Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD + fNJ. HepG2 cells demonstrated more than 80% inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice.
The use of complementary and alternative medicine (CAM) including herbal products, for health maintenance and treatment of chronic diseases is continuously rising in the United States. Although considered safe due to their "natural" origin, herbal products are prone to herb‐drug interactions. Cytochrome (CYP) P450 enzymes are responsible for metabolizing xenobiotics including herbal products. The aim of our study was to investigate the effects of Morinda citrifolia (noni), Euterpe oleracea (açai), Lycium barbarum (goji) and Garcinia mangostana (mangosteen) on CYP1A2 and CYP3A4 activity using human cDNA‐expressed P450 enzymes and human hepatocytes. Açai and mangosteen significantly inhibited cDNA‐expressed CYP‐1A2 and ‐3A4 activities with IC50 values between 0.341% and 1.387% (v/v). In HepG2 cells, CYP‐1A2 and ‐3A4 activities were significantly inhibited after a four hour treatment with all juices, suggestive of direct effects on P450 protein. In contrast, CYP1A2 activity was maximally induced after a 10 h treatment, while CYP3A4 activity was inhibited after a 24 h treatment, suggesting effects at gene expression level. In primary human hepatocytes, CYP‐1A2 and ‐3A4 activities were maximally inhibited by açai and mangosteen. Our results indicate possible drug interactions with noni, açai, goji and mangosteen. USDA‐CREES (2004‐34135‐15182), NIH/NCMHD (P20MD000173‐06).
Lipotoxicity, or accumulation of lipids in non adipose tissue, has been implicated in the pathogenesis of obesity‐associated insulin resistance. Lipotoxicity‐associated mitochondrial and/or ER stress are key events leading to defects in insulin signaling and glucose transport. Morinda citrifolia (noni), has been traditionally used to treat diabetes, infections and cancer. Preliminary studies from our laboratory indicate that noni juice improves high fat diet‐induced plasma fatty acid (FA) levels and insulin resistance in mice. We therefore tested the hypothesis that noni juice will alleviate FA‐mediated inhibition of glucose transport and toxicity in skeletal muscle. In brief, mouse muscle cells, C2C12, were treated with palmitic acid (PA) and noni juice at varying concentrations and analyzed for cell proliferation, free fatty acid and glucose uptake, production of reactive oxygen species (ROS) and cell death. Our results indicate that noni inhibits PA‐induced lipotoxicity by inhibiting ROS production and mitochondrial damage. Such studies are significant as they have potential as prevention strategies, and use as nutraceuticals to promote optimal health. [This work was supported by USDA CSREES (2004‐34135‐15182) and RCMI Program, NIH/ NCRR (G12 RR003061)].
Momordica charantia (bitter melon, BM) is traditionally used to treat diabetes and its complications. However, the safety and interaction of BM with other therapeutic drugs is unknown. The cytochrome (CYP) P450 enzymes metabolize variety of xenobiotics. Since BM modulates CYP in diabetic rats, we hypothesized that BM will also differentially modulate human P450 enzymes. Our aim was to investigate the effects of BM on CYP1A2 and CYP3A4, using cDNA‐expressed human CYP450, human hepatoma cells, HepG2 and primary human hepatocytes. BMJ had no effect on cDNA‐expressed human CYP1A2 but significantly inhibited CYP3A4 activity, up to 85%. BMJ was non‐toxic to both, HepG2 and primary human hepatocytes as measured by cellular ATP levels and had no effect on CYP1A2 induction in HepG2 cells, for up to 72 h, but significantly inhibited the 3‐methylcholanthrene induced CYP1A2 activity by 48%. BMJ exhibited a dose‐ and time‐dependent inhibition of CYP3A4 activity by 64%. BMJ for 4 h demonstrated a significant reduction of CYP1A2 activity by 30% and CYP3A4 by 20% respectively in primary human hepatocytes. CYP3A4 is an important drug metabolizer for majority of clinically relevant therapeutic drugs. Identifying the BMJ‐associated modulation of P450 is important to determine its safety for future clinical trials and to minimize drug‐drug interactions. [NCCAM (R21AT003719) and NCMHD (P20MD000173), NIH].
Renewed interest in traditional medicine prompted us to investigate anti‐diabetic effects of Hawaiian medicinal plant, Morinda Citrifolia (noni) in mice fed high‐fat‐diet (HFD). Preliminary studies indicate that noni juice (NJ) improved glucose metabolism in mice fed HFD. Glucose production is increased in diabetes due to the inability of insulin to suppress gluconeogenesis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Since recent studies indicate that NJ synergistically augment insulin action in diabetic rats, we tested the hypothesis that NJ improves glucose metabolism by modulating gluconeogenesis via FoxO1 phosphorylation. In our studies hypoglycemic properties of NJ were associated with inhibition of hepatic FoxO1 mRNA expression and protein levels with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose‐6‐phosphatase (G6P) were also significantly inhibited in mice fed HFD with NJ. Specificity of NJ‐associated FoxO1 regulation of gluconeogenesis was confirmed by siRNA studies using human hepatoma cells, HepG2. Our data suggests that NJ can offer an economical alternative, specifically for culturally sensitive diabetic individuals or those who cannot afford conventional medicine. [USDA‐CREES, 2004‐34135‐15182; NCCAM, R21AT003719].
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