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PubMed2001

Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control.

OBJECTIVES: This study was designed to determine whether blood thrombogenicity is related to chronic glycemic control in type 2 diabetes mellitus (T2DM). BACKGROUND: Type 2 diabetes mellitus is associated with accelerated atherosclerosis and a high rate of arterial thrombotic complications. Whether increased blood thrombogenicity is associated with glycemic control has not been properly tested. METHODS: Forty patients with T2DM with hemoglobin A1c (HbA1c) > or =7.5% were selected. Maintaining their current hypoglycemic therapies, patients were randomized into a conservative (diet modification plus placebo) or intensive (diet modification plus troglitazone) hypoglycemic regimen for three months. Blood thrombogenicity was measured at baseline and after three months with the Badimon ex vivo perfusion chamber and assessed as platelet-thrombus formation. The repeated measurements allowed every patient to be his/her own control. RESULTS: Patients in both groups (48% and 74% of the conservative and intensive groups, respectively) improved glucose control (HbA1c reduction > or =0.5%), showing a significant decrease in blood thrombogenicity. A significant positive correlation was observed between the reduction in thrombus formation and the reduction in HbA1c (r = 0.47, p < 0.01). The reduction in HbA1c achieved by both treatments was comparable. Patients without glycemic improvement showed no change in blood thrombogenicity. Improved glycemic control was the only significant predictor of a decrease in blood thrombogenicity. CONCLUSIONS: In T2DM, there is an association between improved glycemic control and blood thrombogenicity reduction. The effect of glycemic control on the thrombotic complications of T2DM patients deserves further investigation.

Analysis of Variance↗
PubMed2003

Growth inhibition through activation of peroxisome proliferator-activated receptor gamma in human oesophageal squamous cell carcinoma.

Peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimerises with retinoid X receptor alpha (RXRalpha) and is thought to be a novel therapeutic target for human malignancies. We evaluated the ability of troglitazone (TRO) alone or in combination with 9-cis retinoic acid (9CRA), ligands of PPARgamma and RXRalpha, respectively, to inhibit the growth of oesophageal squamous cell carcinoma (OSCC). All 10 tested OSCC cell lines of a KYSE series expressed PPARgamma and RXRalpha at both the mRNA and protein levels. In four tested cell lines, TRO inhibited growth, and a synergistic effect was observed with simultaneous 9CRA application. In KYSE 270 cells, a luciferase reporter assay showed that the simultaneous application of TRO and 9CRA to the cells increased the relative luciferase activity approximately 20-fold compared with the controls without TRO or 9CRA application. In this cell line, flow cytometry demonstrated that combined treatment with TRO and 9CRA greatly increased the sub-G1 phase, and Hoechst 33342/propidium iodide (PI) staining showed that apoptotic cell death was mainly induced through ligand treatment. In addition, implanted tumours in nude mice showed significant inhibition of tumour growth when treated with TRO. These results suggest that the PPARgamma/RXRalpha heterodimer may be a new therapeutic target for OSCC.

Alitretinoin↗
PubMed2004

Transcriptional inactivation of STAT3 by PPARgamma suppresses IL-6-responsive multiple myeloma cells.

Multiple myeloma (MM) remains largely incurable despite conventional and high-dose therapies. Therefore, novel biologically based treatment approaches are urgently required. Here we demonstrate that expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in MM cells and its agonists 15-d-PGJ2 and troglitazone completely abolished IL-6-inducible MM cell proliferation and induced apoptosis through affecting expression of multiple cell cycle or apoptosis genes, whereas PPARgamma antagonist GW9662 and PPARalpha agonist WY14643 did not display this inhibitory effect. These PPARgamma agonists significantly inhibited DNA binding and transactivation of STAT3 bound to the promoter of target genes in chromatin, but did not affect the expression of IL-6 receptor and phosphorylation of JAK/STAT3, MAPK, and PI3K/Akt. Interestingly, although inactivation of STAT3 by PPARgamma agonists is in a PPARgamma-dependent manner, the molecular mechanism by which two structurally distinct PPARgamma agonists suppress IL-6-activated STAT3 shows the divergent interactions between PPARgamma and STAT3 including direct or SMRT-mediated association.

Anilides↗
PubMed2003

[Should type 2 diabetes prevention pharmacological studies prompt us to change our prescription habits?].

Type 2 diabetes (T2D), a major public health problem in all parts of the world, is preceded by an identifiable phase of impaired glucose tolerance (IGT) during which a therapeutic intervention aimed at preventing the glycaemic decompensation can be considered. The efficacy of a diet resulting in a weight loss and even more of an exercise program has been clearly established, but the long term continuation of these measures is difficult in real life conditions. So, pharmacological interventions on insulin resistance and B cell dysfunction, the major pathophysiologic components of the disease have been tested. A relative risk reduction of conversion from IG to T2D has been obtained with metformin in the Diabetes Prevention Program, but this effect seems to be directly linked to the antihyperglycaemic effect of the drug. Likewise, the relative risk reduction of 25% with acarbose in the Stop-NIDDM trial results more from a short term therapeutic effect than from an action in depth on the mechanisms leading to the glycaemic decompensation. This might does not be the case with troglitazone in the TRIPOD trial, since the protection conferred by this drug largely exceeds the treatment period and the B cell function appears to be preserved. However, these results should be confirmed in larger and more common populations of IGT. Finally, the practical carrying out of a prevention program at the scale of a whole population raises several unsolved problems.

Chromans↗
PubMed2000

The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease.

The liver has long been known to respond to exposure to certain chemicals with hyperplasia and proliferation of the peroxisomal compartment. This response is now known to be mediated by specific receptors. The peroxisome proliferator-activated receptors (PPARs) were cloned 10 years ago, and in that interval, have been found to serve as receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originally led to their study. Three receptors, designated the alpha, delta, and gamma receptors, have been found in mammals. PPARalpha: is the most abundant form found in the liver, with smaller amounts of the delta and gamma forms also expressed there. Kupffer cells, like other macrophages, appear to express the alpha and gamma isoforms. Hepatic stellate cells are reported to express the gamma isoform. PPARalpha knock-out mice fail to undergo peroxisome proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indicating that normal function of the alpha receptors is needed for lipid homeostasis. This in turn suggests that inadequate PPAR-mediated responses may contribute to abnormal fatty acid metabolism in alcoholic and non-alcoholic steatohepatitis. Recent information suggests that PPARgamma receptors may be important in control of the activation state of the stellate cells, and their repression or inactivation may predispose to hepatic fibrosis. The first approved drug that specifically activates PPARgamma, troglitazone, has rarely been found to cause serious liver injury. Although this is likely to represent an idiosyncratic reaction, the medical community will need to be alert to the possibility that activation or blockade of these receptors may cause hepatic dysfunction.

Animals↗
PubMed1998

Differentiation and reversal of malignant changes in colon cancer through PPARgamma.

PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.

Adenocarcinoma↗
PubMed2004

Ox-LDL suppresses PMA-induced MMP-9 expression and activity through CD36-mediated activation of PPAR-g.

During chronic inflammatory response, mono- cytes/macrophages produce 92-kDa matrix metalloproteinase-9 (MMP-9), which may contribute to their extravasation, migration and tissue remodeling. Activation of peroxisome proliferator- activated factor receptor-g (PPAR-g) has been shown to inhibit MMP-9 activity. To evaluate whether ox-LDL, a PPAR-g activator, inhibits PMA-induced MMP-9 expression and activity, and if so, whether CD36 and PPAR-g are involved in this process, we investigated the effect of ox-LDL on MMP-9 expression and activity in PMA-activated human monocytic cell line U937. PMA-induced MMP-9 expression and activity were suppressed by the treatment with ox-LDL (50 mg/ml) or PPAR-g activators such as troglitazone (5 mM), ciglitazone (5 mM), and 15d- PGJ2 (1 mM) for 24 h. This ox-LDL or PPAR-g activator-mediated inhibition of MMP-9 activity was diminished by the pre-treatment of cells with a blocking antibody to CD36, or PGF2a (0.3 mM), which is a PPAR-g inhibitor, as well as overexpression of a dominant-negative form of CD36. Taken together, these results suggest that ox-LDL suppresses PMA-induced MMP-9 expression and activity through CD36-mediated activation of PPAR-g.

Antibodies, Blocking↗
PubMed2005

15-Deoxy-delta12,14-PGJ2 inhibits IL-6-induced Stat3 phosphorylation in lymphocytes.

15-deoxy-delta(12,14)-PGJ(2)(15d-PGJ(2)) is a natural ligand that activates the peroxisome proliferators-activated receptor (PPAR) gamma, a member of nuclear receptor family implicated in regulation of lipid metabolism and adipocyte differentiation. Recent studies have shown that 15d-PGJ(2) is the potent anti-inflammatory agent functioning via PPARgamma-dependent and -independent mechanisms. Most postulated mechanisms for anti-inflammatory action of PPARgamma agonists are involved in inhibiting NF-kappaB signaling pathway. We examined the possibility that IL-6 signaling via the Jak-Stat pathway is modulated by 15d-PGJ(2) in lymphocytes and also examined whether the inhibition of IL-6 signaling is dependent of PPARgamma. 15d-PGJ(2) blocked IL-6 induced Stat1 and Stat3 activation in primary human lymphocytes, Jurkat cells and immortalized rheumatoid arthritis B cells. Inhibition of IL-6 signaling was induced rapidly within 15 min after treatment of 15d-PGJ(2). Other PPARgamma-agonists, such as troglitazone and ciglitazone, did not inhibit IL-6 signaling, indicating that 15d-PGJ(2) affect the IL-6-induced Jak-Stat signaling pathway via PPARgamma-independent mechanism. Although cycloheximide reversed 15d-PGJ(2)-mediated inhibition of Stat3 activation, actinomycin D had no effect on 15d-PGJ(2)-mediated inhibition of IL-6 signaling, indicating that inhibition of IL-6 signaling occur independent of de novo gene expression. These results show that 15d-PGJ(2) specifically inhibit Jak-Stat signaling pathway in lymphocytes, and suggest that 15d-PGJ(2) may regulate inflammatory reactions through the modulation of different signaling pathway other than NF-kappaB in lymphocytes.

Arthritis, Rheumatoid↗
PubMed2005

Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway.

OBJECTIVE: The fat cell hormone leptin is known to be implicated in the pathogenesis of hypertension and cardiovascular disease. Here we tested whether angiotensin (Ang) II is involved in the control of leptin release from human adipocytes. RESEARCH METHODS AND PROCEDURES: Leptin secretion was assessed from in vitro differentiated human adipocytes by radioimmunoassay. Western blot experiments were used to test for the signaling pathway activated by Ang II. RESULTS: Ang II increased leptin secretion into the culture medium in a dose- and time-dependent fashion. At 10(-5) M Ang II, the leptin concentration in the medium was increased at 24 hours by 500+/-222% compared with control cultures (p<0.05). This effect was also seen at the mRNA level. Similar effects were seen after exposure of fat cells to Ang III and Ang IV. Preincubation of fat cells with candesartan, an angiotensin II type 1 receptor antagonist, or the extracellular-signal-regulated kinases 1 and 2 inhibitor UO126 completely abolished the effect of Ang II on leptin production. The peroxisome proliferator-activated receptor-gamma agonist troglitazone modestly attenuated leptin release. DISCUSSION: In conclusion, Ang II and its metabolites stimulated leptin production in human adipocytes. This effect is mediated through an extracellular-signal-regulated kinases 1 and 2-dependent pathway and includes the angiotensin II type 1 receptor subtype.

Adipocytes↗
PubMed2006

Upregulation of MIP-2 (CXCL2) expression by 15-deoxy-Delta(12,14)-prostaglandin J(2) in mouse peritoneal macrophages.

A peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), has been reported to possess anti-inflammatory activity in activated monocytes/macrophages. In this study, we investigated the effect of 15d-PGJ(2) on the lipopolysaccharide (LPS)-induced expression of chemokine mRNAs, especially macrophage inhibitory protein (MIP)-2 (CXCL2), in mouse peritoneal macrophages. The inhibitory actions of the natural PPARgamma ligands, 15d-PGJ(2) and prostaglandin A1 (PGA1), on the expression of RANTES (regulated upon activation, normal T expressed and secreted; CCL5), MIP-1beta (CCL4), MIP-1alpha (CCL3), IFN-gamma-inducible protein 10 kilodaltons (IP-10; CXCL10) and monocyte chemoattractant protein-1 (MCP-1; CCL2) mRNA in LPS-treated cells were stronger than those of the synthetic PPARgamma ligands troglitazone and ciglitazone. However, 15d-PGJ(2) enhanced the expression of LPS-induced MIP-2 (CXCL2) mRNA. A specific PPARgamma antagonist (GW9662) had no effect on the inhibitory action of 15d-PGJ(2) and PGA1 in LPS-induced chemokine mRNA expression and on the synergistic action of 15d-PGJ(2) in LPS-induced MIP-2 (CXCL2) expression. Moreover, LPS itself reduced the expression of PPARgamma. Although the synergistic effect of 15d-PGJ(2) on LPS-induced MIP-2 (CXCL2) mRNA expression was remarkable, the production of MIP-2 (CXCL2) in cells treated with 15d-PGJ(2) and LPS did not increase compared to the production in cells treated with LPS alone. The synergistic action of 15d-PGJ(2) on LPS-induced MIP-2 (CXCL2) mRNA expression was dependent on the activation of nuclear factor-kappaB (NF-kappaB), and 15d-PGJ(2) increased the phosphorylation of p38 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in cells stimulated with LPS. These results suggest that the synergistic effect of 15d-PGJ(2) on LPS-induced MIP-2 (CXCL2) expression is PPARgamma-independent, and is mediated by the p38 and SAPK/JNK pathway in mitogen-activated protein kinase signaling pathways, which activates NF-kappaB. Our data may give more insights into the different mechanisms contrary to the anti-inflammatory effect of 15d-PGJ(2) on the expression of chemokine genes.

Animals↗
PubMed2003

Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women.

OBJECTIVE: To study the relation between body mass index (BMI) and age on the one hand and total number of human (pre-) adipocytes and preadipocyte differentiation capacity on the other hand. SUBJECTS: In total, 189 women undergoing surgical mammary reduction, age range 16-73 y, BMI range 19.7-39.7 kg/m(2). MEASUREMENTS: Differentiation of preadipocytes in primary culture was assessed by morphological criteria, and determination of glycerol-3-phosphate dehydrogenase after stimulation of the cells by standardized adipogenic conditions containing isobutyl-methylxanthine, troglitazone or both compounds. The total number of stromal cells (ie preadipocytes) and fat cells per gram of adipose tissue and per body as well as mature fat cell volume were calculated from isolated stromal cells and adipocytes, respectively, and anthropometric measures. RESULTS: BMI correlated positively to age, mature fat cell size and total number of adipocytes and stromal cells per body (r varying from 0.22 to 0.54, each P<0.05). In contrast, BMI correlated negatively to the number of adipocytes and stromal cells per gram of adipose tissue and the capacity of preadipocytes to differentiate (r varying from -0.20 to -0.37, each P<0.05). No significant correlation was observed between BMI and the ratio of stromal cells to adipocytes. The sample was also divided into three groups: BMI <25 kg/m(2) (lean), BMI 25-29.9 kg/m(2) (overweight) and BMI >/=30 kg/m(2) (obese). The overweight group showed a larger fat cell size but no increase in total fat cell or stromal cell number when compared to the lean subjects. The obese subjects showed larger stromal and fat cell numbers when compared to the lean subjects. Age did not independently correlate to the number of stromal cells or adipocytes per gram of adipose tissue or total body, nor with the capacity of preadipocytes to undergo differentiation and the ratio of stromal cells to adipocytes. CONCLUSION: There seems to be a constant ratio between the number of adipose tissue stromal cells and adipocytes independently of BMI and age in humans. During adipose tissue expansion, there seems to be both a continuous increase in fat cell size, and in stromal cell and adipocyte number, but the increase in fat cell size apparently precedes the increase in fat cell number. The differentiation capacity of the stromal cells appears to decrease with increasing BMI.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Adiponectin receptor gene expression in human skeletal muscle cells is not regulated by fibrates and thiazolidinediones.

BACKGROUND: Thiazolidinediones as PPARgamma agonists and fibrates as PPARalpha agonists improve insulin sensitivity in insulin-responsive tissues. Recent data show an induction of adiponectin receptor 2 (AdipoR2) by PPARalpha and PPARgamma agonists in human macrophages. OBJECTIVE: In this study, we examined the effects of thiazolidinediones and fibrates on the expression of adiponectin receptors in human skeletal muscle cells, an important cell type in the context of insulin resistance. RESULTS AND METHODS: In vitro differentiated human myotubes treated with troglitazone or rosiglitazone (20 h) showed no significant changes in AdipoR1 and AdipoR2 mRNA expression. PPARgamma activation was controlled by determination of PPARgamma mRNA induction. Likewise, differentiated myotubes treated with Wy-14,643 or fenofibrate (20 h) revealed no significant regulation of AdipoR1 and AdipoR2 mRNA. PPARalpha activation was assessed by measuring PDHK4 mRNA expression. CONCLUSION: Induction of AdipoR gene expression in human skeletal muscle cells is not involved in the insulin-sensitizing effects of thiazolidinediones or fibrates.

Adult↗
PubMed2002

Prostaglandin D(2), its metabolite 15-d-PGJ(2), and peroxisome proliferator activated receptor-gamma agonists induce apoptosis in transformed, but not normal, human T lineage cells.

Prostaglandin D(2) (PGD(2)) is abundantly produced by mast cells, platelets, and alveolar macrophages and has been proposed as a key immunoregulatory lipid mediator. 15-Deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)), a key PGD(2) metabolite, is under intense study as a potential anti-inflammatory mediator. Little is known about PGD(2) or the role of 15-d-PGJ(2), if any, in regulating the activities of human T lineage cells. In this report we demonstrate that both PGD(2) and 15-d-PGJ(2) have potent antiproliferative effects, and in fact kill human T lymphocyte lines derived from malignant cells by an apoptotic mechanism. Interestingly, normal human T cells were not similarly affected. Although the T lymphocyte lines express mRNA for the PGD(2) receptor (DP-R), a potent DP receptor agonist, BW245C, did not inhibit the proliferation or viability of the cells, suggesting an alternative mechanism of action. PGD(2) and 15-d-PGJ(2) can bind to the peroxisome proliferator activated receptor-gamma (PPAR-gamma) which is implicated in lipid metabolism and apoptosis. Exposure to synthetic PPAR-gamma ligands (e.g. ciglitazone, troglitazone) mimicked the inhibitory responses of PGD(2) and 15-d-PGJ(2), and induced apoptosis in the transformed T cells consistent with a PPAR-gamma-dependent mechanism. These observations suggest that PPAR-gamma ligands (which may include PGD2) provide strong apoptotic signals to transformed, but not normal T lymphocytes. Thus, the efficacy of utilizing PPAR-gamma and its ligands as therapeutics for human T cell cancers needs to be further evaluated.

Antineoplastic Agents↗
PubMed2002

Effect of PPARgamma ligands on the viability of gastric epithelial cells.

BACKGROUND: [corrected] Peroxisome proliferator-activated receptors (PPAR) are a family of three nuclear receptors (PPARalpha, PPARdelta, and PPARgamma). Although recent evidence suggests a role for PPARgamma in the regulation of colonic epithelial cell growth, the role for PPARgamma in the stomach has not been established. AIM: To examine the expression of PPARgamma and the effects of PPARgamma ligands on the viability of gastric epithelial cells. METHODS: MKN45 cells and primary cultured rat gastric epithelial cells were used. Troglitazone (TGZ) and 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) were used as PPARgamma ligands. Expression of PPARgamma was examined by RT-PCR and Western blot analysis. Cell viability was measured by WST-1 assay and TUNEL assay was performed to detect apoptosis. RESULTS: MKN45 cells expressed all subtypes of PPAR. PPARgamma ligands decreased cell viability and induced cell death in a dose-dependent manner, whereas ligands for PPARalpha and PPARdelta had no significant effect. TUNEL assay showed that this cell death is apoptosis. Primary cultured rat gastric epithelial cells also expressed PPARgamma and activation of PPARgamma decreased cell viability. CONCLUSION: These results suggest that PPARgamma plays an important role in the regulation of cell growth and cell death in gastric epithelial cells.

Animals↗
PubMed2000

Assessment of human muscle glycogen synthesis and total glucose content by in vivo 13C MRS.

BACKGROUND: Obesity is often accompanied by a decreased ability of insulin to stimulate glucose uptake and glycogenesis in skeletal muscle. The aim of this study was to investigate the rate of glycogen formation and of muscular glucose content in relation to insulin sensitivity under euglycemic conditions. MATERIALS AND METHODS: We applied a hyperinsulinemic (430 pmol m-2 min-1) euglycemic clamp with infusion of 20% glucose (30% enriched with 13C-1-glucose) to 8 subjects with a wide range of insulin sensitivities. Glycogen and glucose levels were monitored simultaneously by in vivo 13C MRS of the calf muscle on a clinical MR system at 1.5T field strength. RESULTS AND CONCLUSIONS: Glycogen synthesis rate showed a strong correlation with whole body glucose uptake during the clamp (r = 0.93, P < 0.01). With the use of 13C MRS, total muscular glucose content could be determined in vivo, and showed a positive, linear correlation with glycogen synthesis rate (r = 0.85, P < 0.01). 13C MRS provides important information regarding in vivo insulin action. Preliminary results indicate that the glycogen synthesis rate improves after treatment with troglitazone.

Adult↗
PubMed2002

Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma.

Peroxisome proliferator-activated receptor gamma is a member of the nuclear receptor superfamily involved in adipocyte differentiation and glucose homeostasis. There is evidence that peroxisome proliferator-activated receptor gamma may also act as a tumor suppressor. Here, we demonstrate expression of peroxisome proliferator-activated receptor gamma in benign melanocytic naevi, different variants of primary cutaneous melanomas, and melanoma metastases. Peroxisome proliferator-activated receptor gamma protein and peroxisome proliferator-activated receptor gamma1 mRNA were also detected in human melanoma cell lines. The peroxisome proliferator-activated receptor gamma specific agonists 15-deoxy-Delta12,14-prostaglandin J2, troglitazone, and rosiglitazone dose-dependently inhibited cell proliferation in four melanoma cell lines, whereas a specific agonist of peroxisome proliferator-activated receptor alpha had no such effect. At a concentration of 50 microM rosiglitazone, the most potent peroxisome proliferator-activated receptor gamma agonist tested suppressed cell growth by approximately 90%. Apoptosis could be induced in melanoma cell lines by incubation with tumor-necrosis-factor-related apoptosis-inducing ligand. In contrast, the growth inhibitory effect of peroxisome proliferator-activated receptor gamma activation was independent of apoptosis and seemed to occur primarily through induction of cell cycle arrest. Our data indicate that melanoma cell growth may be modulated through peroxisome proliferator-activated receptor gamma.

Antineoplastic Agents↗
PubMed1999

New agents for Type 2 diabetes.

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.

Anti-Obesity Agents↗
PubMed2000

Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells.

BACKGROUND & AIMS: Proliferation and migration of hepatic stellate cells (HSCs) and expression of chemokines are involved in the pathogenesis of liver inflammation and fibrogenesis. Peroxisome proliferator-activated receptor (PPAR)-gamma is a receptor transcription factor that controls growth and differentiation in different tissues. We explored the effects of PPAR-gamma agonists on the biological actions of cultured human HSCs. METHODS: HSCs were isolated from normal human liver tissue and used in their myofibroblast-like phenotype or immediately after isolation. Activation of PPAR-gamma was induced with 15-deoxy-Delta(12, 14)-prostaglandin J(2) or with troglitazone. RESULTS: PPAR-gamma agonists dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signaling or expression of c-fos and c-myc and was associated with inhibition of cell cycle progression beyond the G(1) phase. Activation of PPAR-gamma also resulted in a complete inhibition of the expression of monocyte chemotactic protein 1 at the gene and protein levels. Comparison of quiescent and culture-activated HSCs revealed a marked decrease in PPAR-gamma expression in activated cells. CONCLUSIONS: Activation of PPAR-gamma modulates profibrogenic and proinflammatory actions in HSCs. Reduced PPAR-gamma expression may contribute to confer an activated phenotype to HSCs.

Antineoplastic Agents↗