the role of mitochondria in cardiac disease. Generalized mechanisms of mitochondrial-derived myocyte injury are also discussed, as are the strengths and weaknesses of experimental models used to study the contribution of mitochondria to cardiac injury. Finally, the involvement of mitochondria in the pathogenesis of specific cardiac disease states (ischemia, reperfusion, aging, ischemic preconditioning, and cardiomyopathy) is addressed.

J Mol Cell Cardiol. 2001 Jun;33(6):1065-89

Effect of lifelong coenzyme Q10 supplementation on age-related oxidative stress and mitochondrial function in liver and skeletal muscle of rats fed on a polyunsaturated fatty acid (PUFA)-rich diet.

This study investigates aging-related changes in lipid peroxidation and functionality in liver and skeletal-muscle mitochondria in rats fed a diet rich in polyunsaturated fatty acids (PUFA), depending on supplementation or not with coenzyme Q(10) (CoQ(10)). Two groups of rats were fed for 24 months on a PUFA-rich diet, differing in supplementation or not with CoQ(10). At 6 and 24 months mitochondria were analyzed for fatty acid profile; hydroperoxides; alpha-tocopherol; CoQ(9;) CoQ(10;) cytochromes b, c+c(1), and a+a(3) contents; cytochrome c oxidase activity; and catalase activity in cytosol. Results of this study showed for the supplemented group an age-associated decrease in the peroxidizability index, an increase in catalase activity in skeletal muscle, and modulation of the aging-related changes in different mitochondrial electron-transport-chain components in skeletal muscle. These findings provide mechanisms to explain the effect of CoQ(10) in extending the life span of animals fed a PUFA-rich diet.

J Gerontol A Biol Sci Med Sci. 2007 Nov;62(11):1211-8

Does the intestinal microflora synthesize pyrroloquinoline quinone?

Pyrroloquinoline quinone (PQQ) functions as a cofactor for prokaryotic oxidoreductases, such as methanol dehydrogenase and glucose dehydrogenase. When chemically-defined diets without PQQ are fed to animals, lathyritic changes are observed. In previous studies, it was assumed that PQQ was produced by the intestinal microflora; consequently, antibiotics were routinely added to diets. In the present study this assumption is tested further in mice by: (i) examining the effects of dietary antibiotics on fecal PQQ excretion, (ii) isolating the intestinal flora to identify bacteria known to synthesize PQQ and (iii) determining in vitro if the intestinal microflora synthesizes PQQ from radio-chemically labeled precursors. The results of these experiments indicate that little if any PQQ is synthesized by the intestinal microflora. Rather, when PQQ is present in the intestine, the diet is a more obvious source.

Biofactors. 1991 Jan;3(1):53-9

The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation.

Pyrroloquinoline quinone (PQQ) is a redox active essential nutrient that can generate or scavenge superoxide depending on its microenvironment. PQQ has been shown previously to be neuroprotective in a rodent stroke model. Here we test whether PQQ interacts with reactive nitrogen species, known to be involved in the pathogenesis of stroke. Using rat forebrain neurons in culture, we determined that the toxicity of SIN-1 was mediated by peroxynitrite and that PQQ could block this toxic action. However, PQQ could not block the toxicity of peroxynitrite itself. Both SIN-1 and peroxynitrite caused ATP depletion, but only SIN-1 evoked ATP depletion was blocked by PQQ. In a cell-free system, PQQ blocked nitration of bovine serum albumin produced by SIN-1, but potentiated peroxynitrite-induced nitration. PQQ was unable to block ATP depletion and cell death induced by NO. donors (DEA/NO, DPT/NO and DETA/NO), indicating that it does not directly interact with nitric oxide, and suggesting that it acts as a superoxide scavenger. PQQ significantly potentiated cGMP accumulation evoked by SIN-1, similar to the effect of superoxide dismutase (SOD). However, unlike SOD, which potentiated neurotoxicity induced by SIN-1, PQQ blocked its toxicity, arguing against the possibility that PQQ functions simply as a SOD mimetic. Indeed, substantially less H2O2 was produced by the incubation of SIN-1 with PQQ, when compared to SOD. These results suggest that PQQ scavenges superoxide without forming toxic levels of H2O2. Therefore, the protective effect of PQQ on stroke might be due, at least in part, to the suppression of peroxynitrite formation.

Eur J Neurosci. 2002 Sep;16(6):1015-24

Pyrroloquinoline quinone is a plant growth promotion factor produced by Pseudomonas fluorescens B16.

Pseudomonas fluorescens B16 is a plant growth-promoting rhizobacterium. To determine the factors involved in plant growth promotion by this organism, we mutagenized wild-type strain B16 using OmegaKm elements and isolated one mutant, K818, which is defective in plant growth promotion, in a rockwool culture system. A cosmid clone, pOK40, which complements the mutant K818, was isolated from a genomic library of the parent strain. Tn3-gusA mutagenesis of pOK40 revealed that the genes responsible for plant growth promotion reside in a 13.3-kb BamHI fragment. Analysis of the DNA sequence of the fragment identified 11 putative open reading frames, consisting of seven known and four previously unidentified pyrroloquinoline quinone (PQQ) biosynthetic genes. All of the pqq genes showed expression only in nutrient-limiting conditions in a PqqH-dependent manner. Electrospray ionization-mass spectrometry analysis of culture filtrates confirmed that wild-type B16 produces PQQ, whereas mutants defective in plant growth promotion do not. Application of wild-type B16 on tomato (Solanum lycopersicum) plants cultivated in a hydroponic culture system significantly increased the height, flower number, fruit number, and total fruit weight, whereas none of the strains that did not produce PQQ promoted tomato growth. Furthermore, 5 to 1,000 nm of synthetic PQQ conferred a significant increase in the fresh weight of cucumber (Cucumis sativus) seedlings, confirming that PQQ is a plant growth promotion factor. Treatment of cucumber leaf discs with PQQ and wild-type B16 resulted in the scavenging of reactive oxygen species and hydrogen peroxide, suggesting that PQQ acts as an antioxidant in plants.

Plant Physiol. 2008 Feb;146(2):657-68

Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice.

When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally complete basal diet, it improves growth-related variables in young mice. We examined PQQ and mitochondrial function based on observations that PQQ deficiency results in elevated plasma glucose concentrations in young mice, and PQQ addition stimulates mitochondrial complex 1 activity in vitro. PQQ-deficient weanling mice had a 20-30% reduction in the relative amount of mitochondria in liver; lower respiratory control ratios, and lower respiratory quotients than PQQ-supplemented mice (2 mg PQQ/kg diet). In mice from dams fed a conventional laboratory diet, but switched at weaning to the basal diet, plasma glucose, Ala, Gly, and Ser concentrations were elevated at 4 wk (PQQ- vs. PQQ+), but not at 8 wk. The relative mitochondrial content (ratio of mtDNA to nuclear DNA) also tended (P<0.18) to be lower (PQQ- vs. PQQ+) at 4 wk, but not at 8 wk. PQQ also counters the mitochondrial complex 1 inhibitor, diphenylene iodonium (DPI). Mice were gavaged with 0, 0.4, or 4 microg PQQ/g body weight (BW) daily for 14 d. At each PQQ level, DPI was injected (i.p.) at 0, 0.4, 0.8, or 1.6 microg DPI/g BW. The PQQ-deficient mice exposed to 0.4 or 4.0 microg DPI/g lost weight and had lower plasma glucose levels than PQQ-supplemented mice (P<0.05). In addition, fibroblasts took up (3)H-PQQ added to cell cultures, and cultured hepatocytes maintained mitochondrial PQQ concentrations similar to those observed in vivo. Collectively, these results indicate that dietary PQQ can influence mitochondrial amount and function, particularly in perinatal and weanling mice.

J Nutr. 2006 Feb;136(2):390-6

Pyrroloquinoline quinone improves growth and reproductive performance in mice fed chemically defined diets.

Growth, reproductive performance, and indices of collagen maturation and expression were investigated in Balb/c mice fed chemically defined, amino acid-based diets with or without the addition 6 micro Mpyrroloquinoline quinone (PQQ)/kg diet. The diets were fed to virgin mice for 8 weeks before breeding. At weaning, the pups from successful pregnancies were fed the same diet as their respective dams. Reproductive performance was compromised in mice fed diets devoid of PQQ, and their offspring grew at slower rates than offspring from mice fed diets supplemented with PQQ. Successful mating (confirmed vaginal plugs) was not affected by the presence or absence of PQQ; however, pup viability (number of pups at parturition/number of pups at Day 4 of lactation) was decreased in PQQ-deprived mice. Conception (percentage of females giving live births) and fertility (percentage of births) were also decreased in PQQ-deprived mice. The slower rates of growth in offspring from PQQ-deprived mice were associated with decreased steady-state mRNA levels for Type I procollagen alpha(1)-chains in skin and lungs from neonatal mice. Values for lysyl oxidase accumulation as protein in PQQ-deficient mice also tended to be lower than corresponding values from PQQ-supplemented or -replete mice. Skin collagen solubility was increased in PQQ-deprived mice. These results indicate that PQQ supplementation can improve reproductive performance, growth, and may modulate indices of neonatal extracellular matrix production and maturation in mice fed chemically defined, but otherwise nutritionally complete diets.

Exp Biol Med (Maywood). 2003 Feb;228(2):160-6

Pyrroloquinoline quinone nutritional status alters lysine metabolism and modulates mitochondrial DNA content in the mouse and rat.

Pyrroloquinoline quinone (PQQ) added to purified diets devoid of PQQ improves indices of perinatal development in rats and mice. Herein, PQQ nutritional status and lysine metabolism are described, prompted by a report that PQQ functions as a vitamin-like enzymatic cofactor important in lysine metabolism (Nature 422 [2003] 832). Alternatively, we propose that PQQ influences lysine metabolism, but by mechanisms that more likely involve changes in mitochondrial content. PQQ deprivation in both rats and mice resulted in a decrease in mitochondrial content. In rats, alpha-aminoadipic acid (alphaAA), which is derived from alpha-aminoadipic semialdehyde (alphaAAS) and made from lysine in mitochondria, and the plasma levels of amino acids known to be oxidized in mitochondria (e.g., Thr, Ser, and Gly) were correlated with changes in the liver mitochondrial content of PQQ-deprived rats, but not PQQ-supplemented rats. In contrast, the levels of NAD dependent alpha-aminoadipate-delta-semialdehyde dehydrogenase (AASDH), a cytosolic enzyme important to alphaAA production from alphaAAS, was not influenced by PQQ dietary status. Moreover, the levels of U26 mRNA were not significantly changed even when diets differed markedly in PQQ and dietary lysine content. U26 mRNA levels were measured, because of U26’s proposed, albeit questionable role as a PQQ-dependent enzyme involved in alphaAA formation.

Biochim Biophys Acta. 2006 Nov;1760(11):1741-8

The Diabetes Prevention Program is a new, 150 million dollar, NIH-sponsored study designed to determine whether non-insulin-dependent diabetes mellitus can be prevented or delayed in persons with impaired glucose tolerance. Four thousand subjects will be randomly assigned to one of four study groups and followed for 4.5 years. Study groups include intensive lifestyle intervention with diet and exercise; metformin (Glucophage) or troglitazone (an investigational drug) with standard diet and exercise; and a control group. Insulin resistance is an important pathogenic factor in impaired glucose tolerance. Trivalent chromium, a dietary supplement that potentiates the action of insulin, was not included in the program. Like metformin and troglitazone, trivalent chromium decreases insulin resistance and has an acceptable side-effect profile; furthermore, it is available at a fraction of their cost. Trivalent chromium should have been included in the Diabetes Prevention Program; it is unfortunate that it was omitted.

Med Hypotheses. 1997 Jul;49(1):47-9

The effects of inorganic chromium and brewer’s yeast supplementation on glucose tolerance, serum lipids and drug dosage in individuals with type 2 diabetes.

OBJECTIVE: To study the effects of supplementation with organic and inorganic chromium on glucose tolerance, serum lipids, and drug dosage in type 2 diabetes patients, in the hope of finding a better and more economical method of control. METHODS: Seventy eight type 2 diabetes patients were divided randomly into two groups and given Brewer’s yeast (23.3ug Cr/day), and CrCl3 (200ug Cr/day) sequentially with placebo in between, in a double blind cross-over design of four stages, each lasting 8 weeks. At the beginning and end of each stage, subjects were weighed, their dietary data and drug dosage recorded, and blood and urine samples were collected for analysis of glucose (fasting and 2 hour post 75g glucose load) fructosamine, triglycerides, total and HDL-cholesterol, and serum and urinary chromium. RESULTS: Both supplements caused a significant decrease in the means of glucose (fasting and 2 hour post glucose load), fructosamine and triglycerides. The means of HDL-cholesterol, and serum and urinary chromium were all increased. The mean drug dosage decreased slightly (and significantly in case of Glibenclamide) after both supplements and some patients no longer required insulin. No change was noted in dietary intakes or Body Mass Index. A higher percentage of subjects responded positively to Brewer’s yeast chromium, which was retained more by the body, with effects on fructosamine, triglycerides, and HDL-cholesterol maintained in some subjects when placebo followed it, and mean urinary chromium remaining significantly higher than zero time mean.CONCLUSION: Chromium supplementation gives better control of glucose and lipid variables while decreasing drug dosage in type 2 diabetes patients. A larger scale study is needed to help decide on the convenient chemical form, and dosage required to achieve optimal response.

Saudi Med J. 2000 Sep;21(9):831-7

Effect of chromium supplementation on glucose tolerance and lipid profile.

OBJECTIVES: To investigate chromium status of the adult population in the western region of Saudi Arabia and the possibility of using serum chromium status measurement as indicator of this status. METHODS: The effect of chromium supplement on glucose tolerance and lipid profile was studied in 44 normal, free living adults. 200mg chromium/day as CrCL3 or a placebo was given in a double blind cross-over study, with 8 weeks experimental periods. Fasting, 1 hour and 2 hour post glucose challenge (75 g of glucose) glucose, serum fructosamine, total cholesterol, high-density lipoprotein-cholesterol, triglycerides, chromium and dietary intakes were estimated at the beginning and the end of each stage.RESULTS: Mean serum chromium increased significantly after supplement (P<.001) indicating proper absorption of the element. Supplement did not effect the total cholesterol, however, the mean high-density lipoprotein-cholesterol level was significantly increased (P<.001), the mean triglycerides levels significantly decreased (P<.001), and the mean fructosamine level significantly decreased (P<.05). In addition, chromium supplement effected 1 hour and 2 hour post glucose challenge glucose levels in subgroups of subjects with 2 hour glucose level > 10% above or below fasting level and significantly differing to it (P<.05 in both cases), by decreasing or increasing them significantly (P<.05 in all cases) so that the 2 hour mean became not significantly different to the fasting mean. Since no significant changes in weight, dietary intake or habits were found, and placebo had no effect, all noted biochemical changes were attributed to chromium. CONCLUSION: Improved glucose control, and lipid profile following chromium supplement suggests the presence of low chromium status in the studied population. However, serum chromium could not be recommended for use as an indicator of chromium status as subjects with widely varying levels responded favorably to the chromium supplement.

Saudi Med J. 2000 Jan;21(1):45-50

Quest for the molecular mechanism of chromium action and its relationship to diabetes.

Despite forty years of research on the potential role of chromium in carbohydrate and lipid metabolism, significant progress has only recently been made regarding the mode of action of chromium at a molecular level. The oligopeptide low-molecular-weight chromium-binding substance (LMWCr) may function as part of a novel insulin-signaling autoamplification mechanism. The proposed mechanism of action also sheds some light on the potential of chromium-containing compounds as nutritional supplements or in the treatment of adult-onset diabetes and other conditions. The potential relationship between the results of recent studies on diabetic patients and the proposed mode of action of LMWCr are discussed.

Nutr Rev. 2000 Mar;58(3 Pt 1):67-72

Glycemic control in patients with type 2 diabetes mellitus with a disease-specific enteral formula: stage II of a randomized, controlled multicenter trial.

BACKGROUND: Stage I of a preplanned 2-stage study has provided good evidence for improved glycemic control with a disease-specific enteral formula low in carbohydrates and high in monounsaturated fatty acids (MUFAs), fish oil, chromium, and antioxidants in insulin-treated type 2 diabetes. The study was continued with stage II to give confirmatory proof of these beneficial effects.

METHODS: 105 patients with HbA1C>or=7.0% and/or fasting blood glucose (FG)>6.7 mmol/L (>120 mg/dL) requiring enteral tube feeding due to neurological dysphagia received 113 kJ (27 kcal)/kg body weight of either test formula (Diben) or an isoenergetic, isonitrogenous standard formula (control) for up to 84 days. Total insulin (TI) requirements, FG, and afternoon blood glucose (AG) were assessed daily. HbA1C and safety criteria were evaluated on days 1, 28, 56, and 84. RESULTS: 55 patients completed the study; on day 84, median changes from baseline (data as available, test vs control) were the following: TI, -8.0 vs +2.0 IU; FG, -2.17 vs -0.67 mmol/L (-39.0 vs -12.1 mg/dL); HbA(1C), -1.30% vs -1.20%; AG, -2.36 vs -0.49 mmol/L (-42.5 vs -8.9 mg/dL). The number of relevant hypoglycemic episodes (FG<3.33 mmol/L<60 mg/dL) was 1 vs 5. Feeding tolerance was comparable in both groups.CONCLUSIONS: Long-term tube feeding with a disease-specific enteral formula was safe and well tolerated in type 2 diabetic patients with neurological disorders. When compared with a standard diet, TI requirement decreased significantly with less hypoglycemia whereas FG and AG were significantly lowered, resulting in improved glycemic control.

JPEN J Parenter Enteral Nutr. 2009 Jan-Feb;33(1):37-49

Chromium as adjunctive treatment for type 2 diabetes.

OBJECTIVE: To review the chemistry, pharmacology, efficacy, and safety of trivalent chromium in the treatment of type 2 diabetes and hyperlipidemia. DATA SOURCES: The English literature was searched from 1966 through May 2002 using MEDLINE, International Pharmaceutical Abstracts, and EMBASE. The key words included chromium, glucose, lipids, and diabetes. Pertinent references from review articles and studies were used as additional sources. DATA SYNTHESIS: Trivalent chromium is an essential nutrient and has a key role in lipid and glucose metabolism. Supplementation with chromium does not appear to reduce glucose levels in euglycemia. It may, however, have some efficacy in reducing glucose levels in hyperglycemia. The effects of chromium on lipid levels are variable. Chromium in doses <1000 microg/d appears to be safe for short-term administration. Kidney function and dermatologic changes need to be monitored.CONCLUSIONS: Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed.

Ann Pharmacother. 2003 Jun;37(6):876-85

Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus.

The objective of the study was to provide a comprehensive evaluation of chromium (Cr) supplementation on metabolic parameters in a cohort of type 2 diabetes mellitus subjects representing a wide phenotype range and to evaluate changes in “responders” and “nonresponders.” After preintervention testing to assess glycemia, insulin sensitivity (assessed by euglycemic clamps), Cr status, and body composition, subjects were randomized in a double-blind fashion to placebo or 1000 microg Cr. A substudy was performed to evaluate 24-hour energy balance/substrate oxidation and myocellular/intrahepatic lipid content. There was not a consistent effect of Cr supplementation to improve insulin action across all phenotypes. Insulin sensitivity was negatively correlated to soleus and tibialis muscle intramyocellular lipids and intrahepatic lipid content. Myocellular lipids were significantly lower in subjects randomized to Cr. At preintervention, responders, defined as insulin sensitivity change from baseline of at least 10% or greater, had significantly lower insulin sensitivity and higher fasting glucose and A(1c) when compared with placebo and nonresponders, that is, insulin sensitivity change from baseline of less than 10%. Clinical response was significantly correlated (P < .001) to the baseline insulin sensitivity, fasting glucose, and A(1c). There was no difference in Cr status between responder and nonresponders. Clinical response to Cr is more likely in insulin-resistant subjects who have more elevated fasting glucose and A(1c) levels. Chromium may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 diabetes mellitus who do respond clinically independent of effects on weight or hepatic glucose production. Thus, modulation of lipid metabolism by Cr in peripheral tissues may represent a novel mechanism of action.

Metabolism. 2010 May;59(5):755-62

Effects of acute chromium supplementation on postprandial metabolism in healthy young men.

BACKGROUND: Chromium (Cr) potentiates the action of insulin in the cell and improves glucose tolerance after long-term supplementation. OBJECTIVE: We hypothesized that Cr may also have acute effects and might be beneficial in lowering the glycemic index of a meal. METHODS: We studied the effects of short-term Cr supplementation using a randomized crossover design. Thirteen apparently healthy, non-smoking young men of normal body mass index performed three trials each separated by one week. Test meals, providing 75 g of available carbohydrates, consisted of white bread with added Cr (400 or 800 microg as Cr picolinate) or placebo. RESULTS: After addition of 400 and 800 microg Cr incremental area under the curve (AUC) for capillary glucose was 23% (p = 0.053) and 20% (p = 0.054), respectively, lower than after the white bread meal. These differences reached significance if the subjects were divided into responders (n = 10) and non-responders (n = 3). For the responders AUC after 400 and 800 microg Cr was reduced by 36% and 30%, respectively (Placebo 175 +/- 22, Cr400 111 +/- 14 (p < 0.01), Cr800 122 +/- 15 mmol. min/L (p < 0.01)). Glycemia was unchanged after addition of Cr in the non-responders. Responders and non-responders differed significantly in their nutrient intake and eating pattern, and total serum iron concentration tended to be lower in the responder group (p = 0.07).CONCLUSIONS: Acute chromium supplementation showed an effect on postprandial glucose metabolism in most but not all subjects. The response to Cr may be influenced by dietary patterns.

J Am Coll Nutr. 2004 Aug;23(4):351-7

Trivalent chromium inhibits protein glycosylation and lipid peroxidation in high glucose-treated erythrocytes.

Epidemiological studies have shown lower levels of chromium among men with diabetes and cardiovascular disease (CVD) compared with healthy control subjects. The mechanism by which chromium may decrease the incidence of CVD and insulin resistance is not known. Using erythrocytes as a model, this study demonstrates that chromium inhibits the glycosylation of proteins and oxidative stress, both risk factors in the development of CVD. Erythrocytes were treated with high levels of glucose (mimicking diabetes) in the presence or absence of chromium chloride in the medium at 37 degrees C for 24 hours. Chromium supplementation prevented the increases in protein glycosylation and oxidative stress caused by the high levels of glucose in erythrocytes. This study demonstrates for the first time that chromium supplementation inhibits protein glycosylation in erythrocytes exposed to high glucose medium, which appears to be mediated by its antioxidative effect. This provides evidence for a novel mechanism by which chromium supplementation may decrease incidence of CVD in diabetic patients.

Antioxid Redox Signal. 2006 Jan-Feb;


Chromium (III)-ion enhances the utilization of glucose in type-2 diabetes mellitus.

INTRODUCTION: The prevalence of the type 2 diabetes mellitus is still growing. Although the occurrence of insulin resistance is quite frequent in the whole population, diabetes not always develops because for a time the compensating mechanism avoids it. In a

frequent variation of type-2 diabetes the disease is not the result of an alteration in the insulin receptor or the glucose transporter, but a genetically determined defect of the postreceptorial intracellular signaling mechanism plays a role in its occurrence. There have been investigations for decades to find out more about the role of chromium (III) ions in glucose metabolism and in the prevention of type-2 diabetes. It has also been investigated if chromium substitution can prevent or treat those forms of diabetes where chromium deficiency is suspected to be in the background of the disorder.AIM: The aim of our present investigation is to test the role of chromium (III) compounds in glucose metabolism that are known from literature. The authors examined the effect of oral chromium supplementation on antidiabetic treatment. Chromium supplementation was applied for 6 months.METHODS: Before, through and after the investigation changes in the patient’s carbohydrate and lipid metabolism were followed by laboratory tests. RESULTS: At the end of our examination the cholesterin level significantly, the HbA1c level close to the significant value decreased. Due to their results the authors presume that chromium (III) compounds may be effective in the treatment of patients’ with decreased glucose tolerance or type-2 diabetes mellitus as a supplement to their therapy.

Orv Hetil. 2003 Oct 19;144(42):2073-6

Cinnamon and health.

Cinnamon has been used as a spice and as traditional herbal medicine for centuries. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumor, cardiovascular, cholesterol-lowering, and immunomodulatory effects. In vitro studies have demonstrated that cinnamon may act as an insulin mimetic, to potentiate insulin activity or to stimulate cellular glucose metabolism. Furthermore, animal studies have demonstrated strong hypoglycemic properties. However, there are only very few well-controlled clinical studies, a fact that limits the conclusions that can be made about the potential health benefits of cinnamon for free-living humans. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area, but further research is needed before definitive recommendations can be made.

Crit Rev Food Sci Nutr. 2010 Oct;50(9):822-34

Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats.

We reported earlier that dietary cinnamon extract (CE) improves systemic insulin sensitivity and dyslipidemia by enhancing insulin signaling. In the present study, we have examined the effects of CE on several biomarkers including plasma levels of adipose-derived adipokines, and the potential molecular mechanisms of CE in epididymal adipose tissue (EAT). In Wistar rats fed a high-fructose diet (HFD) to induce insulin resistance, supplementation with a CE (Cinnulin PF, 50 mg/kg daily) for 8 weeks reduced blood glucose, plasma insulin, triglycerides, total cholesterol, chylomicron-apoB48, VLDL-apoB100, and soluble CD36. CE also inhibited plasma retinol binding protein 4 (RBP4) and fatty acid binding protein 4 (FABP4) levels. CE-induced increases in plasma adiponectin were not significant. CE did not affect food intake, bodyweight, and EAT weight. In EAT, there were increases in the insulin receptor ( IR) and IR substrate 2 ( IRS2) mRNA, but CE-induced increases in mRNA expression of IRS1, phosphoinositide-3-kinase, AKT1, glucose transporters 1 and 4 , and glycogen synthase 1 expression and decreased trends in mRNA expression of glycogen synthase kinase 3beta were not statistically significant. CE also enhanced the mRNA levels of ADIPOQ, and inhibited sterol regulatory element binding protein-1c mRNA levels. mRNA and protein levels of fatty acid synthase and FABP4 were inhibited by CE and RBP4, and CD36 protein levels were also decreased by CE. These results suggest that CE effectively ameliorates circulating levels of adipokines partially mediated via regulation of the expression of multiple genes involved in insulin sensitivity and lipogenesis in the EAT.

Horm Metab Res. 2010 Mar;42(3):187-93