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ABSTRACT: Increasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways, which regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport, and metabolism and is closely linked to systemic lipid metabolism. Cinnamon polyphenols have been shown to improve glucose, insulin, and lipid metabolism and improve inflammation in cell culture, animal, and human studies. However, little is known of the effects of an aqueous cinnamon extract (CE) on the regulation of genes and signaling pathways related to intestinal metabolism. The aim of the study was to investigate the effects of a CE on the primary enterocytes of chow-fed rats.
Freshly isolated intestinal enterocytes were used to investigate apolipoprotein-B48 secretion by immunoprecipitation; gene expressions by quantitative reverse transcriptase-polymerase chain reaction and the protein and phosphorylation levels were evaluated by western blot and flow cytometric analyses.
Ex vivo, the CE significantly decreased the amount of apolipoprotein-B48 secretion into the media, inhibited the mRNA expression of genes of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, and induced the expression of the anti-inflammatory gene, Zfp36. CE also increased the mRNA expression of genes leading to increased insulin sensitivity, including Ir, Irs1, Irs2, Pi3k, and Akt1, and decreased Pten expression. CE also inhibited genes associated with increased cholesterol, triacylglycerols, and apolipoprotein-B48 levels, including Abcg5, Npc1l1, Cd36, Mttp, and Srebp1c, and facilitated Abca1 expression. CE also stimulated the phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular-signal-regulated kinase expressions determined by flow cytometry, with no changes in protein levels.
These results demonstrate that the CE regulates genes associated with insulin sensitivity, inflammation, and cholesterol/lipogenesis metabolism and the activity of the mitogen-activated protein kinase signal pathway in intestinal lipoprotein metabolism.
Nutrition 08/2012; 28(11-12):1172-9. · 3.03 Impact Factor
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ABSTRACT: Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production.
At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats.
These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.
Atherosclerosis 04/2012; 222(2):409-16. · 3.79 Impact Factor
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ABSTRACT: Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-α and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3β. The protein and gene expression of adiponectin and Pparγ mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1β, Il6 and Tnfα were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation.
The British journal of nutrition 12/2011; 108(4):581-7. · 3.45 Impact Factor
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ABSTRACT: The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3β messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant.
Metabolism: clinical and experimental 05/2011; 60(11):1590-7. · 2.59 Impact Factor
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ABSTRACT: Epidemiological studies indicate that the consumption of green tea polyphenols (GTP) may reduce the risk of coronary artery disease. To explore the underlying mechanisms of action at the molecular level, we examined the effects of GTP on the cardiac mRNA and protein levels of genes involved in insulin and lipid metabolism and inflammation. In rats fed a high-fructose diet, supplementation with GTP (200 mg/kg BW daily dissolved in distilled water) for 6 wk, reduced systemic blood glucose, plasma insulin, retinol-binding protein 4, soluble CD36, cholesterol, triglycerides, free fatty acids and LDL-C levels, as well as the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and IL-6. GTP did not affect food intake, bodyweight and heart weight. In the myocardium, GTP also increased the insulin receptor (Ir), insulin receptor substrate 1 and 2 (Irs1 and Irs2), phosphoinositide-3-kinase (Pi3k), v-akt murine thymoma viral oncogene homolog 1 (Akt1), glucose transporter 1 and 4 (Glut1 and Glut4) and glycogen synthase 1 (Gys1) expression but inhibited phosphatase and tensin homolog deleted on chromosome ten (Pten) expression and decreased glycogen synthase kinase 3beta (Gsk3beta) mRNA expression. The sterol regulatory element-binding protein-1c (Srebp1c) mRNA, microsomal triglyceride transfer protein (Mttp) mRNA and protein, Cd36 mRNA and cluster of differentiation 36 protein levels were decreased and peroxisome proliferator-activated receptor (Ppar)gamma mRNA levels were increased. GTP also decreased the inflammatory factors: Tnf, Il1b and Il6 mRNA levels, and enhanced the anti-inflammatory protein, zinc-finger protein, protein and mRNA expression. In summary, consumption of GTP ameliorated the detrimental effects of high-fructose diet on insulin signaling, lipid metabolism and inflammation in the cardiac muscle of rats.
Molecular Nutrition & Food Research 05/2010; 54 Suppl 1:S14-23. · 4.30 Impact Factor
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ABSTRACT: Metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve all of these variables in in vitro, animal, and/or human studies. In addition, cinnamon has been shown to alleviate factors associated with Alzheimer's disease by blocking and reversing tau formation in vitro and in ischemic stroke by blocking cell swelling. In vitro studies also show that components of cinnamon control angiogenesis associated with the proliferation of cancer cells. Human studies involving control subjects and subjects with metabolic syndrome, type 2 diabetes mellitus, and polycystic ovary syndrome all show beneficial effects of whole cinnamon and/or aqueous extracts of cinnamon on glucose, insulin, insulin sensitivity, lipids, antioxidant status, blood pressure, lean body mass, and gastric emptying. However, not all studies have shown positive effects of cinnamon, and type and amount of cinnamon, as well as the type of subjects and drugs subjects are taking, are likely to affect the response to cinnamon. In summary, components of cinnamon may be important in the alleviation and prevention of the signs and symptoms of metabolic syndrome, type 2 diabetes, and cardiovascular and related diseases.
Journal of diabetes science and technology 05/2010; 4(3):685-93.
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ABSTRACT: The aim of this study was to determine whether systemic elevation of tumor necrosis factor (TNF)-alpha induces intestinal-derived apolipoprotein B (apoB)48-containing very low-density lipoprotein (VLDL) production in hamsters after fat loading and whether TNF-alpha disturbs the related mRNA expression in inflammatory, insulin and lipoprotein signaling pathways in primary enterocytes. In vivo TNF-alpha and Triton-WR1339 infusion, Western blotting and reverse transcriptase-polymerase chain reaction were combined to explore the mechanisms underlying intestinal overproduction of apoB48-containing chylomicrons and VLDL(1) particles by TNF-alpha. TNF-alpha infusion increased intestinal production of chylomicron and VLDL(1)-apoB48 in postprandial (fat load) states. Following TNF-alpha-treatment in enterocytes, there was enhanced gene expression of Il1alpha and beta, Il6 and Tnf and decreased mRNA levels of components of the insulin signaling pathway including the insulin receptor (Ir), Ir substrate-1 and 2, PI3 k, and Akt, but increased phosphatase and tensin homolog deleted on chromosome ten (Pten) protein and mRNA expression. TNF-alpha also induced Cd36 and peroxisome proliferators-activated receptor (Ppar)gamma expression, as well as microsomal triglyceride transfer protein (Mtp) protein and mRNA, but suppressed the sterol regulatory element binding protein (Srebp)1c protein and mRNA level. Systemic elevation of TNF-alpha stimulates the postprandial overproduction of apoB48-containing chylomicrons and VLDL(1) particles by disturbing intestinal gene expression of the inflammatory, insulin and lipoprotein pathways. These findings provide mechanistic links among the inflammatory factor, TNF-alpha, intestinal inflammatory/insulin insensitivity and the overproduction of intestinal apoB48-containing lipoproteins.
Experimental Biology and Medicine 02/2010; 235(2):199-205. · 2.64 Impact Factor
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ABSTRACT: We have reported previously that a cinnamon extract (CE), high in type A polyphenols, prevents fructose feeding-induced decreases in insulin sensitivity and suggested that improvements of insulin sensitivity by CE were attributable, in part, to enhanced insulin signaling. In this study, we examined the effects of CE on postprandial apolipoprotein (apo) B-48 increase in fructose-fed rats, and the secretion of apoB48 in freshly isolated intestinal enterocytes of fructose-fed hamsters. In an olive oil loading study, a water-soluble CE (Cinnulin PF, 50 mg/kg body weight, orally) decreased serum triglyceride (TG) levels and the over production of total- and TG-rich lipoprotein-apoB48. In ex vivo (35)S labeling study, significant decreases were also observed in apoB48 secretion into the media in enterocytes isolated from fructose-fed hamsters. We also investigated the molecular mechanisms of the effects of CE on the expression of genes of the insulin signaling pathway [insulin receptor (IR), IR substrate (IRS)1, IRS2 and Akt1], and lipoprotein metabolism [microsomal TG transfer protein (MTP), sterol regulatory element-binding protein (SREBP1c) in isolated primary enterocytes of fructose-fed hamsters, using quantitative real-time polymerase chain reaction. The CE reversed the expression of the impaired IR, IRS1, IRS2 and Akt1 mRNA levels and inhibited the overexpression of MTP and SREBP1c mRNA levels of enterocytes. Taken together, our data suggest that the postprandial hypertriglycerides and the overproduction of apoB48 can be acutely inhibited by a CE by a mechanism involving improvements of insulin sensitivity of intestinal enterocytes and regulation of MTP and SREBP1c levels. We present both in vivo and ex vivo evidence that a CE improves the postprandial overproduction of intestinal apoB48-containing lipoproteins by ameliorating intestinal insulin resistance and may be beneficial in the control of lipid metabolism.
The Journal of nutritional biochemistry 12/2008; 20(11):901-8. · 4.29 Impact Factor
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ABSTRACT: Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-alpha and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-alpha can directly stimulate the hepatic assembly and secretion of apolipoprotein B (apoB) 100-containing VLDL(1), using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF-alpha infusion for 4 h in chow-fed hamsters induced whole-body insulin resistance on the basis of euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF-alpha-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-beta, IR substrate-1 (Tyr), Akt (Ser(473)), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser(307)) and Shc. TNF-alpha infusion also significantly increased hepatic production of total circulating apoB100 and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF-alpha-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-alpha decreased the sterol regulatory element-binding protein-1c mass and mRNA levels but significantly increased microsomal triglyceride transfer protein mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF-alpha induces whole-body insulin resistance and impairs hepatic insulin signaling accompanied by overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.
AJP Gastrointestinal and Liver Physiology 06/2008; 294(5):G1120-9. · 3.43 Impact Factor
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ABSTRACT: It is well known that exercise training, including voluntary running (VR), improves insulin resistance. However, the effect of VR on insulin resistance induced by high salt intake is unclear. The aim of this study was to determine whether VR would improve the glucose utilization in normal male Sprague-Dawley rats fed a high-salt diet (HSD) on 2-week early prevention and 1-week midway intervention protocols. In vivo glucose utilization was measured by euglycemic clamp technique. Further analyses of the possible changes in insulin signaling occurring in skeletal muscle were performed by Western blot and reverse transcription polymerase chain reaction (RT-PCR). The glucose infusion rates (GIRs) after 2 weeks of HSD feeding were decreased (HSD vs. control: 21.5 +/- 0.8 vs. 27 +/- 0.5 mg/kg body wt/min; P < 0.05), and improved by 2 weeks VR to 30.5 +/- 1.5 mg/kg body wt/min. Additionally, the GIRs after 3 weeks of HSD feeding were decreased (HSD vs. control: 20.0 +/- 0.3 vs. 26.5 +/- 0.6 mg/kg body wt/min; P < 0.05), and they also improved by the third week of VR (28.5 +/- 0.7 mg/ kg body wt/min vs. sedentary; P < 0.01). There were no differences in skeletal muscle for the total mass of insulin receptor-beta (IR-beta), IR substrate-1 (IRS-1), Akt, and glucose transporter 4 (GLUT4) in any of the groups of 2 weeks of HSD loading control and VR. VR did not regulate the enhanced tyrosine phosphorylation of IR-beta and IRS-1 by 2 weeks of HSD feeding. However, the enhanced serine phosphorylation of Akt and the tyrosine phosphorylation of GLUT4 were significantly inhibited by the early VR. HSD also impaired GLUT4 content in the plasma membrane and mRNA expression, but the decreases were improved by 2 weeks of VR. These results suggest that early voluntary exercise would prevent the development of insulin resistance induced by an HSD due in part by enhancing the impaired GLUT4 translocation and mRNA expression in skeletal muscle.
Experimental Biology and Medicine 11/2007; 232(10):1330-7. · 2.64 Impact Factor
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ABSTRACT: There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-alpha infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-alpha-treated hamsters indicated impaired phosphorylation of insulin receptor-beta, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH(2)-terminal kinase. TNF-alpha infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-alpha on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-alpha-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-alpha increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-alpha receptor types (p55 and p75), and antibodies against either of the two TNF-alpha receptors partially blocked the stimulatory effect of TNF-alpha on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-alpha infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-alpha-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-alpha receptors and the p38 mitogen-activated protein kinase pathway.
Diabetes 03/2007; 56(2):450-61. · 8.29 Impact Factor
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ABSTRACT: The activity of the pyruvate dehydrogenase complex (PDC) is regulated by covalent modification of its E1 component, which is catalyzed by specific pyruvate dehydrogenase kinases (PDKs) and phosphatases. In the liver, PDK2 and PDK4 are the most abundant PDK isoforms, which are responsible for inactivation of PDC when glucose availability is scarce in the body. In the present study, regulatory mechanisms of hepatic PDC were examined before and after the onset of type 2 diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using Long-Evans Tokushima Otsuka (LETO) rats as controls. Plasma glucose and insulin concentrations were at normal levels in rats aged 8 weeks, but were significantly higher in OLETF than in LETO rats aged 25 weeks, indicating insulin resistance in OLETF rats. Plasma free fatty acids (FFAs) were 1.6-fold concentrated, and the liver PDC activity was significantly lower in OLETF than in LETO rats at both ages, suggesting suppression of pyruvate oxidative decarboxylation in OLETF rats before and after the onset of diabetes. Pyruvate dehydrogenase kinase activity and abundance of PDK2 and PDK4 proteins, as well as mRNAs, were greater in OLETF rats at both ages. These results suggest that persistently elevated levels of circulating free fatty acid in normal and diabetic OLETF rats play an important role in stimulating PDK2 and PDK4 expression in liver.
Metabolism 04/2006; 55(3):317-23. · 2.66 Impact Factor
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ABSTRACT: Previous studies have shown that the traditional herbal complex Gosha-jinki-gan (GJG) improves diabetic neuropathy and insulin resistance. The present study was undertaken to elucidate the molecular mechanisms related with the long-term effects of GJG administration on insulin action in vivo and the early steps of insulin signaling in skeletal muscle in streptozotocin (STZ) diabetes. Rats were randomized into five subgroups: (1) saline treated control, (2) GJG treated control, (3) 2-unit insulin + saline treated diabetic, (4) saline + GJG treated diabetic and (5) 2-unit insulin + GJG treated diabetic groups. After seven days of treatment, euglycemic clamp experiment at an insulin infusion rate of 6 mU/kg/min was performed in overnight fasted rats. Despite the 2-unit insulin treatment, the metabolic clearance rates of glucose (MCR, ml/kg/min) in diabetic rats were significantly lower compared with the controls (11.4 +/- 1.0 vs 44.1 +/- 1.5; P < 0.001), and were significantly improved by insulin combined with GJG or GJG alone (26 +/- 3.2 and 24.6 +/- 2.2, P < 0.01, respectively). The increased insulin receptor (IR)-beta protein content in skeletal muscle of diabetic rats was not affected by insulin combined with GJG administration. However, the decreased insulin receptor substrate-1 (IRS-1) protein content was significantly improved by treatment with GJG. Additionally, the increased tyrosine phosphorylation levels of IR-beta and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. The present results suggest that the improvement of the impaired insulin sensitivity in STZ-diabetic rats by administration of GJG may be due, at least in part, to correction in the abnormal early steps of insulin signaling in skeletal muscle.
Evidence-based Complementary and Alternative Medicine 12/2004; 1(3):269-276. · 4.77 Impact Factor
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ABSTRACT: Cinnamon has been shown to potentiate the insulin effect through upregulation of the glucose uptake in cultured adipocytes. In the present study, we evaluated the effect of the cinnamon extract on the insulin action in awaked rats by the euglycemic clamp and further analyzed possible changes in insulin signaling occurred in skeletal muscle. The rats were divided into saline and cinnamon extract (30 and 300 mg/kg BW-doses: C30 and C300) oral administration groups. After 3-weeks, cinnamon extract treated rats showed a significantly higher glucose infusion rate (GIR) at 3 mU/kg per min insulin infusions compared with controls (118 and 146% of controls for C30 and C300, respectively). At 30 mU/kg per min insulin infusions, the GIR in C300 rats was increased 17% over controls. There were no significant differences in insulin receptor (IR)-beta, IR substrate (IRS)-1, and phosphatidylinositol (PI) 3-kinase protein content between C300 rats and controls. However, the skeletal muscle insulin-stimulated IR-beta and the IRS-1 tyrosine phosphorylation levels in C300 rats were 18 and 33% higher, respectively, added to 41% higher IRS-1/PI 3-kinase association. These results suggest that the cinnamon extract would improve insulin action via increasing glucose uptake in vivo, at least in part through enhancing the insulin-signaling pathway in skeletal muscle.
Diabetes Research and Clinical Practice 01/2004; 62(3):139-48. · 2.75 Impact Factor
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ABSTRACT: This study investigated the effects of the traditional herbal medicine, Keishi-ka-jutsubu-to (KJT) on insulin action in vivo and insulin signaling in skeletal muscle in STZ-induced diabetes. Rats were divided into single and 7-days oral administration groups. Euglycemic clamp (insulin infusion rates: 3 and 30 mU/kg/min) was used in awaked rats and the insulin signaling in skeletal muscle was evaluated. At low-dose insulin infusion, the decreased metabolic clearance rates of glucose (MCR) in diabetic rats were improved by a single and 7-days administration of KJT (800 mg/kg BW, p.o.; acute effect: 6.7 +/- 0.6 vs. 12.3 +/- 1.2, and 7-days effect: 6.3 +/- 0.5 vs. 13.9 +/- 1.0 ml/kg/min, P<0.001, respectively). During high-dose insulin infusion, the MCR was increased in 7-days KJT treated diabetes compared with saline diabetes, but, these changes were not observed after a single KJT treatment. About 90% of the increasing effect in MCR induced by the 7-days KJT treatment was blocked by L-NMMA. However, no further additive effects were seen in KJT + SNP treatment. IRbeta protein increase and decreased IRS-1 protein expression in diabetes were significantly improved by KJT treatment. KJT had no effect on the GLUT4 protein content. The increased tyrosine phosphorylation level of IRbeta, IRS-1, and IRS-1 associated with PI 3-kinase were significantly inhibited in KJT treated diabetes. The present study suggests that the improvement of impaired insulin action in STZ-diabetes by administration of KJT may be due, at least in part, to enhanced insulin signaling, which may be involved with production of nitric oxide (NO).
Life Sciences 11/2003; 73(21):2687-701. · 2.53 Impact Factor
