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Ruth Lupu - One of the best experts on this subject based on the ideXlab platform.
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mediterranean dietary traditions for the molecular treatment of human cancer anti oncogenic actions of the main olive oil s Monounsaturated Fatty Acid oleic Acid 18 1n 9
Current Pharmaceutical Biotechnology, 2006Co-Authors: Javier A Menendez, Ruth LupuAbstract:The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical "Mediterranean diet", exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary Fatty Acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic Acid (OA; 18:1n-9), the main olive oil's Monounsaturated Fatty Acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185(Her-2/neu) protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of "cell fuel" availability capable to suppress HER2 expression via formation of inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the "Mediterranean diet" must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease.
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a genomic explanation connecting mediterranean diet olive oil and cancer oleic Acid the main Monounsaturated Fatty Acid of olive oil induces formation of inhibitory pea3 transcription factor pea3 dna binding site complexes at the her 2 neu erbb 2 onc
European Journal of Cancer, 2006Co-Authors: Javier A Menendez, Luciano Vellon, Ruth Lupu, Adriana PapadimitropoulouAbstract:Abstract Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering risk of several cancers. We recently hypothesized that the anti-cancer actions of olive oil may relate to its Monounsaturated Fatty Acid (MUFA) oleic Acid (OA; 18:1 n −9) content to specifically regulate oncogenes. In this study, transient transfection experiments with human Her-2/ neu promoter-driven luciferase gene established the ability of OA to specifically repress the transcriptional activity of Her-2/ neu gene. Gene repression was seen in tumour-derived cell lines with Her-2/ neu gene amplification and overexpression, including SK-Br3 (⩽56% reduction), SK-OV3 (⩽75% reduction) and NCI-N87 (55% reduction) breast, ovarian and stomach cancer cell lines, respectively. Also marginal decreases in promoter activity were observed in cancer cells expressing physiological levels of Her-2/ neu (⩽20% reduction in MCF-7 breast cancer cells). Remarkably, OA treatment in Her-2/ neu -overexpressing cancer cells was found to induce up-regulation of the Ets protein polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/ neu promoter. Also, an intact PEA3 DNA-binding-site at endogenous Her-2/ neu gene promoter was essential for OA-induced repression of this gene. Moreover, OA treatment failed to decrease Her-2/ neu protein levels in MCF-7/Her2-18 transfectants, which stably express full-length human Her-2/ neu cDNA controlled by a SV40 viral promoter. OA-induced transcriptional repression of Her-2/ neu through the action of PEA3 protein at the promoter level may represent a novel mechanism linking "Mediterranean diet" and cancer.
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oleic Acid the main Monounsaturated Fatty Acid of olive oil suppresses her 2 neu erbb 2 expression and synergistically enhances the growth inhibitory effects of trastuzumab herceptin in breast cancer cells with her 2 neu oncogene amplification
Annals of Oncology, 2005Co-Authors: Javier A Menendez, Luciano Vellon, Ramon Colomer, Ruth LupuAbstract:Abstract Background The relationship between the intake of olive oil, the richest dietary source of the Monounsaturated Fatty Acid oleic Acid (OA; 18:1n-9), and breast cancer risk and progression has become a controversial issue. Moreover, it has been suggested that the protective effects of olive oil against breast cancer may be due to some other components of the oil rather than to a direct effect of OA. Methods Using flow cytometry, western blotting, immunofluorescence microscopy, metabolic status (MTT), soft-agar colony formation, enzymatic in situ labeling of apoptosis-induced DNA double-strand breaks (TUNEL assay analyses), and caspase-3-dependent poly-ADP ribose polymerase (PARP) cleavage assays, we characterized the effects of exogenous supplementation with OA on the expression of Her-2/neu oncogene, which plays an active role in breast cancer etiology and progression. In addition, we investigated the effects of OA on the efficacy of trastuzumab (Herceptin™), a humanized monoclonal antibody binding with high affinity to the ectodomain of the Her-2/neu-coded p185Her-2/neu oncoprotein. To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the Her-2/neu oncogene. Results Flow cytometric analyses demonstrated a dramatic (up to 46%) reduction of cell surface-associated p185Her-2/neu following treatment of the Her-2/neu-overexpressors BT-474 and SK-Br3 with OA. Indeed, this effect was comparable to that found following exposure to optimal concentrations of trastuzumab (up to 48% reduction with 20μg/ml trastuzumab). Remarkably, the concurrent exposure to OA and suboptimal concentrations of trastuzumab (5μg/ml) synergistically down-regulated Her-2/neu expression, as determined by flow cytometry (up to 70% reduction), immunoblotting, and immunofluorescence microscopy studies. The nature of the cytotoxic interaction between OA and trastuzumab revealed a strong synergism, as assessed by MTT-based cell viability and anchorage-independent soft-agar colony formation assays. Moreover, OA co-exposure synergistically enhanced trastuzumab efficacy towards Her-2/neu overexpressors by promoting DNA fragmentation associated with apoptotic cell death, as confirmed by TUNEL and caspase-3-dependent PARP cleavage. In addition, treatment with OA and trastuzumab dramatically increased both the expression and the nuclear accumulation of p27Kip1, a cyclin-dependent kinase inhibitor playing a key role in the onset and progression of Her-2/neu-related breast cancer. Finally, OA co-exposure significantly enhanced the ability of trastuzumab to inhibit signaling pathways downstream of Her-2/neu, including phosphoproteins such as AKT and MAPK. Conclusions These findings demonstrate that OA, the main Monounsaturated Fatty Acid of olive oil, suppresses Her-2/neu overexpression, which, in turn, interacts synergistically with anti-Her-2/neu immunotherapy by promoting apoptotic cell death of breast cancer cells with Her-2/neu oncogene amplification. This previously unrecognized property of OA offers a novel molecular mechanism by which individual Fatty Acids may regulate the malignant behavior of breast cancer cells and therefore be helpful in the design of future epidemiological studies and, eventually, dietary counseling.
Yurevich Dmitrij Murzin - One of the best experts on this subject based on the ideXlab platform.
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catalytic deoxygenation of unsaturated renewable feedstocks for production of diesel fuel hydrocarbons
Fuel, 2008Co-Authors: Mathias Snare, D Chichova, Iva Kubickova, Paivi Makiarvela, Kari Eränen, Yurevich Dmitrij MurzinAbstract:Abstract The liquid-phase deoxygenation reaction of unsaturated renewables has been investigated in a semi-batch reactor. The reactants examined were the Monounsaturated Fatty Acid, oleic Acid, the diunsaturated Fatty Acid, linoleic Acid and the Monounsaturated Fatty Acid ester, methyl oleate. The reactions were carried out over a Pd/C catalyst under constant pressure and temperature in the following domain, 15–27 bar and 300–360 °C, respectively. The influence of carrier gas was additionally investigated. The impact as solvent (mesitylene) was studied as well and reaction pathways were proposed. Furthermore, continuous deoxygenation experiments were conducted, facilitating understanding of the catalyst stability and catalyst deactivation. The deoxygenation catalyst was characterized by physisorption, temperature programmed desorption (TPD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM).
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catalytic deoxygenation of unsaturated renewable feedstocks for production of diesel fuel hydrocarbons
Fuel, 2008Co-Authors: Mathias Snare, D Chichova, Iva Kubickova, Paivi Makiarvela, Kari Eränen, Yurevich Dmitrij MurzinAbstract:Abstract The liquid-phase deoxygenation reaction of unsaturated renewables has been investigated in a semi-batch reactor. The reactants examined were the Monounsaturated Fatty Acid, oleic Acid, the diunsaturated Fatty Acid, linoleic Acid and the Monounsaturated Fatty Acid ester, methyl oleate. The reactions were carried out over a Pd/C catalyst under constant pressure and temperature in the following domain, 15–27 bar and 300–360 °C, respectively. The influence of carrier gas was additionally investigated. The impact as solvent (mesitylene) was studied as well and reaction pathways were proposed. Furthermore, continuous deoxygenation experiments were conducted, facilitating understanding of the catalyst stability and catalyst deactivation. The deoxygenation catalyst was characterized by physisorption, temperature programmed desorption (TPD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM).
Javier A Menendez - One of the best experts on this subject based on the ideXlab platform.
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mediterranean dietary traditions for the molecular treatment of human cancer anti oncogenic actions of the main olive oil s Monounsaturated Fatty Acid oleic Acid 18 1n 9
Current Pharmaceutical Biotechnology, 2006Co-Authors: Javier A Menendez, Ruth LupuAbstract:The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical "Mediterranean diet", exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary Fatty Acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic Acid (OA; 18:1n-9), the main olive oil's Monounsaturated Fatty Acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185(Her-2/neu) protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of "cell fuel" availability capable to suppress HER2 expression via formation of inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the "Mediterranean diet" must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease.
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a genomic explanation connecting mediterranean diet olive oil and cancer oleic Acid the main Monounsaturated Fatty Acid of olive oil induces formation of inhibitory pea3 transcription factor pea3 dna binding site complexes at the her 2 neu erbb 2 onc
European Journal of Cancer, 2006Co-Authors: Javier A Menendez, Luciano Vellon, Ruth Lupu, Adriana PapadimitropoulouAbstract:Abstract Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering risk of several cancers. We recently hypothesized that the anti-cancer actions of olive oil may relate to its Monounsaturated Fatty Acid (MUFA) oleic Acid (OA; 18:1 n −9) content to specifically regulate oncogenes. In this study, transient transfection experiments with human Her-2/ neu promoter-driven luciferase gene established the ability of OA to specifically repress the transcriptional activity of Her-2/ neu gene. Gene repression was seen in tumour-derived cell lines with Her-2/ neu gene amplification and overexpression, including SK-Br3 (⩽56% reduction), SK-OV3 (⩽75% reduction) and NCI-N87 (55% reduction) breast, ovarian and stomach cancer cell lines, respectively. Also marginal decreases in promoter activity were observed in cancer cells expressing physiological levels of Her-2/ neu (⩽20% reduction in MCF-7 breast cancer cells). Remarkably, OA treatment in Her-2/ neu -overexpressing cancer cells was found to induce up-regulation of the Ets protein polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/ neu promoter. Also, an intact PEA3 DNA-binding-site at endogenous Her-2/ neu gene promoter was essential for OA-induced repression of this gene. Moreover, OA treatment failed to decrease Her-2/ neu protein levels in MCF-7/Her2-18 transfectants, which stably express full-length human Her-2/ neu cDNA controlled by a SV40 viral promoter. OA-induced transcriptional repression of Her-2/ neu through the action of PEA3 protein at the promoter level may represent a novel mechanism linking "Mediterranean diet" and cancer.
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oleic Acid the main Monounsaturated Fatty Acid of olive oil suppresses her 2 neu erbb 2 expression and synergistically enhances the growth inhibitory effects of trastuzumab herceptin in breast cancer cells with her 2 neu oncogene amplification
Annals of Oncology, 2005Co-Authors: Javier A Menendez, Luciano Vellon, Ramon Colomer, Ruth LupuAbstract:Abstract Background The relationship between the intake of olive oil, the richest dietary source of the Monounsaturated Fatty Acid oleic Acid (OA; 18:1n-9), and breast cancer risk and progression has become a controversial issue. Moreover, it has been suggested that the protective effects of olive oil against breast cancer may be due to some other components of the oil rather than to a direct effect of OA. Methods Using flow cytometry, western blotting, immunofluorescence microscopy, metabolic status (MTT), soft-agar colony formation, enzymatic in situ labeling of apoptosis-induced DNA double-strand breaks (TUNEL assay analyses), and caspase-3-dependent poly-ADP ribose polymerase (PARP) cleavage assays, we characterized the effects of exogenous supplementation with OA on the expression of Her-2/neu oncogene, which plays an active role in breast cancer etiology and progression. In addition, we investigated the effects of OA on the efficacy of trastuzumab (Herceptin™), a humanized monoclonal antibody binding with high affinity to the ectodomain of the Her-2/neu-coded p185Her-2/neu oncoprotein. To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the Her-2/neu oncogene. Results Flow cytometric analyses demonstrated a dramatic (up to 46%) reduction of cell surface-associated p185Her-2/neu following treatment of the Her-2/neu-overexpressors BT-474 and SK-Br3 with OA. Indeed, this effect was comparable to that found following exposure to optimal concentrations of trastuzumab (up to 48% reduction with 20μg/ml trastuzumab). Remarkably, the concurrent exposure to OA and suboptimal concentrations of trastuzumab (5μg/ml) synergistically down-regulated Her-2/neu expression, as determined by flow cytometry (up to 70% reduction), immunoblotting, and immunofluorescence microscopy studies. The nature of the cytotoxic interaction between OA and trastuzumab revealed a strong synergism, as assessed by MTT-based cell viability and anchorage-independent soft-agar colony formation assays. Moreover, OA co-exposure synergistically enhanced trastuzumab efficacy towards Her-2/neu overexpressors by promoting DNA fragmentation associated with apoptotic cell death, as confirmed by TUNEL and caspase-3-dependent PARP cleavage. In addition, treatment with OA and trastuzumab dramatically increased both the expression and the nuclear accumulation of p27Kip1, a cyclin-dependent kinase inhibitor playing a key role in the onset and progression of Her-2/neu-related breast cancer. Finally, OA co-exposure significantly enhanced the ability of trastuzumab to inhibit signaling pathways downstream of Her-2/neu, including phosphoproteins such as AKT and MAPK. Conclusions These findings demonstrate that OA, the main Monounsaturated Fatty Acid of olive oil, suppresses Her-2/neu overexpression, which, in turn, interacts synergistically with anti-Her-2/neu immunotherapy by promoting apoptotic cell death of breast cancer cells with Her-2/neu oncogene amplification. This previously unrecognized property of OA offers a novel molecular mechanism by which individual Fatty Acids may regulate the malignant behavior of breast cancer cells and therefore be helpful in the design of future epidemiological studies and, eventually, dietary counseling.
Shinji Takada - One of the best experts on this subject based on the ideXlab platform.
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Monounsaturated Fatty Acid modification of wnt protein its role in wnt secretion
Developmental Cell, 2006Co-Authors: Ritsuko Takada, Yoshinori Satomi, Tomoko Kurata, Naoto Ueno, Shigemi Norioka, Hisato Kondoh, Toshifumi Takao, Shinji TakadaAbstract:The secretion and extracellular transport of Wnt protein are thought to be well-regulated processes. Wnt is known to be acylated with palmitic Acid at a conserved cysteine residue (Cys77 in murine Wnt-3a), and this residue appears to be required for the control of extracellular transport. Here, we show that murine Wnt-3a is also acylated at a conserved serine residue (Ser209). Of note, we demonstrated that this residue is modified with a Monounsaturated Fatty Acid, palmitoleic Acid. Wnt-3a defective in acylation at Ser209 is not secreted from cells in culture or in Xenopus embryos, but it is retained in the endoplasmic reticulum (ER). Furthermore, Porcupine, a protein with structural similarities to membrane-bound O-acyltransferases, is required for Ser209-dependent acylation, as well as for Wnt-3a transport from the ER for secretion. These results strongly suggest that Wnt protein requires a particular lipid modification for proper intracellular transport during the secretory process.
Kazunori Utsunomiya - One of the best experts on this subject based on the ideXlab platform.
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effects of low carbohydrate high Monounsaturated Fatty Acid liquid diets on diurnal glucose variability and insulin dose in type 2 diabetes patients on tube feeding who require insulin therapy
Diabetes Technology & Therapeutics, 2013Co-Authors: Yutaka Mori, Teruo Ohta, Junichi Yokoyama, Kazunori UtsunomiyaAbstract:Abstract Objective: A low-carbohydrate/high-Monounsaturated Fatty Acid liquid diet (LC/HMD) was investigated for its role in long-term glycemic control in tube-fed type 2 diabetes patients who require insulin therapy. Patients and Methods: The study included 10 type 2 diabetes patients requiring insulin therapy who were being tube-fed with a high-carbohydrate liquid diet (HCD). With stable glucose control maintained, these patients were monitored for glucose levels for 4 consecutive days by using continuous glucose monitoring (CGM). The patients were continued on HCD during the first 2 days and were switched to an LC/HMD during the final 2 days. The patients were then continued on the LC/HMD, and seven of the 10 patients were monitored for glucose levels for 2 consecutive days by using CGM after 3 months of feeding with the LC/HMD. Insulin regimens used included basal-bolus insulin in five of these seven patients and intermediate-acting insulin in two patients. Results: Based on CGM data, the indices for ...
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the effect of a low carbohydrate high Monounsaturated Fatty Acid liquid diet and an isoleucine containing liquid diet on 24 h glycemic variability in diabetes patients on tube feeding a comparison by continuous glucose monitoring
Diabetes Technology & Therapeutics, 2012Co-Authors: Yutaka Mori, Teruo Ohta, Junichi Yokoyama, Masatsugu Shiozaki, Kazunori UtsunomiyaAbstract:Abstract Objective: This study compare the effect of various liquid diets on 24-h glycemic variability in diabetes patients on tube feeding. Patients and Methods: The study included type 2 diabetes patients in whom percutaneous endoscopic gastrostomy had been performed for dysphagia as a sequela of cerebrovascular disease and who had been put on tube feeding with a standard high-carbohydrate liquid diet (HCD). Once stable glycemic control was achieved, these patients were continuously monitored for glucose levels for 5 days on continuous glucose monitoring. Of the 14 patients included, seven were given HCD on day 1, a low-carbohydrate/high-Monounsaturated Fatty Acid liquid diet (LCD) on Days 2 and 3, and a isoleucine-containing liquid diet (ICD), which is known to promote glycemic uptake by skeletal muscle, thus suppressing increases in glucose levels, on Days 4 and 5, with the remaining seven given the same diets but ICD given on Days 2 and 3 and LCD given on Days 4 and 5. All comparisons were made under...