Metformin is the first-line treatment for patients with diabetes because it reduces mortality rates. If metformin is contraindicated or is not tolerated, any one of the other available antihyperglycemic drugs may be used as monotherapy. These drugs are equally effective for glucose control, lowering A1c by approximately 1%. Evidence of their benefit for reducing mortality or morbidity, or improving health-related quality of life is lacking. A sulfonylurea, pioglitazone, or exenatide can be added to maximally dosed metformin if additional glycemic control is necessary. Sulfonylureas and pioglitazone often cause weight gain. The combination of metformin plus a sulfonylurea is associated with a greater risk of hypoglycemia and mortality than the combination of metformin and a thiazolidinedione (ie, glitazone). Thiazolidinediones are contraindicated in patients with severe heart failure or liver disease. Newer drug classes target incretin, the hormone that stimulates food-dependent insulin secretion. The incretin mimetic exenatide, a high-cost injectable drug, is similar to metformin for reduction of A1c and body mass index. Incretin-enhancing dipeptidyl-peptidase 4 inhibitors (ie, gliptins) are inferior to metformin for lowering A1c and body mass index; little is known about their effect on all-cause mortality. Fixed combination products might improve ease of use and adherence; they might also reduce cost and risk of adverse effects.

AIMS/

HYPOTHESIS:

Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype.

METHODS:

Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation.

RESULTS:

As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice.

CONCLUSIONS

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INTERPRETATION:

Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.

Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-γ to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on β-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs-especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, β cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to-benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns.

INTRODUCTION:

This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats.

MATERIALS AND METHODS:

An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT1), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox), level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected.

RESULTS:

After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47(phox) and AT1, NADPH oxidase activity, and nitrotyrosine level.

CONCLUSIONS:

Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.

Monascin (MS) is a yellow compound isolated from Monascus-fermented products that has pancreatic protective, anti-inflammatory, anti-oxidative, and hypolipidemic activity. We recently found that MS also acts as a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, thereby promoting insulin sensitivity in C2C12 cells. However, the attenuation of hyperglycemia by MS treatment in vivo remains uncertain. In the present study, both MS and pioglitazone significantly down-regulated blood glucose and hyperinsulinemia in fructose-rich diet (FRD)-induced C57BL/6 mice (8 weeks). In addition, inhibitions of inflammatory factor production, serum dyslipidemia, and hepatic fatty acid accumulation by MS and pioglitazone were attenuated by GW9662 (PPARγ antagonist). These results were mediated by MS-suppressing FRD-elevated lipogenic transcription factors, including sterol regulatory element-binding protein-1c (SREBP-1c), carbohydrate response element-binding protein (ChREBP), PPARγ coactivator-1α (PGC-1α), and PPARγ coactivator-1β (PGC-1β). Taken together, de novo lipogenesis results in hyperlipidemia and hyperglycemia by fructose induction thereby leading to diabetes development; we found that MS may inhibit lipogenesis in FRD-induced mice. These findings suggest that MS acts as an antidiabetic agent and thus may have therapeutic potential for prevention of diabetes.

To investigate the effect of MEK/ERK1/2 pathway on peroxisome proliferator-activated receptors (PPARγ) agonist-induced alterations in Δ6-desaturase (Δ6D) and stearoyl-CoA desaturase 1 (SCD1) in hepatocellular carcinoma cell line HepG2.HepG2 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and PPARγ agonist, pioglitazone. Total RNA was isolated and reverse transcribed from treated cells. Changes in gene expression and metabolites ratio, as activity index for Δ6D and SCD1, were then determined using reverse transcription-polymerase chain reaction and gas liquid chromatography, respectively.The expression of both Δ6D (P = 0.03) and SCD1 (P = 0.01) increased following PD98059 treatment, with a higher impact on SCD1 (24.5% vs 62.5%). Although pioglitazone increased the mRNA level (1.47 ± 0.10 vs 0.88 ± 0.02, P = 0.006) and activity index (1.40 ± 0.07 vs 0.79 ± 0.11, P < 0.001) of Δ6D, no such changes have been observed for SCD1 activity index in pioglitazone-treated cells. SCD1 gene expression (+26.4%, P = 0.041) and activity index (+52.8%, P = 0.035) were significantly increased by MEK inhibition in the presence of pioglitazone, as compared with pioglitazone alone and control cells. However, the response of Δ6D expression and activity index to pioglitazone was unaffected by incubation with PD98059.PPARγ and ERK1/2 signaling pathway affect differentially and may have inhibitory crosstalk effects on the genes expression of ∆6D and SCD1, and subsequently on their enzymatic activities.

To investigate the effects of pioglitazone on transforming growth factor beta1 (TGFbeta1) expression in ischemia/reperfusion injury myocardium of rats.Thirty SD rats were randomly divided into five groups (n = 6): ischemia/reperfusion group, pioglitazone 5 mg/(kg x d) group, pioglitazone 10 mg/(kg x d) group, pioglitazone 20 mg/(kg x d) group and pioglitazone 20 mg/(kg x d) + peroxisome proliferator-activated receptor gamma (PPARgamma) specific antagonist GW9662 group. Left anterior descending coronary artery of rats were ligated for 30 min and reperfused for 120 min to establish the model of ischemia/reperfusion in vivo. RT-PCR was performed to detect the expression of TGFbeta1 mRNA. Western blot was performed to detect the expression of TGFbeta1 protein.Myocardial apoptosis was significantly suppressed by pioglitazone. Pioglitazone upregulated TGFPbeta1 expression both in mRNA and protein level. GW9662 reversed the inhibition of myocardial apoptosis and the upregulation of TGFbeta1 expression by pioglitazone.Pioglitazone can inhibit the myocardial apoptosis induced by ischemia/reperfusion. Pioglitazone may protect the myocardium from ischemia/reperfusion via upregulation of TGFbeta1. This protection may be mediated by PPARgamma.

To compare and study the dipeptidy1 peptidase-4 (DPP-4) inhibitors in combination with metformin against established combination therapies.This 16-week study was designed to compare sitagliptin versus pioglitazone as add-on therapy in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. Fifty-two patients were randomized into two groups to receive either sitagliptin 100 mg (group 1) or pioglitazone 30 mg (group 2) in addition to metformin. The primary efficacy end point was change in HbA1c. Secondary end points included change in fasting plasma glucose (FPG), body weight and lipid profile. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire. Both the groups had a significant decrease in HbA1c.There was no significant difference between mean reductions in FPG in both the groups. There was a significant decrease in the mean body weight and body mass index in group 1 in contrast to the significant increase in the same in group 2. Both the treatment groups reported a significant decrease in High-density lipoprotein (HDL-C) and Triglyceride.Sitagliptin was well tolerated without any incidence of hypoglycemia. It was concluded that sitagliptin as an add-on to metformin is as effective and well tolerated as pioglitazone.

To explore the role of peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway in osteo- blast differentiation of rat bone marrow mesenchymal stem cells (BMSCs) cultured in simulated microgravity.Rat BMSCs were cultured in simulated microgravity (by rotating clinostat) in the presence of 10 µmol/L pioglitazone, 10 µmol/L GW9662, or both pioglitazone and GW9662, with the cells cultured in normal gravity as the control group. After osteogenic induction for 14 days, the cells were stained with alizarin red for the bone nodules and with oil red-O for the fat cells, and the fat rate was calculated. ALP activity in the cells was determined in each group, and RT-PCR was performed to detect cellular expressions of PPARγ mRNA.Pioglitazone significantly inhibited osteoblast differentiation of the BMSCs, whereas GW9662 promoted the cell differentiation by suppressing the activation of PPARγ.We hypothesize that the activation of PPARγ signaling pathway is one of the main mechanisms for inhibited osteoblast differentiation of rat BMSCs in simulated microgravity, and inhibiting PPARγ pathway activation can effectively prevent and treat microgravity-induced osteoporosis.

BACKGROUND:

Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.

METHODS:

We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.

RESULTS:

After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.

CONCLUSIONS:

Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.Trial registration: UMIN-CTR: UMIN000010142.