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Hepatic inflammation and insulin resistance in pre-diabetes - further evidence for the beneficial actions of PPAR-gamma agonists and a role for SOCS-3 modulation
British Journal of Pharmacology
Abstract
Pre‐diabetes is a condition affecting increasing numbers of the population who find themselves caught in the grey area between normal glucose regulation and diabetes mellitus and who experience impaired glucose tolerance or fasting glucose. The ability of thiozolidinediones (TZDs) to ameliorate the clinical signs of diabetes mellitus is well‐known but there is also emerging evidence for the benefits of PPAR‐γ agonists in pre‐diabetes. In this issue of the British Journal of Pharmacology , Collino and colleagues report that pioglitazone can reduce hepatic inflammation and insulin resistance in rats administered a high cholesterol and fructose diet. Furthermore, pioglitazone reduced the expression of suppressor of cytokine signalling (SOCS)‐3 – considered to be a key link between inflammation and insulin resistance. Although much work remains to be performed in fully understanding how TZDs modulate the cellular mechanisms which underlie pre‐diabetes, these findings provide preliminary evidence that administration of TZDs to pre‐diabetics could be beneficial.
This article is a commentary on Collino et al. , pp. 1892–1902 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00671.x
... Moreover, the downstream signals of MD2/TLR4 appear to be modulated through cross-talk with PPARc (peroxisome proliferatoractivated receptor gamma), a member of the nuclear receptor superfamily which can be activated by a variety of ligands, for example eicosanoids and fatty acids [23]. Several reports indicate that PPARc agonists are protective against NAFLD/NASH by reducing inflammation, possibly through inhibiting production of inflammatory cytokines [24][25][26][27][28][29]. MEKs, the activator of MAPKs (a key signalling target of MD2/TLR4), is reported to directly interact with PPARc, resulting in down-regulation of PPARc through nuclear export [30], suggesting an intriguing mechanism of promoting pro-inflammatory activity through suppressing PPARc's anti-inflammatory activity. ...
... Evidence implicates PPARc in contributing to the pathogenesis of NAFLD [23][24][25][26]. We next explored whether PPARc's involvement was associated with the MD2/TLR4 signalling pathway. ...
... Several lines of evidence indicate that PPARc has anti-inflammatory properties [27,28,30,36,37] and moreover could limit the inflammatory injury in NALD-NASH [25,26]. The anti-inflammatory action of PPARc has been linked to its ability to decrease expression of pro-inflammatory molecules [29,36]. ...
Non-alcoholic fatty liver disease (NAFLD) can progress to the more serious non-alcoholic steatohepatitis (NASH), characterized by inflammatory injury and fibrosis. The pathogenic basis of NAFLD progressing to NASH is currently unknown, but growing evidence suggests MD2 (myeloid differentiation factor 2), an accessory protein of TLR4, is an important signalling component contributing to this disease. We evaluated the effectiveness of the specific MD2 inhibitor, L6H21, in reducing inflammatory liver injury in a relevant high-fat diet (HFD) mouse model of NASH and in the palmitic acid (PA)-stimulated human liver cell line (HepG2). For study, genetic knockout (MD2−/−) mice were fed a HFD or control diet for 24 weeks, or wild-type mice placed on a similar diet regimen and treated with L6H21 for the last 8 or 16 weeks. Results indicated that MD2 inhibition with L6H21 was as effective as MD2 knockout in preventing the HFD-induced hepatic lipid accumulation, pro-fibrotic changes and expression of pro-inflammatory molecules. Direct challenge of HepG2 with PA (200 μM) increased MD2-TLR4 complex formation and expression of pro-inflammatory and pro-fibrotic genes and L6H21 pre-treatment prevented these PA-induced responses. Interestingly, MD2 knockout or L6H21 increased expression of the anti-inflammatory molecule, PPARγ, in liver tissue and the liver cell line. Our results provide further evidence for the critical role of MD2 in the development of NASH and conclude that MD2 could be a potential therapeutic target for NAFLD/NASH treatment. Moreover, the small molecule MD2 inhibitor, L6H21, was an effective and selective investigative agent for future mechanistic studies of MD2.
... Regarding insulin resistance (IR), this parameter reportedly decreases when employing some OHDs (e.g., thiazolidinediones), either as the primary treatment or a co-adjuvant for controlling T2DM and its possible associated complications [32,33]. Various studies on BROMO have described its capacity, alone or combined with ME, to improve sensitivity to insulin [13,20,34]. ...
... A certain association has been established between the disruption of the circadian rhythm of T2DM patients [35][36][37] and an increase in IR [38,40], which coincides with the demonstrated ability of BROMO to normalize the circadian cycle [41,42] and reduce IR [33,43]. Further research is needed on the application of BROMO therapy to better understand its mechanisms and effects. ...
Background and aims: Bromocriptine is a dopaminergic (D2) agonist that has shown hypoglycemic and normotensive activity in preclinical and clinical studies. The main objective of this study was to investigate the effect of bromocriptine plus metformin on glycaemia and blood pressure in patients with type 2 diabetes mellitus (T2DM).
Material and methods: An open-label randomised controlled trial was conducted for three months. It involved two groups (n=10), each containing 2 women and 8 men with an average age of 50 years. One group was given monotherapy (MT) with metformin (850 mg every 12 h) and the other combined therapy (CT) with the same dose of metformin plus an increasing dose of bromocriptine (from 1.25 mg per day to 2.5 mg per day). The parameters monitored were glycaemia, glycated hemoglobin (HbA1c), serum creatinine, blood pressure, and the body mass index.
Results: CT was able to significantly decrease the level of glycaemia, HbA1c and diastolic blood pressure, whereas MT had no effect on any of the measured variables.
Conclusions: The ability of CT with bromocriptine and metformin to control glycaemia and produce a normotensive effect reaffirms its advantages for controlling T2DM. Further research is needed to improve this therapeutic strategy.
... Experiments with cultured cells overexpression of either SOCS1 or SOCS3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3-L1 adipocytes [61]. By contrast, a reduction of SOCS1 or SOCS3 by knockout or antisense treatment partially restores TNFa-induced downregulation of tyrosine phosphorylation of IRS proteins in primary hepatocytes and 3T3-L1 adipocytes [61,64]. Liver-specific deletion of SOCS3 improves insulin sensitivity under normal chow diet, but increases lipogenesis and SREBP1 expression in the liver, leading to fatty liver disease, inflammation, and obesity [64]. ...
... By contrast, a reduction of SOCS1 or SOCS3 by knockout or antisense treatment partially restores TNFa-induced downregulation of tyrosine phosphorylation of IRS proteins in primary hepatocytes and 3T3-L1 adipocytes [61,64]. Liver-specific deletion of SOCS3 improves insulin sensitivity under normal chow diet, but increases lipogenesis and SREBP1 expression in the liver, leading to fatty liver disease, inflammation, and obesity [64]. SOCS proteins act as negative regulators in insulin signaling and serve as one of the key linkers between chronic inflammation and insulin resistance. ...
Insulin resistance and dysregulated lipid metabolism are major causes of type 2 diabetes. Insulin and inflammatory signal pathways play key roles in insulin resistance and fat accumulation. Specifically, adapter proteins transduce signals from insulin or cytokine receptors to the downstream pathways and may contribute to insulin resistance and disordered lipid metabolism in obesity and type 2 diabetes. Here, the recent advances in understanding the roles of adapter proteins in insulin resistance and lipid homeostasis are discussed.
... Correlation between HOMA-IR and LH/FSH ratio: Apre-treatment with metformin, or its combination with losartan, valsartan or telmisartan. B-The correlation post-treatment 78 3.30 ...
... PPARs are targets for some clinically used drugs like fibrates that used for treatment of hyper triglyceridemia and act especially on PPAR-alpha type [73][74][75]. Thiazolidinediones are other group of compounds that act on those receptors, but especially on gamma type which affect glucose and lipid metabolism [76][77][78]. Additionally, there are some experimental compounds that used to activate delta type, which were found predominantly in the heart, and could be with benefit and promising effectiveness in congestive heart failure [79]. ...
Background and Objective: PPARγ agonists are used in type 2 diabetic patients to reduce insulin resistance. Recently, many AT1 receptor antagonists (ARBs) were reported to function as a partial agonist of PPARγ based on in vitro experiments. The aim of the present study was to investigate the effects adjuvant use of
ARBs (losartan, telmisartan or valsartan) with metformin on metabolic, hormonal status and clinical outcome in women with polycystic ovary syndrome (PCOS). Patients Methods: Using multi-centers, single-blinded clinical trial, we compared the effects of losartan, telmisartan or valsartan, when adjunctly used with metformin, on insulin sensitivity, body mass index, glycemic control and insulin resistans, serum levels of various hormones (FSH, LH and testosterone), in addition to the clinical outcome assessed by ultrasonography. In total, 74 Iraqi females with PCOS, who intended A-Elwiya and Al-Samarraee Maternity Teaching Hospitals, were enrolled in the study and allocated into 4 treatment groups and treated as follow; metformin only (1000mg/day) and metformin with losartan (25mg), telmisartan (40mg) or valsartan (40mg) groups. Results: All ARBs significantly reduced BMI, FBG and C-peptide values compared to metformin only treated group; they also showed significantly greater effects in increasing plasma levels of FSH and decreasing both LH and testosterone levels compared to metformin only. Moreover, they produce
significant improvement in the ultrasonograph pictures indicating increase
in ovulation. The rank for the effects of the used ARBs in this respect was:
telmisartan>losartan>valsartan after 4 months of treatment. This improvement in the metabolic and hormonal picture was associated with significant rate of improvement in ovulation which revealed clearly in the ultrasonographs. Conclusion: Adjuvant use of ARBs with metformin improves its effect in treatment of
women with PCOS, with most pronounced effect for telmisartan in this respect.
... This causes the expression of 4-1BBL and activates its receptor signaling, which in turn causes insulin resistance (Kim et al. 2011;Bodogai et al. 2018). Furthermore, butyrate could activate PPAR-γ and upregulate the expression of GLUT-4 (an insulin-dependent glucose transporter protein) in adipose tissue and transverse muscle, which promotes the uptake of fatty acid and increases insulin sensitivity (Chatterjee 2010;Mattace Raso et al. 2013). Thus, a decrease in the level of butyrate leads to decreased insulin sensitivity. ...
Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.
... Recent studies have investigated the role of infiltration and activation of inflammatory immune cells in hepatic insulin resistance 7,28,29 . Immune cells, including CD4 + and CD8 + T cells, iNKT cells, B cells, neutrophils, and macrophages, release inflammatory cytokines and chemokines. ...
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease, and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7−/− mice than in the wild type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7−/− mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7−/− mice. Moreover, liver inflammation was detected in obese CCR7−/− mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d−/− or interleukin-10-deficient (IL-10−/−) mice. Overall, these results suggest that CCR7⁺ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells.
... Hyperglycemia is primarily caused by the failure of pancreatic β cells to sufficiently secrete insulin and compensate for the insulin resistance of tissues. This results in reduced glucose absorption and increased lipidolysis (17). Hyperglycemia may also be the result of excessive glucagon secretion by pancreatic α cells, which leads to an increase in gluconeogenesis. ...
In the present study, a novel antagonist of the peroxisome proliferator-activated receptor-γ (PPARγ) was screened and identified, and a cell-based evaluation of the biological activity of this PPARγ antagonist was conducted. The aim of the study was to produce results that may provide a foundation for the development of a novel compound in the treatment of type 2 diabetes mellitus. Since obesity is the main cause of insulin resistance and type 2 diabetes, identifying a new reagent that is able to inhibit adipocyte differentiation and lipid accumulation is a feasible method of developing novel anti-diabetes drugs. The PPARγ antagonist was screened using a mammalian one-hybrid system and transcriptional activation. The effects of the compound on adipocyte differentiation were investigated by staining the preadipocytes with Oil Red O. In addition, the effects of the compound on the expression levels of genes associated with lipid metabolism were detected using quantitative polymerase chain reaction on differentiated mature 3T3-L1 adipocytes. As a PPARγ antagonist, N-((1H-benzo[d]imidazol-2-yl)methyl) aniline (Compound Q) was shown to depress the transcriptional activity and coactivator recruitment of PPARγ, as well as preadipocyte differentiation, in a concentration-dependent manner. The compound was also shown to decrease the expression levels of genes associated with PPARγ-regulated lipid metabolism. In conclusion, the compound screening platform was demonstrated to be valid, and the present study identified a novel PPARγ antagonist that was shown to effectively reduce the rate of adipocyte differentiation and the expression of genes associated with lipid metabolism.
... Rosi belongs to the thiazolidinedione class of drugs, which are ligands for the nuclear hormone receptor peroxisome proliferation-activated receptor-g (PPAR-g), and have been shown to attenuate inflammation in experimental injury models (Park et al., 2003;Cuzzocrea et al., 2004;Hasegawa-Moriyama et al., 2012). Mechanistically, Rosi action on macrophages enhances tissue repair by decreasing tumor necrosis factor (TNF)-a and inducible nitric oxide synthase (iNOS) via induction of suppressor of cytokine signaling (SOCS3), a negative regulator of signal transducer and activator of transcription 3 (STAT3)dependent cytokine signaling (Jiang et al., 1998;Cuzzocrea et al., 2004;Odegaard et al., 2007;Sener et al., 2007;Chatterjee, 2010). SOCS3 expression is regulated by IL-6, a pleiotropic acute-phase mediator with dual pro-and anti-inflammatory effects (Xing et al., 1998;Li et al., 2012;Tanaka and Kishimoto, 2012). ...
Injury initiates recruitment of macrophages to support tissue repair however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the PPAR-γ agonist, rosiglitazone (Rosi), a medication recently re-introduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6 deficient mice and control wildtype (WT) mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6-deficiency in human diseases. IL-6-deficiency when combined with Rosi-mediated upregulation of SOCS3, leads to an altered ratio of nuclear STAT3/NF-κB that allows hyper-induction of iNOS. Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6-deficiency.Journal of Investigative Dermatology accepted article preview online, 03 September 2014. doi:10.1038/jid.2014.375.
... As known, adiponectin up-regulation by PPARγ, provides a connection between the two PPAR isotypes [39]. PPARγ promotes fatty acid uptake and increases insulin sensitivity by up-regulating GLUT4, an insulin dependent glucose transporter in adipose tissue and striated muscle [40] and attenuating the induction of SOCS3 [41]. Consistently with the modulation of adiponectin synthesis, the synbiotic also modulates PPARγ and GLUT4 expression in visceral adipose tissue. ...
... We studied PPAR-α and PPAR-γ expression in tissues where they are more abundant, liver and adipose tissue, respectively [28]. PPAR-γ promotes fatty acid uptake and increases insulin sensitivity by upregulating GLUT-4, an insulin dependent glucose transporter in adipose tissue and striated muscle [29] and attenuating the induction of SOCS3 [30]. In the current report, we provide evidence that butyrate and FBA not only prevent, in adipose tissue, the HFD-induced reduction of PPAR-γ but also positively modulate PPAR-γ-coactivator PGC-1α [31]. ...
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD).
After weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined.
Evaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation.
Our results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance.
... As a consequence, the excess energy which is supposed to be stored in SC fat of sun-exposed skin may, instead, accumulate as non-SC fat in various internal organs, which is strongly associated with several deleterious health outcomes such as dyslipidemia and metabolic syndrome. Moreover, UV-induced SOCS-3, which is considered to be a key link between inflammation and insulin resistance (Chatterjee, 2010), may be related to the regulation of the lipid metabolism. Our data support a function for cytokines, originating from epidermis and dermis, in underlying SC lipid synthesis, and suggest that regulation of local cytokine Figure 4. UV-induced IL-6, IL-8, and placenta growth factor (PlGF) mediate suppressor of cytokine signaling (SOCS)-3 expression in the subcutaneous (SC) fat tissue of human skin. ...
Adipose tissue is not a homogeneous organ. Visceral fat accumulation is associated with atherosclerosis and metabolic syndrome, but peripheral subcutaneous (SC) fat accumulation may be protective. Human skin is continuously exposed to UV light. UV can penetrate the epidermis and into the mid-dermis, but not into the SC fat tissue of human skin. However, we here show that SC fat tissue in chronically sun-damaged skin contains less fat than naturally aged skin, and even a single UV exposure of human skin reduced lipid synthesis in the underlying SC fat tissue through transcriptional regulation of the lipogenic enzymes, acetyl CoA carboxylase, fatty acid synthase, and stearoyl CoA desaturase, of their transcription activator sterol regulatory element-binding protein-1 (SREBP-1), and of two key adipogenic transcription factors, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ. The cytokines IL-6, IL-8, monocyte chemoattractant protein-3 (MCP-3), and placenta growth factor, produced by keratinocytes and fibroblasts in response to UV, may be responsible for the reduction of SC fat, and these cytokines, except MCP-3, may act by upregulation of suppressor of cytokine signaling-3 expression. Our data demonstrate the inhibitory effects of UV light on SC lipid synthesis and provide proof of concept for targeting cytokines for SC fat tissue modification.
The present study investigated the effect of hydroalcoholic extract of Duranta repens Linn over gluconeogenesis, glycolysis, glycogenesis, leptin, and dipeptidyl peptidase-4 regulation in fructose-induced insulin-resistant rats. Initially, hyperinsulinemia was induced by supplementing fructose in drinking water for fifty-four days. Glucose intolerance was confirmed using oral glucose tolerance test and subjected for extract treatment for next thirty days. After thirty days of treatment, animals fasted and an oral glucose tolerance test was performed followed by an insulin tolerance test. After that, animals were overdosed with anesthetic ether, blood was collected to separate plasma and serum. Further, multiple biochemical parameters i.e. lipid profile, hepatic enzymes, enzymatic and non-enzymatic antioxidant biomarkers, glycogen content, leptin, and the glucagon-like peptide-1 level were quantified. Additionally, the glucose uptake in rat hemidiaphragm and hepatic histology were performed. Further, molecular docking was performed using AutoDock Vina and the ligand pose with minimum binding energy was chosen to visualize the ligand-protein interaction. After the thirty days of treatment with extract, it was observed to ameliorate the fructose-induced alterations in body weight, food intake, and water intake. Further, it improved glucose tolerance. This was confirmed via the quantification of the total triglycerides and assessing oral glucose and insulin tolerance test. Additionally, it also improved the level of hepatic enzymes involved in gluconeogenesis and glycolysis. Also, it upregulated the leptin pathway; however, did not influence the dipeptidyl peptidase-4-glucagon-like peptide-1. Similarly, a docking study predicted scutellarein, pseudo-ginsenoside-RT1, repennoside, and durantanin I as probable lead hits from Duranta repens as prime regulators of gluconeogenesis. Additionally, molecular docking revealed scutellarein, pseudo-ginsenoside-RT1, repennoside, and durantanin I as the probable lead hits in regulating the enzymes involved in hepatic glucose catabolism and anabolism. Treatment with the hydroalcoholic extract of Duranta repens extract ameliorated fructose-induced gluconeogenesis, glycolysis, glycogenesis, and leptin regulation; however, did not influence the dipeptidyl-peptidase 4- glucagon-like peptide-1 pathway.
Ethnopharmacological relevance
Bark of Ficus benghalensis L. (family: Moraceae), commonly known as Banyan is recorded as Nyagrodha in Ayurvedic Pharmacopeia of India to manage burning sensation, obesity, diabetes, bleeding disorders, thirst, skin diseases, wounds, and dysmenorrhoea. One of our previous studies identified lead hits from F. benghalensis as α-glucosidase inhibitor which was also predicted to regulate the p53 signaling pathway. However, the role of F. benghalensis bark over glycolysis, gluconeogenesis, and appetite regulation in insulin-resistant pathogenesis has not been reported yet.
Aim of the study
The present study aimed to investigate the effect of hydroalcoholic extract of F. benghalensis bark in gluconeogenesis, glycolysis, and appetite regulation in fructose-induced insulin resistance in experimental rats.
Materials and methods
Wister rats were supplemented with fructose in drinking water (10% w/v for 42 days and 20% w/v for next 12 days; a total of 54 days); insulin resistance was confirmed via the elevated area under the curve of the glucose during oral glucose tolerance test after 54 days and was subjected with extract treatment for 30 days. After 30 days of treatment, animals were fasted to perform oral glucose and insulin tolerance test to estimate glucose and insulin levels. The blood sample was collected for biochemical estimation and the liver was isolated to estimate hepatic enzymes and enzymatic and non-enzymatic anti-oxidant biomarkers followed by histopathological evaluation. Also, glycogen content was quantified in gastrocnemius muscle and liver homogenates. Further, reported bioactives from the F. benghalensis were retrieved from the ChEBI database and docked against hexokinase, phosphofructokinase, glucose-6-phosphatase, lactate dehydrogenase, and fructose-1,6-biphosphatase to identify the probable lead hit against the enzymes involved in gluconeogenesis.
Results
Treatment with the F. benghalensis bark extract significantly increased the body weight and food intake and significantly decreased fructose supplemented water intake. Further, treatment with extract significantly increased the exogenous glucose clearance and well responded to the exogenous insulin. Further, extract treatment improved lipid metabolism, ameliorated plasma leptin, and enzymatic and non-enzymatic antioxidant biomarkers. Likewise, it also improved gluconeogenesis mediated pathogenesis of non-alcoholic fatty liver injury. Additionally, molecular docking also identified mucusisoflavone A and B as lead hits in downregulating gluconeogenesis.
Conclusion
Hydroalcoholic extract of F. benghalensis bark may prevent insulin resistance by downregulating gluconeogenesis and improving the appetite in fructose-induced insulin-resistant rats.
Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n=76 psoriasis participants and 76 controls), non-alcoholic fatty liver disease (NAFLD), assessed by the sonographic hepatorenal index (SHRI), was more prevalent in psoriasis than controls (61% vs 45%; p=.04). Psoriasis participants with NAFLD had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than psoriasis without NAFLD (61% vs 23%; p=.006) and controls with NAFLD (61% vs 32%; p<.05). SHRI was a determinant of subclinical atherosclerosis in psoriasis (OR, 3.5; p=.01). In the United States cohort, (n=162 psoriasis participants who underwent positron emission tomography and coronary CT angiography), those with high hepatic ¹⁸F-FDG uptake had higher noncalcified (1.3 (0.49 mm²) vs 1.0 (0.40 mm²)), fibrofatty (0.23 (0.15 mm²) vs 0.11 (0.087 mm²)), and lipid rich necrotic core (4.3 (2.3 mm²) vs 3.0 (1.7 mm²)) coronary burden (all p<.001,). Hepatic ¹⁸F-FDG uptake associated with noncalcified (β=0.28; p<.001), fibrofatty (β=0.49; p<.001) and lipid rich necrotic core (β=0.28; p=.003) burden. These results demonstrate the downstream cardiovascular effects of subclinical liver disease in psoriasis.
Closely associated with visceral obesity, hepatic steatosis resulting from non-alcoholic fatty liver disease (NAFLD) exacerbates insulin resistance. Developing effective drugs to treat NAFLD is imperative. Here, we investigated the pharmacological mechanism of ugonin J (UJ) in controlling metabolic disorder and ameliorating NAFLD pathophysiology in diet-induced obese mice. The effects of UJ were assessed in 5-week-old C57BL/6 J mice fed a high-fat diet (HFD) for 12 weeks. UJ treatment averted HFD-induced body weight gain by reducing fat deposition in adipose tissues and reduced HFD-induced hyperlipidemia and hepatic inflammation. UJ also improved HFD-induced glucose tolerance and insulin resistance. Moreover, the mode of action of UJ was analyzed in palmitate (PA)-induced steatotic human HuS-E/2 hepatocytes and in hyperglycemia-simulating rat BRIN-BD11 pancreatic β cells. In PA-induced steatotic human hepatocytes, UJ treatment promoted lipid clearance via pAMPK, pACC and CPT-1 upregulation and SREBP-1c downregulation. Interestingly, UJ upregulated Akt activity in hepatocytes and increased insulin secretion from β cells in acute insulin secretion tests. Taken together, UJ improved adipocyte hypertrophy, hyperinsulinemia, hyperglycemia, hyperlipidemia and fat deposition in livers. UJ also reduced fatty acid accumulation by modulating key metabolic regulators. Our findings demonstrated the therapeutic potential of UJ for the treatment of NAFLD and diet-induced metabolic disorders.
Higher levels of lipid peroxidation and hypomagnesaemia are frequently associated with Type 2 Diabetes mellitus (T2DM). Addressing these issues would definitely help us in preventing or prolonging the onset of pathogenesis of micro and macrovascular complications. Pioglitazone is used as a trusted insulin sensitizer and an adjuvant to the conventional oral hypoglycemic agents. This study was planned to explore the effects of pioglitazone on oxidative stress, serum magnesium, blood pressure, hepato-biliary and renal systems in addition to its effects on glycemic control.
Sixty-three T2DM cases, who were started on pioglitazone were included in this study. All the physiological and biochemical parameters were estimated prior to and following three months of therapy with pioglitazone.
There was significant improvement in the glycemic control, serum magnesium and MDA levels with p values of 0.000, 0.023 and 0.000 respectively. Pioglitazone did not have any significant effects on the serum lipids and blood pressure in T2DM cases following three months of treatment. We did not observe any pronounced changes in hepato-biliary enzymes, serum urea and creatinine levels reaffirming safety of pioglitazone in T2DM.
Three-month duration of treatment with Pioglitazone in T2DM cases helps in alleviating the levels of lipid peroxides, besides being associated with improved serum magnesium status and glycemic control.
Diabetes mellitus is one of the most emerging diseases threatening the present world. Thus, intensive investigations are carried out to better understand the mechanisms occurring in type 1 (T1D) and 2 (T2D) diabetes, and to elaborate more potent methods to fight the disease. In this aspect, the suppressors of cytokine signalling (SOCS) are one of the most studied factors of recent years. SOCS proteins have been discovered as cytokine pathway inhibitors; however, presently, their influence seems wider. Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β-cell failure and eventually T1D and T2D. They are also involved in complications related with diabetes, such as retinopathy, nephropathy and cardiomyopathy. In T1D, SOCS proteins regulate β-cell mass, mediate resistance to damaging factors and improve pancreatic islet graft survival. Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. However, not all of the present data are consistent, and thus, further studies are required. Finally, for several pharmacologically active substances of importance regarding the treatment of diabetes, SOCS-modulating properties have already been described. Here, we review the findings of SOCS-diabetes relations of the last decade. Copyright © 2013 John Wiley & Sons, Ltd.
Purpose:
To identify genetic variants that predispose to type 2 diabetes (T2D) with cataract.
Patients and methods:
Genome-wide association study (GWAS) of T2D patients with cataract, as graded by Lens Opacities Classification System (LOCS). A total of 109 T2D patients with cataract score equal to or above 10 designated as the study group, 649 T2D patients with cataract score equal to or below 3 as the control group. Single nucleotide polymorphisms (SNPs) with p-values < 10(-5) were considered to be putatively associated with the diabetic cataract.
Results:
Fifteen SNPs were found to be putatively associated with diabetic cataract. These variants were located near the following genes: PPARD, CCDC102A, GBA3, NEDD9, GABRR1/2, RPS6KA2, tcag7.1163, TAC1, GALNTL1 and KIAA1671. We defined haplotype 1 to haplotype 4 from the alternative alleles of related polymorphisms. Distribution of haplotype 2 on chromosome 4 and haplotype 4 on chromosome 7 revealed significant differences (OR = 1.86 and 1.69, respectively; 95% confidence interval were 1.26-2.76 and 1.23-2.31, respectively).
Conclusions:
The 15 loci coded on chromosomes 4, 6, 7, 14, 16 and 22 were associated with diabetic cataract. Gene functions are either with mechanisms of regulating blood sugar or formation of cataract. High linkage disequilibrium appeared on chromosome 4p15.31 and chromosome 7q21.3.
Background:
To evaluate whether co-administration of R/S-α-lipoic acid can prevent the development of oxidative stress and metabolic changes induced by a fructose-rich diet (F).
Methods:
We assessed glycemia in the fasting state and during an oral glucose tolerance test, triglyceridemia and insulinemia in rats fed with standard diet (control) and fructose without or with R/S-α-lipoic acid. Insulin resistance and hepatic insulin sensitivity were also calculated. In liver, we measured reduced glutathione, protein carbonyl groups, antioxidant capacity by ABTS assay, antioxidant enzymes (catalase and superoxide dismutase 1 and 2), uncoupling protein 2, PPARδ and PPARγ protein expressions, SREBP-1c, fatty acid synthase and glycerol-3-phosphate acyltransferase-1 gene expression, and glucokinase activity.
Results:
R/S-α-lipoic acid co-administration to F-fed rats a) prevented hyperinsulinemia, hypertriglyceridemia and insulin resistance, b) improved hepatic insulin sensitivity and glucose tolerance, c) decreased liver oxidative stress and increased antioxidant capacity and antioxidant enzymes expression, d) decreased uncoupling protein 2 and PPARδ protein expression and increased PPARγ levels, e) restored the basal gene expression of PPARδ, SREBP-1c and the lipogenic genes fatty acid synthase and glycerol-3-phosphate acyltransferase, and f) decreased the fructose-mediated enhancement of glucokinase activity.
Conclusions:
Our results suggest that fructose-induced oxidative stress is an early phenomenon associated with compensatory hepatic metabolic mechanisms, and that treatment with an antioxidant prevented the development of such changes.
General significance:
This knowledge would help to better understand the mechanisms involved in liver adaptation to fructose-induced oxidative stress and to develop effective strategies to prevent and treat, at early stages, obesity and type 2 diabetes mellitus.
Objective: PPARγ agonists are used in type 2 diabetic patients to reduce insulin resistance. Recently, many AT1 receptor antagonists (ARBs) were reported to function as a partial agonist of PPARγ based on in vitro experiments. The aim of the present study was to investigate the effects adjuvant use of ARBs (losartan, telmisartan or valsartan) with metformin on metabolic and hormonal status in women with polycystic ovary syndrome (PCOS).
Methods: Using single-blinded clinical trial, we compared the effects of losartan, telmisartan or valsartan, when adjunctly used with metformin, on insulin sensitivity, body mass index, glycemic control the serum levels of various hormones (FSH, LH and testosterone).
Patients: In total, 74 Iraqi females with PCOS were enrolled in the study and allocated into 4 treatment groups; metformin only (1000mg/day) and metformin with losartan (25mg), telmisartan (40mg) or valsartan (40mg) groups.
Results: All ARBs significantly reduced BMI, FBG and C-peptide values compared to metformin only treated group; they also showed significantly greater effects in increasing plasma levels of FSH and decreasing both LH and testosterone levels compared to metformin only. The rank for the effects of the used ARBs in this respect was: telmisartan>losartan>valsartan after 4 months of treatment.
Conclusion: Adjuvant use of ARBs with metformin improves its effect in treatment of women with PCOS, with most pronounced effect for telmisartan in this respect.
Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a role in regulating a myriad of biological processes in virtually all brain cell types, including neurons. We and others have reported recently that drugs which activate PPARgamma are effective in reducing damage to brain in distinct models of brain disease, including ischemia. However, the cell type responsible for PPARgamma-mediated protection has not been established. In response to ischemia, PPARgamma gene is robustly upregulated in neurons, suggesting that neuronal PPARgamma may be a primary target for PPARgamma-agonist-mediated neuroprotection. To understand the contribution of neuronal PPARgamma to ischemic injury, we generated conditional neuron-specific PPARgamma knock-out mice (N-PPARgamma-KO). These mice are viable and appeared to be normal with respect to their gross behavior and brain anatomy. However, neuronal PPARgamma deficiency caused these mice to experience significantly more brain damage and oxidative stress in response to middle cerebral artery occlusion. The primary cortical neurons harvested from N-PPARgamma-KO mice, but not astroglia, exposed to ischemia in vitro demonstrated more damage and a reduced expression of numerous key gene products that could explain increased vulnerability, including SOD1 (superoxide dismutase 1), catalase, glutathione S-transferase, uncoupling protein-1, or transcription factor liver X receptor-alpha. Also, PPARgamma agonist-based neuroprotective effect was lost in neurons from N-PPARgamma neurons. Therefore, we conclude that PPARgamma in neurons play an essential protective function and that PPARgamma agonists may have utility in neuronal self-defense, in addition to their well established anti-inflammatory effect.
We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.
Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.
Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.
Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a crucial role in adipocyte differentiation, glucose metabolism, and other physiological processes. To further explore the role of PPARgamma in adipose tissues, we used a Cre/loxP strategy to generate adipose-specific PPARgamma knockout mice. These animals exhibited marked abnormalities in the formation and function of both brown and white adipose tissues. When fed a high-fat diet, adipose-specific PPARgamma knockout mice displayed diminished weight gain despite hyperphagia, had diminished serum concentrations of both leptin and adiponectin, and did not develop glucose intolerance or insulin resistance. Characterization of in vivo glucose dynamics pointed to improved hepatic glucose metabolism as the basis for preventing high-fat diet-induced insulin resistance. Our findings further illustrate the essential role for PPARgamma in the development of adipose tissues and suggest that a compensatory induction of hepatic PPARgamma may stimulate an increase in glucose disposal by the liver.
Peroxisome proliferator-activated receptors (PPARs) are a subfamily of nuclear hormone receptors that function as ligand-activated transcription factors to regulate lipid metabolism and homeostasis. In addition to their ability to promote gene transcription in a PPAR-dependent manner, ligands for this receptor family have recently been shown to induce mitogen-activated protein kinase (MAPK) phosphorylation. It is noteworthy that the transcriptional changes induced by PPAR ligands can be separated into distinct PPAR- and MAPK-dependent signaling pathways, suggesting that MAPKs alone mediate some of the effects of PPAR agonists in a nongenomic manner. This review will highlight recent studies that elucidate the nongenomic mechanisms of PPAR ligand-induced MAPK phosphorylation. The potential relevance of MAPK signaling in PPAR biology is also discussed.
Pioglitazone is widely used for the treatment of diabetic patients with insulin resistance. The mechanism of pioglitazone to improve insulin sensitivity is not fully understood. Recent studies have shown that the induction of suppressor of cytokine signaling 3 (SOCS3) is related to the development of insulin resistance. Here, we examined whether the insulin-sensitizing effect of pioglitazone affects the SOCS induction. In db/db mice and high-fat-fed mice, expression of SOCS3 mRNA in fat tissue was increased compared with that in lean control mice, and pioglitazone suppressed SOCS3 levels. In 3T3-L1 adipocytes, mediators of insulin resistance such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6, growth hormone, and insulin increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNF-alpha was greatly augmented by peroxisome proliferator-activated receptor gamma overexpression. SOCS3 overexpression and tyrphostin AG490, a Janus kinase 2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin secretion and was accompanied by decreased STAT3 phosphorylation. Conversely, pioglitazone increased adiponectin secretion and STAT3 phosphorylation in fat tissue of db/db mice and in 3T3-L1 adipocytes. These results suggest that pioglitazone exerts its effect to improve whole-body insulin sensitivity in part through the suppression of SOCS3, which is associated with the increase in STAT3 phosphorylation and adiponectin production in fat tissue.
Although interferon α (IFN-α ) has been used for a decade to treat viral hepatitis, a disease that affects millions of people worldwide, more than 60% of viral hepatitis patients respond poorly. It has been reported that high levels of tumor necrosis factor α (TNF-α ) correlated highly with resistance to IFN-α therapy. Here we demonstrate that injection of TNF- α suppresses IFN-α signaling and markedly induces expression of suppressor of cytokine signaling 3 (SOCS3) and SH2 containing protein-tyrosine phosphatase 2 (SHP2) in the liver. TNF- α induction of SOCS3 and SHP2 remains unchanged while induction of STAT1 protein expression is completely abolished in IL-6-deficient mice. Immunoprecipitation experiments show that injection of TNFα increases SHP2 association with JAKs. Overexpression of SOCS3 and SHP2 inhibits IFN-α signaling in hepatic cells. Injection of carbon tetrachloride, which is known to induce TNF- α in the liver, attenuates IFN- α signaling in the liver. This attenuation is also observed in TNF- α receptor II- (TNF-R2-) deficient mice but is markedly diminished in TNF-R1-deficient mice. Taken together, these findings suggest that TNF- α may be involved in resistance to IFN- α therapy by induction of SOCS3 and SHP2, and they could be therapeutic targets for improving the efficacy of IFN-α therapy.
Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease, less is known as to whether insulin resistance causes an altered cardiac phenotype independent of coronary atherosclerosis. In this study, we investigated the relationship between insulin resistance and cardiac contractile dysfunctions by generating a new insulin resistance animal model with rats on high cholesterol-fructose diet. Male Sprague-Dawley rats were given high cholesterol-fructose (HCF) diet for 15 wk; the rats developed insulin resistance syndrome characterized by elevated blood pressure, hyperlipidemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. The results show that HCF induced insulin resistance not only in metabolic-response tissues (i.e., liver and muscle) but also in the heart as well. Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 wk of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with glucose transporter GLUT4 translocation. Basal fatty acid transporter FATP1 levels were increased in HCF rat hearts. The cardiac performance of the HCF rats exhibited a marked reduction in cardiac output, ejection fraction, stroke volume, and end-diastolic volume. It also showed decreases in left ventricular end-systolic elasticity, whereas the effective arterial elasticity was increased. In addition, the relaxation time constant of left ventricular pressure was prolonged in the HCF group. Overall, these results indicate that insulin resistance reduction of cardiac glucose uptake is associated with defects in insulin signaling. The cardiac metabolic alterations that impair contractile functions may lead to the development of cardiomyopathy.
Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)gamma agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARgamma are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARgamma activation in a non-genetic insulin-resistant animal model.
Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg x kg(-1)) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARgamma, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3beta phosphorylation were assessed in rat liver.
Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-alpha and markers of neutrophil infiltration. Diet-induced PPARgamma expression was unaffected by the pioglitazone treatment.
Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.
Unlabelled:
Pathogenesis of metabolic syndrome-related nonalcoholic steatohepatitis (NASH) involves abnormal tissue-repairing responses in the liver. We investigated the effect of pioglitazone, a thiazolidinedione derivative (TZD), on hepatic regenerative responses in obese, diabetic KK-A(y) mice. Male KK-A(y) mice 9 weeks after birth underwent two-thirds partial hepatectomy (PH) after repeated intragastric injections of pioglitazone (25 mg/kg) for 5 days. Almost half of the KK-A(y) mice died within 48 hours of PH;however, mortality was completely prevented in mice pretreated with pioglitazone. In KK-A(y) mice, bromodeoxyuridine (BrdU) incorporation to hepatocyte nuclei 48 hours after PH reached only 1%; however, pioglitazone pretreatment significantly increased BrdU-positive cells to 8%. Cyclin D1 was barely detectable in KK-A(y) mice within 48 hours after PH. In contrast, overt expression of cyclin D1 was observed 24 hours after PH in KK-A(y) mice pretreated with pioglitazone. Hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) was tremendously increased 1 hour after PH in KK-A(y) mice, the levels reaching ninefold over C57Bl/6 given PH, whereas pioglitazone blunted this increase by almost three-fourths. Pioglitazone normalized hypoadiponectinemia in KK-A(y) mice almost completely. Serum interleukin (IL)-6 and leptin levels were elevated extensively 24 hours after PH in KK-A(y) mice, whereas the levels were largely decreased in KK-A(y) mice given pioglitazone. Indeed, pioglitazone prevented aberrant increases in signal transducers and activators of transcription (STAT)3 phosphorylation and suppressor of cytokine signaling (SOCS)-3 mRNA in the liver in KK-A(y) mice.
Conclusion:
These findings indicated that pioglitazone improved hepatic regeneration failure in KK-A(y) mice. The mechanism underlying the effect of pioglitazone on regeneration failure most likely involves normalization of expression pattern of adipokines and subsequent cytokine responses during the early stage of PH.
Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.
Although interferon α (IFN-α ) has been used for a decade to treat viral hepatitis, a disease that affects millions of people worldwide, more than 60% of viral hepatitis patients respond poorly. It has been reported that high levels of tumor necrosis factor α (TNF-α ) correlated highly with resistance to IFN-α therapy. Here we demonstrate that injection of TNF- α suppresses IFN-α signaling and markedly induces expression of suppressor of cytokine signaling 3 (SOCS3) and SH2 containing protein-tyrosine phosphatase 2 (SHP2) in the liver. TNF- α induction of SOCS3 and SHP2 remains unchanged while induction of STAT1 protein expression is completely abolished in IL-6-deficient mice. Immunoprecipitation experiments show that injection of TNF- α increases SHP2 association with JAKs. Overexpression of SOCS3 and SHP2 inhibits IFN-α signaling in hepatic cells. Injection of carbon tetrachloride, which is known to induce TNF- α in the liver, attenuates IFN- α signaling in the liver. This attenuation is also observed in TNF- α receptor II- (TNF-R2-) deficient mice but is markedly diminished in TNF-R1-deficient mice. Taken together, these findings suggest that TNF- α may be involved in resistance to IFN- α therapy by induction of SOCS3 and SHP2, and they could be therapeutic targets for improving the efficacy of IFN-α therapy.
Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.
The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARalpha, PPARdelta/beta, and PPARgamma. PPARalpha is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake (beta-oxidation and omega-oxidation). PPARdelta/beta is involved in fatty acid oxidation in muscle. PPARgamma has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARgamma. By activating a number of genes in tissues, PPARgamma increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. There is a sound rationale for the use of TZDs in patients with type 2 diabetes mellitus and promising preliminary data in patients with patients with pre-diabetes. In patients with type 2 diabetes, thiazolidinediones had been shown to decrease mean HbA(1c)by 1.5% and lower HbA(1c) to less than 7% in 30% of patients. Decreased muscle insulin resistance primarily mediates the glucose lowering effect. In addition, there are several nonhypoglycemic effects of TZDs which may be beneficial to both diabetics and patients with pre-diabetes. These include effects on lipid metabolism, blood pressure, endothelial function, atherosclerotic plaque, coagulation, and albuminuria. In a pilot study, we recently demonstrated that insulin sensitizers such as thiazolidinediones appear to be associated with better clinical outcomes compared to insulin providers in diabetic patients presenting with acute coronary syndromes. In another study, we showed that the prediabetic state is a marker for worse prognosis in patients with acute coronary syndromes. In this article, we review the existing literature on the effectiveness of PPAR-gamma agonists in patients with either overt diabetes or a prediabetic state.
PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome.
We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001).
These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.
First discovered as inhibitors of cytokine signalling, the suppressor of cytokine signalling (SOCS) proteins have appeared, over recent years, as potent repressors of other signalling pathways including the one induced by insulin. SOCS-1 and SOCS-3 have been extensively studied both in vitro and in vivo in the context of insulin action. It has been shown that these two SOCS members are able to inhibit the insulin signalling pathway by three different mechanisms: (1) inhibition of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins because of competition at the docking site on the insulin receptor (IR), (2) induction of the proteasomal degradation of the IRS and (3) inhibition of the IR kinase. A key feature of the SOCS proteins is that they are induced regulators. Indeed, expression of SOCS proteins is virtually absent in basal conditions, but is rapidly and robustly induced in response to several stimuli such as hormones, cytokines and growth factors. A significant correlation between SOCS-3 expression and insulin resistance has been demonstrated in vivo. Interestingly, the level of SOCS-3 expression is strikingly enhanced in insulin-sensitive tissues from both patients and animal models with type 2 diabetes and insulin resistance. While it remains to be established whether the increased expression of SOCS is a cause or a consequence of insulin resistance, a large body of observations supports a role for SOCS proteins in the disease process found in states with insulin resistance.
Fructose, a naturally found sugar in many fruits, is now commonly used as an industrial sweetener and is excessively consumed in Western diets. High fructose intake is increasingly recognized as causative in development of prediabetes and metabolic syndrome. The mechanisms underlying fructose-induced metabolic disturbances are unclear but are beginning to be unravelled. This review presents recent findings in this field and an overall mechanistic insight into the metabolic effects of dietary fructose and its role in metabolic syndrome.
Recent animal studies have confirmed the link between fructose feeding and increased plasma uric acid, a potentially causative factor in metabolic syndrome. Advanced glycation end products are also implicated because of their direct protein modifications and indirect effects on inflammation and oxidative stress. Human studies have demonstrated fructose's ability to change metabolic hormonal response, possibly contributing to decreased satiety.
There is much evidence from both animal models and human studies supporting the notion that fructose is a highly lipogenic nutrient that, when consumed in high quantities, contributes to tissue insulin insensitivity, metabolic defects, and the development of a prediabetic state. Recently evidence has helped to decipher the mechanisms involved in these metabolic changes.
Insulin resistance and hyperglycemia characterize type 2 diabetes mellitus. Type 2 diabetes mellitus is usually accompanied by concomitant disorders, such as dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones are antidiabetic drugs that increase insulin sensitivity by activating the peroxisome proliferator-activated receptor gamma. There is evidence that thiazolidinediones exert a number of pleiotropic effects that may play an important role in the treatment of type 2 diabetes mellitus.
The purpose of the present article was to review the 'pleiotropic' effects of thiazolidinediones (i.e., their effects beyond glucose lowering).
The study involved searching PubMed up to February 2008 using relevant keywords.
Thiazolidinediones favorably alter fat distribution and improve cardiovascular risk factors, such as blood pressure, inflammation markers and uric acid and they may also delay the progression of atherosclerosis. The effects on the lipid profile differ between the two thiazolidinediones studied with pioglitazone having more positive effects compared with rosiglitazone. Furthermore, thiazolidinediones improve diabetic complications, such as diabetic nephropathy and non-alcoholic fatty liver disease. Thiazolidinediones may also play a role in other diseases, such as polycystic ovary syndrome. These pleiotropic effects may prove to be clinically relevant. There has been recent debate about the possible differences between the two thiazolidinediones in terms of cardiovascular disease outcome. In this context, differences in the lipid effects between the two drugs may be relevant.
Thiazolidinediones are insulin-sensitizing drugs which have been proved to be effective in the treatment of type 2 diabetes. However, the action of thiazolidinediones on myocardial metabolism is only poorly recognized. Therefore, the aim of our study was to investigate the effects of two-week pioglitazone treatment (3 mg/kg/d) on lipid and carbohydrate metabolism in the heart of rats fed on a standard chow or on a high-fat diet (HFD) for three weeks. High-fat feeding increased myocardial protein expression of all peroxisome proliferator-activated receptor (PPAR) isoforms. The greatest response was, however, noted in the case of PPARgamma. Surprisingly, administration of pioglitazone induced accumulation of free fatty acids (FFA) and diacylglycerol in the heart in both groups, despite concomitant reduction in plasma FFA concentration. The content of triacylglycerol was increased only in the HFD group. Pioglitazone treatment also shifted myocardial substrate utilization towards greater contribution of glucose in both groups, as evidenced by decreased rate of palmitate oxidation and higher 2-deoxyglucose uptake and elevated glycogen content. This could induce a mismatch between the rate of myocardial fatty acid uptake and oxidation leading to increased intracellular availability of fatty acids for non-oxidative metabolic pathways like synthesis of acylglycerols. Our data suggests that thiazolidinediones improve cardiac insulin sensitivity by mechanisms other than reduction in intramyocardial lipid content.
Beneficial effects of PPARg agonism in overweight rats fed a Western-type diet involve SOCS-3 hepatic modulation
- M Collino
- M Aragno
- S Catiglia
- G Miglio
- C Tomasinelli
- G Boccuzzi
Collino M, Aragno M, Catiglia S, Miglio G, Tomasinelli C, Boccuzzi G
et al. (2010). Beneficial effects of PPARg agonism in overweight rats
fed a Western-type diet involve SOCS-3 hepatic modulation. Br J
Pharmacol 160: 1892-1902.
Beneficial effects of PPARγ agonism in overweight rats fed a Western-type diet involve SOCS-3 hepatic modulation
- Collino
Report of the expert committee on the diagnosis and classification of diabetes mellitus
- Expert Committee on the Diagnosis and Classification of Diabetes Mellitus