Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although ...there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that, there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.
Obesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the ...essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines. In this review, multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance. The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand, which we have named "mitochondrial overheating." Overheating occurs because of substrate oversupply to mitochondria, leading to extra ATP production. The ATP overproduction contributes to the systemic insulin resistance through several mechanisms, such as inhibition of AMPK, induction of mTOR, hyperinsulinemia, hyperglucagonemia, and mitochondrial dysfunction. Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates. Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading. The downregulation of the mitochondrial overloading by medicines, bypass surgeries, calorie restriction, and physical exercise leads to insulin sensitization in patients. Therefore, ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply. The prevention of ATP overproduction represents a key strategy for insulin sensitization.
Inflammation regulates energy metabolism in both physiological and pathological conditions. Pro-inflammatory cytokines involves in energy regulation in several conditions, such as obesity, aging ...(calorie restriction), sports (exercise), and cancer (cachexia). Here, we introduce a view of integrative physiology to understand pro-inflammatory cytokines in the control of energy expenditure. In obesity, chronic inflammation is derived from energy surplus that induces adipose tissue expansion and adipose tissue hypoxia. In addition to the detrimental effect on insulin sensitivity, pro-inflammatory cytokines also stimulate energy expenditure and facilitate adipose tissue remodeling. In caloric restriction (CR), inflammatory status is decreased by low energy intake that results in less energy supply to immnue cells to favor energy saving under caloric restriction. During physical exercise, inflammatory status is elevated due to muscle production of pro-inflammatory cytokines, which promote fatty acid mobilization from adipose tissue to meet the muscle energy demand. In cancer cachexia, chronic inflammation is elevated by the immune response in the fight against cancer. The energy expenditure from chronic inflammation contributes to weight loss. Immune tolerant cancer cells gains more nutrients during the inflammation. In these conditions, inflammation coordinates energy distribution and energy demand between tissues. If the body lacks response to the pro-inflammatory cytokines (Inflammation Resistance), the energy metabolism will be impaired leading to an increased risk for obesity. In contrast, super-induction of the inflammation activity leads to weight loss and malnutrition in cancer cachexia. In summary, inflammation is a critical component in the maintenance of energy balance in the body. Literature is reviewed in above fields to support this view.
Abstract Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 ...diabetes mellitus patients. In study A, 36 adults with newly diagnosed type 2 diabetes mellitus were randomly assigned to treatment with berberine or metformin (0.5 g 3 times a day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (from 9.5% ± 0.5% to 7.5% ± 0.4%, P < .01), fasting blood glucose (from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L, P < .01), postprandial blood glucose (from 19.8 ± 1.7 to 11.1 ± 0.9 mmol/L, P < .01), and plasma triglycerides (from 1.13 ± 0.13 to 0.89 ± 0.03 mmol/L, P < .05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes mellitus were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering fasting blood glucose and postprandial blood glucose from 1 week to the end of the trial. Hemoglobin A1c decreased from 8.1% ± 0.2% to 7.3% ± 0.3% ( P < .001). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were reduced by 28.1% and 44.7% ( P < .001), respectively. Total cholesterol and low-density lipoprotein cholesterol were decreased significantly as well. During the trial, 20 (34.5%) patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.
Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms ...involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
c-JUN is a major component of heterodimer transcription factor AP-1 (Activator Protein-1) that activates gene transcription in cell proliferation, inflammation and stress responses. SIRT1 (Sirtuin 1) ...is a histone deacetylase that controls gene transcription through modification of chromatin structure. However, it is not clear if SIRT1 regulates c-JUN activity in the control of gene transcription. Here, we show that SIRT1 associated with c-JUN in co-immunoprecipitation of whole cell lysate, and inhibited the transcriptional activity of c-JUN in the mammalian two hybridization system. SIRT1 was found in the AP-1 response element in the matrix metalloproteinase-9 (MMP9) promoter DNA leading to inhibition of histone 3 acetylation as shown in a ChIP assay. The SIRT1 signal was reduced by the AP-1 activator PMA, and induced by the SIRT1 activator Resveratrol in the promoter DNA. SIRT1-mediaetd inhibition of AP-1 was demonstrated in the MMP9 gene expression at the gene promoter, mRNA and protein levels. In mouse embryonic fibroblast (MEF) with SIRT1 deficiency (SIRT1
−/−), mRNA and protein of MMP9 were increased in the basal condition, and the inhibitory activity of Resveratrol was significantly attenuated. Glucose-induced MMP9 expression was also inhibited by SIRT1 in response to Resveratrol. These data consistently suggest that SIRT1 directly inhibits the transcriptional activity of AP-1 by targeting c-JUN.
For the first time CoS-nanoparticles attached ZnS rods (CoS/ZnS composites) have been synthesized using cobalt(II)-ion-exchanged zinc-based biological metal-organic framework-1 (Zn-bio-MOF-1) as ...precursors by a solvothermal method. Among them, the cobalt(II)-ion-exchanged Zn-bio-MOF-1 was obtained by exchanging the dimethylammonium cations (Me
2
NH
2
+
) of Zn-bio-MOF-1 with cobalt ions. A novel electrochemical sensor based on CoS/ZnS composites and molecularly imprinted polymers (MIPs) was proposed for rapid, sensitive, and highly selective detection of organochlorine pesticide chloroneb. The MIP film was obtained by cyclic voltammetry (CV), and differential pulse voltammetry (DPV) was used to detect chloroneb. Under the optimal conditions, the oxidation peak current density of chloroneb was linearly related to the concentration from 0.003 to 0.2 μM and 0.2 to 3.2 μM with a detection limit of 0.87 nM (S/
N
= 3) and a sensitivity of 52.27 μA·μM
−1
·cm
−2
. The proposed sensor exhibits a favorable selectivity, stability, and reproducibility, and was applied to detect chloroneb residues in licorice, cucumber, river water, and soil samples with satisfactory results.
Graphical abstract
Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium ...butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator-activated receptor-α function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.
1 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana; 2 Shanghai Institute of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong ...University Medical School, Shanghai, China; and 3 Medicinal Plant Research Laboratory, School of Renewable Natural Resources, Louisiana State University Agricultural Center, Baton Rouge, Louisiana
Submitted 5 April 2007
; accepted in final form 19 October 2007
Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C 2 C 12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3- O -methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser 307/312 ), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for 16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.
type 2 diabetes; insulin sensitivity; oxygen consumption; mitochondrial function; adenosine 5'-monophosphate-activated protein kinase
Address for reprint requests and other correspondence: J. Ye, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808 (e-mail: yej{at}pbrc.edu )
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