Bezafibrate reduces blood glucose in type 2 diabetes mellitus

doi:10.1016/S0026-0495(00)90176-8

Metabolism

Volume 49, Issue 3, March 2000, Pages 331-334

https://doi.org/10.1016/S0026-0495(00)90176-8 Get rights and content

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% ± 1.6%, total cholesterol (TC) by 12% ± 1.1%, plasma glucose (PG) from 151.3 ± 3.5 to 128.6 ± 3.4 mg/dL, and hemoglobin A_1c (HbA_1c) from 7.2% ± 0.1% to 6.9% ± 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% ± 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-α) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.

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However, PPAR-α agonist fibrates are used to decrease plasma triglycerides and increase high-density lipoprotein cholesterol in clinical (Tenenbaum et al., 2005). Moreover, fibrates also modulates lipid metabolism and improves insulin resistance in obese mice (Ogawa et al., 2000). In addition, another PPAR-α agonist Wy-14643 has been proved to lower hepatic TG and improves insulin sensitivity in mice (Ye et al., 2001).
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C57BL/6 mice were fed high-fat diet (HFD) for 14 weeks to induce obesity, hyperglycemia, and fatty liver. These mice were subsequently treated with HFD alone or mixed with sweroside (at a daily dosage of 60 mg per kg of BW, 120 mg per kg of BW and 240 mg per kg of BW) for 6 weeks. BW and food intake was monitored weekly. Biochemical and pathological analysis were conducted to investigate the effect of sweroside on NAFLD. RNA-sequence and RT-qPCR analysis were performed to analyze the potential mechanism.
The mice treated with sweroside were resistant to HFD-induced body weight gain, insulin resistance and hepatic steatosis. Ingenuity pathway analysis (IPA) demonstrated that hepatic gene networks related to lipid metabolism and inflammatory response were down-regulated in the HFD + sweroside group. PPAR-ɑ was located in the center of the hepatic gene network, and the significantly altered genes were CD36 and FGF21, which are related to hepatic inflammation and lipid metabolism. Consistently, upstream-regulators analysis revealed that the main enriched upstream-regulator was PPAR-ɑ.
Our results indicate that sweroside may ameliorate obesity with fatty liver via the regulation of lipid metabolism and inflammatory responses. The beneficial effects of sweroside might be closely associated with the regulation of PPAR-α.
Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes
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Synthetic agonists of PPARα, such as fibrates, are clinically used to lower plasma triglycerides and increase high-density lipoprotein cholesterol [14]. In addition to the beneficial lipid modulation, fibrates improve insulin sensitivity in animal models of obesity [15]. The PPARγ isoform is also highly expressed in various cell types and organs, including adipocytes, muscle cells, the liver and the kidney, and is recognized as a master regulator of glucose homeostasis.
Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)α and γ, combining in a single molecule the metabolic and inflammatory-regulatory properties of α and γ agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation.
Here we investigated the effects of the dual PPARα/γ agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or ⿿ for comparison ⿿ the selective agonists for PPARα or γ fenofibrate or rosiglitazone, respectively, for 24 h before stimulation with TNF-α. Aleglitazar, at concentrations as low as 10 nmol/L, providing the half-maximal transcriptional activation of both PPARα and PPARγ, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-α-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-α-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARα and γ agonists.
In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARα and γ agonism, but with no evidence of synergism.
Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions
2015, Biochemical and Biophysical Research Communications
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It is expected that a longer period of treatment than one week would lead to greater improvement of critical GSIS-associated genes, such as Gck and Kcnj11, and better β-cell function. However, we chose a shorter period of treatment because long-term administration of SGLT2 inhibitors or fibrates were reported to relieve hyperlipidemia [23,24] or hyperglycemia [25,26], respectively, and we thought that these would make it difficult to evaluate the individual effects of alleviating glucotoxicity or lipotoxicity on β-cell gene expression and function. As a result, our data clearly showed that selective reduction of glucotoxicity for one week resulted in beneficial effects on the expression of key β-cell molecules and initiated improvements of β-cell function and mass, although further reduction of glucotoxicity or lipotoxicity may be required for a substantial restoration of β-cell function.
Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced β-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key β-cell factors critical for β-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions.
Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study
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Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers.
An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200 mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m², total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks.
Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p < 0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (−38.3%, p < 0.001 vs. −32.9%, p < 0.01) and increases in HDL-C (+18.0%, p < 0.001 vs. +11.7%, p < 0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, −11.2%, p < 0.01; non-HDL-C, −17.3%, p < 0.01; apolipoprotein B, −15.1%, p < 0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, −17.0%, p < 0.05) and metabolic markers (γ-GTP, −38.9%, p < 0.01; adiponectin, +15.4%, p < 0.05; urine 8-OHdG/Cre, −9.5%, p < 0.05).
Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.
Activation of peroxisome proliferator-activated receptor-α enhances fatty acid oxidation in human adipocytes
2011, Biochemical and Biophysical Research Communications
Peroxisome proliferator-activated receptor-α (PPARα) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPARα in adipocytes have been unclarified. We examined the functions of PPARα using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPARα by GW7647, a potent PPARα agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPARγ, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPARα activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPARγ is activated. On the other hand, PPARα activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPARα-dependent manner. Moreover, PPARα activation increased the production of CO₂ and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPARα stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPARα agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected effects of PPARα activation are very valuable for managing diabetic conditions accompanied by obesity, because PPARγ agonists, usually used as antidiabetic drugs, induce excessive lipid accumulation in adipocytes in addition to improvement of insulin resistance.
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Numerous multicenter randomized trials and smaller studies have estimated the effects of hypolipi-demic drugs on the serum concentrations of adipokines.[31] The treatment with bezafibrate [32] or the administration of fenofibrate [9] reduced the leptin levels in dyslipidemic patients who had type 2 diabetes mellitus. The bezafibrate-treated subjects who were enrolled in the Bezafibrate Infarction Prevention study displayed higher adiponectin levels than the placebo-treated patients [18].
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The visceral adipocytes released significantly more adiponectin and IL-6 and less PAI-1 than those that were obtained from subcutaneous tissue. The levels and patterns of adipokine release differed between the patients with or without lipid abnormalities and between the adipocytes that were obtained from visceral or subcutaneous adipose tissue. The culture that contained hypolipidemic drugs resulted in the significant changes of the release of adipokines. The effects of atorvastatin and fenofibric acid on the hormonal function of human adipocytes may be, in part, responsible for the clinical efficacy of these drugs in the prevention and treatment of dyslipidemia-related cardiovascular and metabolic disorders. The study supports the concept that the pleiotropic effects of fenofi-brate and atorvastatin may be, in part, a result of their impact on the secretory function of adipocytes.

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Bezafibrate reduces blood glucose in type 2 diabetes mellitus

Biochim Biophys Acta

Biochem Biophys Res Commun

Atherosclerosis

Metabolism

Apolipoproteins in diabetes mellitus

Prospective analysis of the insulin-resistance (syndrome X)

Diabetes

Contribution of intraabdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity

Metabolism

Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease

Diabetes Care

Tumor necrosis factor alpha: A key component of the obesity-diabetes link

Diabetes

Tumor necrosis factor α acutely inhibits insulin signaling in human adipocytes

Diabetes