Chlorogenic Acid’s positive effect on glucose management and blood glucose levels:

Chlorogenic Acid and Hydroxynitrobenzaldehyde: New Inhibitors of Hepatic Glucose 6-Phosphatase

WILLIAM J. ARION, WESLEY K. CANFIELD, FRANCIS C. RAMOS, PETER W. SCHINDLER, HANS-JOERG BURGER, HORST HEMMERLE, GERRIT SCHUBERT, PETER BELOW, AND ANDREAS W. HERLING

Archives of Biochemistry and Biophysics, Vol. 339, No. 2, March 15, pp. 315-322, 1997, Article No. BB969874

Abstract: We have studied the interactions of Chlorogenic acid (CHL) and 2-hydroxy-5-nitrobenzaldehyde (HNB) with the components of the rat hepatic glucose 6-phosphatase (Glc-6-Pase) system. CHL and HNB are competitive inhibitors of glucose 6-phosphate (Glc-6-P) hydrolysis in intact microsomes with K_i values of 0.26 and 0.22 mM, respectively. CHL is without effect on the enzyme of fully disrupted microsomes or the system inorganic pyrophosphatase (PP_iase) activity. HNB is a potent competitive inhibitor of the system PP_iase activity (K_i = 0.56 mM) and a somewhat weaker noncompetitive inhibitor of enzyme activity (K_i = 2.1 mM). These findings indicate CHL binds to T1, the Glc-6-P transporter, and HNB inhibits through interaction with both T1 and T2 the phosphate (P_i)-PP_i transporter. Binding of the CHL and HNB is freely reversible. However, the inhibition of both PP_iase and GLC-6-Pase by HNB becomes irreversible following incubation of HNB-exposed microsomes with 2.5 mM sodium borohydride, indicating that inhibition involves the formation of a Schiff base. The presence of CHL effectively protects T1, but not T2, against the irreversible inhibition by HNB. In contrast, PP_i and P_i are effective in protecting T2, but not T1. This is the first report describing an effective inhibitor of the system PP_iase activity (T2). CHL is the most specific T1 inhibitor described to date.

Chlorogenic Acid and Synthetic Chlorogenic Acid Derivatives: Novel Inhibitors of Hepatic Glucose-6-Phosphate Translocase

HORST HEMMERLE, HANS-JOERG BURGER, PETER BELOW, GERRIT SCHUBERT, ROBERT RIPPEL, PETER W. SCHINDLER, ERICH PAULUS AND ANDREAS W. HERLING

Journal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Abstract: The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major role in the homeostatic regulation of blood glucose. It is responsible for the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, Chlorogenic acid was identified as a specific inhibitor of the glucose-6-phosphate translocase component (G1-6-P-translocase) of this enzyme system in microsomes of rat liver. Glucose-6-phosphate hydrolysis was determined in the presence of chlorogenic

acid or of new synthesized derivatives in intact rat liver microsomes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipohilic side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependent inhibition of gluconeogenesis and glycogenolysis, suggesting glucose-6-phosphatase as the locus of interference of the compound for inhibition of hepatic glucose production also in the isolated organ model. G1-6-P translocase inhibitors may be useful for the reduction of inappropriately high rates of hepatic glucose output often found in non-insulin-dependent diabetes.

Related Citations:

1. Pharmacodynamic profile of a novel inhibitor of the hepatic glucose 6-phosphatase system

ANDREAS W. HERLING, HANS-JOERG BURGER, DIETMAR SCHWAB, HORST HEMMERLE, PETER BELOW, AND GERRIT SCHUBERT

American Physiological Society, 1998, pp. G1087-G1093

2. Upregulation of Hepatic Glucose 6-Phosphatase Gene Expression in Rats Treated with an Inhibitor of Glucose-6-phosphate Translocase

CAECILIA SIMON, ANDREAS W. HERLING, GERALD PREIBISCH, AND HANS-JOERG BURGER

Archives of Biochemistry and Biophysics, Vol. 373, No. 2, January 15, pp. 418-428, 2000

Inhibitory effect of green coffee bean extract on fat accumulation and body weight in mice

HIROSHI SHIMODA; EMI SEKI; MICHIO AITANI

BMC Complementary and Alternative Medicine 2006, 6:9 doi:10.1186/1472-6882-6-9

ABSTRACT:

Background

An epidemiological study conducted in Italy indicated that coffee has the greatest antioxidant capacity among the commonly consumed beverages. Green coffee bean is

rich in chlorogenic acid and its related compounds. The effect of green coffee bean extract (GCBE) on fat accumulation and body weight in mice was assessed with the objective of investigating the effect of GCBE on mild obesity.

Methods

Male ddy mice were fed a standard diet containing GCBE and its principal constituents, namely, caffeine and chlorogenic acid, for 14 days. Further, hepatic triglyceride (TG) level was also investigated after consecutive administration (13 days) of GCBE and its constituents. To examine the effect of GCBE and its constituents on fat absorption, serum TG changes were evaluated in olive oil-loaded mice. In addition, to investigate the effect on hepatic TG metabolism, carnitine palmitoyltransferase (CPT) activity in mice was evaluated after consecutive ingestion (6 days) of GCBE and its constituents (caffeine, chlorogenic acid, neochlorogenic acid and feruloylquinic acid mixture).

Results

It was found that 0.5% and 1% GCBE reduced visceral fat content and body weight.

Caffeine and chlorogenic acid showed a tendency to reduce visceral fat and body weight. Oral administration of GCBE (100 and 200 mg/kg·day) for 13 days showed a tendency to reduce hepatic TG in mice. In the same model, chlorogenic acid (60 mg/kg·day) reduced hepatic TG level. In mice loaded with olive oil (5 mL/kg), GCBE (200 and 400 mg/kg) and caffeine (20 and 40 mg/kg) reduced serum TG level. GCBE (1%), neochlorogenic acid (0.028% and 0.055%) and feruloylquinic acid mixture (0.081%) significantly enhanced hepatic CPT activity in mice. However, neither caffeine nor chlorogenic acid alone was found to enhance CPT activity.

Conclusions

These results suggest that GCBE is possibly effective against weight gain and fat accumulation by inhibition of fat absorption and activation of fat metabolism in the liver. Caffeine was found to be a suppressor of fat absorption, while chlorogenic acid was found to be partially involved in the suppressive effect of GCBE that resulted in the reduction of hepatic TG level. Phenolic compounds such as neochlorogenic acid and feruloylquinic acid mixture, except chlorogenic acid, can enhance hepatic CPT activity.

Chlorogenic acid modifies plasma and liver concentrations of: cholesterol, triacylglycerol, and minerals in (fa/fa) Zucker rats.

DELCY V. RODRIGUEZ DE SOTILLO AND M. HADLEY

Journal of Nutritional Biochemistry, 2002, Vol. 13, No. 12, pp. 717-726

Abstract: Chlorogenic acid, a phenolic compound found ubiquitously in plants, is an in vitro antioxidant and metal chelator. Some derivatives of chlorogenic acid are hypoglycemic agents and may affect lipid metabolism. Concentrations of cholesterol and triacylglycerols are of interest due to their association with diseases such as non-insulin-dependent-diabetes- mellitus and obese insulin resistance. As little is known about the effects of chlorogenic acid in vivo, studies using obese, hyperlipidemic, and insulin resistant (fa/fa) Zucker rats were conducted to test the effect of chlorogenic acid on fasting plasma glucose, plasma and liver triacylglycerols and cholesterol concentrations. Additionally, the effects of chlorogenic acid on selected mineral concentrations in plasma, spleen, and liver were determined. Rats were implanted with jugular vein catheters. Chlorogenic acid was infused (5 mg/Kg body weight/day) for 3 weeks via intravenous infusion. Chlorogenic acid did not promote sustained hypoglycemia and significantly lowered the postprandial peak response to a glucose challenge when compared to the same group of rats before chlorogenic acid treatment. In Chlorogenic acid-treated rats, fasting plasma cholesterol and triacylglycerols concentrations significantly decreased by 44% and 58% respectively, as did in liver triacylglycerols concentrations (24%). We did not find differences (p>0.05) in adipose triacylglycerols concentration. Significant differences (p<0.05) in the plasma, liver, and spleen concentration of selected minerals were found in chlorogenic acid-treated rats. In vivo, chlorogenic acid was found to improve glucose tolerance, decreased some plasma and liver lipids, and improve mineral pool distribution under the conditions of this study.

Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: Glycemic effects of chlorogenic acid and caffeine.

MORGAN, LINDA M.; CLIFFORD, MICHAEL N.; JOHNSTON, KELLY L.

American Journal of Clinical Nutrition, Volume 78, No. 4, October 2003, pp. 728-733

ABSTRACT:

Background: Accumulating evidence suggests that certain dietary polyphenols have biological effects in the small intestine that alter the pattern of glucose uptake. Their effects, however, on glucose tolerance in humans are unknown.

Objective: The objective was to investigate whether chlorogenic acids in coffee modulate glucose uptake and gastrointestinal hormone and insulin secretion in humans.

Design: In a 3-way, randomized, crossover study, 9 healthy fasted volunteers consumed 25 g glucose in either 400 mL water (control) or 400 mL caffeinated or decaffeinated coffee (equivalent to 2.5 mmol chlorogenic acid/L). Blood samples were taken frequently over the following 3 h.

Results: Glucose and insulin concentrations tended to be higher in the first 30 min after caffeinated coffee consumption than after consumption of decaffeinated coffee or the control (P < 0.05 for total and incremental area under the curve for glucose and insulin ). Glucose-dependent insulinotropic polypeptide secretion decreased throughout the experimental period (P < 0.005), and glucagon-like peptide 1 secretion increased 0-120 min postprandially (P < 0.01) after decaffeinated coffee consumption compared with the control. Glucose and insulin profiles were consistent with the known metabolic effects of caffeine. However, the gastrointestinal hormone profiles were consistent with delayed intestinal glucose absorption.

Conclusions: Differences in plasma glucose, insulin, and gastrointestinal hormone profiles further confirm the potent biological action of caffeine and suggest that chlorogenic acid might have an antagonistic effect on glucose transport. Therefore, a novel function of some dietary phenols in humans may be to attenuate intestinal glucose absorption rates and shift the site of glucose absorption to more distal parts of the intestine.

Coffee Consumption and Risk of Type 2 Diabetes Mellitus Among Middle-aged Finnish Men and Women

JAAKKO TUOMILEHTO, MD, PHD; GANG HU, MD, PHD; SIAMAK BIDEL, MD; JAANA LINDSTRÖM, MSC; PEKKA JOUSILAHTI, MD, PHD

The Journal of the American Medical Association, Volume 291, No. 10, March 10, 2004, pp. 1213-1219.

Context Only a few studies of coffee consumption and diabetesmellitus (DM) have been reported, even though coffee is themost consumed beverage in the world.

Objective To determine the relationship between coffee consumption and the incidence of type 2 DM among Finnish individuals, who have the highest coffee consumption in the world.

Design, Setting, and Participants A prospective study from combined surveys conducted in 1982, 1987, and 1992 of 6974 Finnish men and 7655 women aged 35 to 64

years without history of stroke, coronary heart disease, or DM at baseline, with 175 682 person-years of follow-up. Coffee consumption and other study parameters were determined at baseline using standardized measurements.

Main Outcome Measures Hazard ratios (HRs) for the incidence of type 2 DM were estimated for different levels of daily coffee consumption.

Results During a mean follow-up of 12 years, there were 381 incident cases of type 2 DM. After adjustment for confounding factors (age, study year, body mass index, systolic blood pressure, education, occupational, commuting and leisure-time physical activity, alcohol and tea consumption, and smoking), the HRs of DM associated with the amount of coffee consumed daily (0-2, 3-4, 5-6, 7-9, 10 cups) were 1.00, 0.71 (95% confidence interval [CI], 0.48-1.05), 0.39 (95% CI, 0.25-0.60), 0.39 (95% CI, 0.20-0.74), and 0.21 (95% CI, 0.06-0.69) (P for trend<.001) in women, and 1.00, 0.73 (95% CI, 0.47-1.13), 0.70 (95% CI, 0.45-1.05), 0.67 (95% CI, 0.40-1.12), and 0.45 (95% CI, 0.25-0.81) (P for trend = .12) in men, respectively. In both sexes combined, the multivariate-adjusted inverse association was significant (P for trend <.001) and persisted when stratified by younger and older than 50 years; smokers and never smokers; healthy weight, overweight, and obese participants; alcohol drinker and nondrinker; and participants drinking filtered and nonfiltered coffee.

Conclusion Coffee drinking has a graded inverse association with the risk of type 2 DM; however, the reasons for this risk reduction associated with coffee remain unclear.

Coffee consumption and risk of type 2 diabetes mellitus

ROB M VAN DAM, EDITH J M FESKENS

THE LANCET, Research Letters, Vol. 360, November 9, 2002, pp. 1477-1478

Abstract: Coffee is a major source of caffeine, which has been shown to acutely reduce sensitivity to insulin, but also potentially beneficial effects. We prospectively investigated the association between coffee consumption and risk of clinical type 2 diabetes in a population-based cohort of 17 111 Dutch men and women aged 20-60 years. During 125 774 person years of follow-up, 306 new cases of type 2 diabetes were reported. After adjustment for potential cofounders, individuals who drank at least seven cups of coffee a day were 0.50 (95% CI 0.35-0.72, p=0.0002) times as likely as those who drank two cups or fewer a day to develop type 2 diabetes. Coffee consumption was associated with a substantially lower risk of clinical type 2 diabetes.

Dietary phenolic compounds: inhibition of Na+-dependent D-glucose uptake in rat intestinal brush border membrane vesicles.

C.A. WELSCH, P.A. LACHANCE, AND B.P. WASSERMAN

Journal of Nutrition, November 1989, Volume 119(11); pp. 1698-1704

Abstract: The effects of phenolic compounds on Na+-dependent D-glucose transport were investigated in brush border membrane vesicles isolated from rat small intestine. Screening experiments were conducted with different classes of phenolic compounds in both their native and oxidized forms. Pretreatment of vesicles with tannic acid (1 mg/ml) completely abolished the characteristic overshoot of active glucose accumulation. With chlorogenic acid (1mM), 80% of the glucose transport capacity was lost. Reductions of 30-40% were observed in vesicles treated with catechin, ferulic or caffeic acids. Treatment with gallic acid (1 mM) had little effect. Phenolic oxidation state did not exacerbate the degree of glucose transport inhibition, with the exception of catechol (1 mM), which gave maximal inhibition (86%) in its oxidized form. Gradient-independent glucose uptake was not altered, nor did phenolic treatment increase nonspecific binding of glucose to the membrane vesicles. Possible mechanisms of D-glucose transport inhibition were examined in chlorogenic acid-and tannic acid-treated vesicles. Factors such as alterations in vesicle permeability, size and leakage of transported glucose out of the vesicles were ruled out. Measurements of D-glucose uptake under conditions of Na+ equilibrium suggest that tannic and chlorogenic acids reduce glucose uptake by favoring the dissipation of the Na+ electrochemical gradient, which provides the driving force for active glucoseaccumulation.

Caffeic Acid’s positive effect on glucose management and blood glucose levels:

Stimulatory effect of caffeic acid on _1A-adrenoceptors to increase glucose uptake into cultured C₂C₁₂ cells.

JUEI-TANG CHENG AND I-MIN LIU Naunyn-Schmiedebergs Archives of Pharmacology, Volume 362, Issue 2, pp 122-127

Abstract. In an attempt to understand the antihyperglycemic action of caffeic acid, the myoblast C₂C₁₂ cells were employed to investigate the glucose uptake in the present study. Caffeic acid enhanced the uptake of radioactive glucose into C₂C₁₂ cells in a concentration-dependent manner. Similar effect of phenylephrine on the uptake of radioactive glucose was also observed in C₂C₁₂ cells. Prazosin attenuated the action of caffeic acid in a way parallel to the blockade of phenylephrine. Effect of caffeic acid on ₁-adrenoceptors was further supported by the displacement of [³H]prazosin binding in C₂C₁₂ cells. Moreover, the glucose uptake-increasing action of phenylephrine in C₂C₁₂ cells was inhibited by the antagonists of _1A-adrenoceptors, both tamsulosin and WB 4101, but not by the antagonist of _1B-adrenoceptors, chlorethylclonidine (CEC). The presence of _1A-adrenoceptors in C₂C₁₂ cells can thus be considered. Similar inhibition of the action of caffeic acid was also obtained in C₂C₁₂ cells co-incubating these antagonists. An activation of _1A-adrenoceptors seems responsible for the action of caffeic acid in C₂C₁₂ cells. In the presence of U73312, the specific inhibitor of phospholipase C, caffeic acid-stimulated uptake of radioactive glucose into C₂C₁₂ cells was reduced in a concentration-dependent manner and it was not affected by U73343, the negative control of U73312. Moreover, chelerythrine and GF 109203X diminished the action of caffeic acid at concentrations sufficient to inhibit protein kinase C. Therefore,

the obtained data suggest that an activation of _1A-adrenoceptors in C₂C₁₂ cells by caffeic acid may increase the glucose uptake via phospholipase C-protein kinase C pathway.

Caffeic Acid as active principle from the fruit of Xanthiumstrumarium to lower plasma glucose in diabetic rats.

FENG-LIN HSU, YUN-CHUEH CHEN, AND JUEI-TANG CHENG

Planta Medica, 2000, Volume 66, Issue 3, pp. 228-30

Abstract: The antihyperglycemic effect of caffeic acid, one of the phenolic compounds contained in the fruit of Xanthium strumarium, was investigated. After an intravenous injection of caffeic acid into diabetic rats of both streptozotocin-induced and insulin-resistant models, a dose-dependent decrease of plasma glucose was observed. However, a similar effect was not produced in normal rats. An insulin-independent action of caffeic acid can thus be considered. Otherwise, this compound reduced the elevation of plasma glucose level in insulin-resistant rats receiving a glucose challenge test. Also, glucose uptake into the isolated adipocytes was raised by caffeic acid in a concentration-dependent manner. Increase of glucose utilization by caffeic acid seems to be responsible for the lowering of plasma glucose.

Absorption and bioavailability of Chlorogenic Acid and Caffeic Acid in humans:

Absorption of Phenolic Acids in Humans after Coffee Consumption

M. NARDINI, E. CIRILLO, F. NATELLA, AND C. SCACCINI

Journal of Agricultural and Food Chemistry 2002, 50, 5735-5741

Abstract: Despite extensive literature describing the biological effects of polyphenols, little is known about their absorption from diet, one major unresolved point consisting of the absorption of the bound forms of polyphenols. In this view, in the present work we studied the absorption in humans of phenolic acids from coffee, a common beverage particularly rich in bound phenolic acids, such as caffeic acid, ferulic acid, and p-coumaric acid. Coffee brew was analyzed for free and total (free + bound) phenolic

acids. Chlorogenic acid (5’-caffeoylquinic acid), a bound form of caffeic acid, was present in coffee at high levels, while free phenolic acids were undetectable. After alkaline hydrolysis, which released bound phenolic acids, ferulic acid, p-coumaric acid, and high levels of caffeic acid were detected. Plasma samples were collected before and 1 and 2 h after coffee administration and analyzed for free and total phenolic acid content. Two different procedures were applied to release bound phenolic acids in plasma: ‚-glucuronidase treatment and alkaline hydrolysis. Coffee administration resulted

in increased total plasma caffeic acid concentration, with an absorption peak at 1 h. Caffeic acid was the only phenolic acid found in plasma samples after coffee administration, while chlorogenic acid was undetectable. Most of caffeic acid was present in plasma in bound form, mainly in the glucuronate/sulfate forms. Due to the absence of

free caffeic acid in coffee, plasma caffeic acid is likely to be derived from hydrolysis of chlorogenic acid in the gastrointestinal tract.

Chlorogenic Acid and Caffeic Acid are absorbed in Humans

MARGREET R. OLTHOF, PETER C.H. HOLLMAN, AND MARTJIN B. KATAN

Human Nutrition and Metabolism, American Society for Nutritional Sciences (2001), pp. 66-71

Abstract: Chlorogenic acid, an ester of caffeic acid and quinic acid, is a major phenolic compound in coffee; daily intake in coffee drinkers is 0.5-1 g. Chlorogenic acid and caffeic acid are antioxidants in vitro and might therefore contribute to the prevention of cardiovascular disease. However, data on the absorption of chlorogenic acid and caffeic acid are lacking. We determined the absorption of chlorogenic acid and caffeic acid in a crossover study with 4 female and 3 male healthy ileostomy subjects. In such subjects, degradation by the colonic microflora is minimal and absorption can be calculated as the amount ingested minus the amount excreted in ileostomy effluent. The ileostomy subjects ingested 2.8 mmol chlorogenic acid and 2.8 mmol caffeic acid on separate days in random order and subsequently collected ileostomy fluid and urine for 24 k. Absorption of chlorogenic acid was 33 ± 17% (mean ± _SD) and of caffeic acid 95 ± 4%. Traces of the ingested chlorogenic acid and 11% of the ingested caffeic acid were excreted in the urine. Thus, one third of chlorogenic acid and almost all of the caffeic acid were absorbed in the small intestine of huma, ns. This implies that part of chlorogenic acid from foods will enter into the blood circulation, but most will reach the colon.

Isolation and characterization of human colonic bacteria able to hydrolyse chlorogenic acid

D. COUTEAU, A.L. MCCARTNEY, G.R. GIBSON, G. WILLIAMSON AND C.B. FAULDS

Journal of Applied Microbiology 2001, 90, 873-881

Abstract: Conjugated hydroxycinnamates, such as chlorogenic acid (caffeoyl-quinic acid), are widely consumed in a Western diet, coffee being one of the richest sources. Ingested hydroxycinnamate esters can reach the large intestine essentially unaltered, and may then be hydrolysed by esterases produced by the indigenous microflora. This study is aimed at identifying bacterial species responsible for the release of natural antioxidants, such as hydroxycinnamic acids, in the human large intestine. Thirty-five isolates recovered after anaerobic batch culture incubation of human faecal bacteria in a chlorogenic acid-based medium wee screened for cinnamoyl esterase activity. Six isolates released the hydroxycinnamate, ferulic acid, from its ethyl ester in a plate-screening assay, and these were identified through genotypic characterization (16S rRNA sequencing) as Escherichia coli (three isolates), Bifidobacterium lactis and Lactobacillus gasseri (two strains). Chlorogenic acid hydrolyzing activities were essentially intracellular. These cinnamoyl esterase-producing organisms were devoid of other phenolic-degrading activities. The results that certain gut bacteria, including some already recognized as potentially health-promoting (i.e. species belonging to the genera Bifidobacterium and Lactobacillus), are involved in the release of bioactive hydroxycinnamic acids in the human colon. Free hydroxycinnamates, including caffeic,

ferulic and p-coumaric acids, exhibit antioxidant and anticarcinogenic properties both in vitro and in animal models. Given that the gut flora has a major role in human nutrition and health, some of the beneficial effects of phenolic acids may be ascribed to the microflora involved in metabolism.