Effects of Gemfibrozil Therapy on Glucose Tolerance, Insulin Sensitivity and Plasma Plasminogen Activator Inhibitor Activity in Hypertriglyceridaemia

Asplund-Carlson, Anette

doi:10.1177/174182679600300409

Cited by 10 publications

(6 citation statements)

References 19 publications

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“…In fact, the fibrate class of PPAR-␣ agonists has been safely used in humans to treat hypertriglyceridemia, and no hepatic carcinogenesis has been reported (34). Although the effect of PPAR-␣ activation on insulin sensitivity is inconclusive in humans, some recent clinical studies have shown improved insulin sensitivity by fibrates (35,36). It should be noted that the fenofibrate doses used in the present study (ϳ74 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) were much higher than those clinically used in the treatment of dyslipidemia (100 -250 mg/day).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

et al. 2003

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Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-␣ and PPAR-␥ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. I ncreasing evidence suggests that lipid accumulation in nonadipose tissues, such as skeletal muscle and pancreatic islet, is causally related to the development of type 2 diabetes in obese individuals (1,2). Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear transcription factors that regulate lipid metabolism (3). Thiazolidinedione (TZD), a high-affinity ligand for PPAR-␥, is now widely used as an insulin-sensitizing drug (4) and has been shown to reduce fat accumulation in skeletal muscle (5). TZD has also been suggested to reduce fat accumulation in other nonadipose tissues such as islets and heart (6). However, these favorable effects of TZD on nonadipose tissues may not arise directly from PPAR-␥ activation in these tissues. PPAR-␥ is highly expressed in adipose tissue, but its expression is low in nonadipose tissues such as skeletal muscle or pancreatic ␤-cells (7). Therefore, it has been suggested that TZD improves muscle insulin action and prevents apoptosis of pancreatic ␤-cells by sequestering lipids in adipose tissue (8) or by increasing production of adiponectin (9), an adipocytokine that has been shown to increase insulin sensitivity (10).The role of PPAR-␣ in the regulation of intracellular lipid homeostasis in nonadipose tissues may be more straightforward. Normally, it is expressed in nonadipose tissues at relatively high levels compared with PPAR-␥ (11). PPAR-␣ is a transcription factor that has been shown to upregulate fatty acid oxidative enzymes mainly in the liver (12), but recent studies have indicated that it also increases fatty acid oxidation in skeletal muscle (13). It was also reported that PPAR-␣ stimulators increase insulin sensitivity and reduce adiposity (14) and lipid accumulation in skeletal muscle (5). The expression of PPAR-␣ and enzymes of fatty acid oxidation is markedly reduced in the fat-laden dysfunctional islets of obese prediabetic Zucker diabetic fatty (fa/fa) rats (15). It is unknown, however, whether PPAR-␣ stimulators can prevent ␤-cell destruction and diabetes in diabetes-prone animals. The present study was therefore undertaken to examine the potential preventive effects of PPAR-␣ stimulation on the development of diabetes in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and diabetes. RESEARCH DESIGN AND METHODS Animals.Male OLETF rats and their lean nondiabetic counterparts, LongEvans Tokushima Otsuka (LETO) rats, were supplied at 4 weeks of age by the Otsuka Pharmaceutical Company (Tokushima, Japan). The rats were maintained at an ambient temperature (22 Ϯ 1°C) with 12:12-h light-dark cycles and free access to water and rat food. All procedures were approved by the Institutional Animal Care ...

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

et al. 2003

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“…The literature is inconsistent regarding whether fibrates improve glucose homeostasis; some studies showed improved insulin sensitivity (Jonkers et al, 2001;Damci et al, 2003;Kim et al, 2003;Cree et al, 2007;Tenenbaum et al, 2007), but others report that fibrates raise glucose and glycosylated hemoglobin and do not improve insulin sensitivity (Sane et al, 1995;Asplund-Carlson, 1996;Anderlová et al, 2007). Because hyperlipidemia and FFA overload contribute to insulin resistance (Carpentier, 2008), triglyceride lowering with bezafibrate seems to have been coincident with improved insulin sensibility.…”

Section: Discussionmentioning

confidence: 99%

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Tremblay‐Mercier¹,

Tessier²,

Plourde³

et al. 2010

J Pharmacol Exp Ther

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Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferatoractivated receptor (PPAR)-␣ agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 Ϯ 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). ␤-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid ␤-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-13 C]linoleic acid. As expected, 12weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial ␤-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p ϭ 0.03). ␤-Oxidation of [U-13 C]linoleic acid increased by 30% (p ϭ 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p ϭ 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPAR␣ stimulation and to moderately improved glucose metabolism.As the population ages, the prevalence of cognitive impairment in the elderly, particularly Alzheimer's disease (AD), is increasing markedly. Glucose is the brain's main energy substrate, providing energy to make ATP to maintain ion gradients, synaptic transmission, protein synthesis (for review, see Hoyer, 1996), and fatty acid turnover in membranes phospholipids (Rapoport et al., 2001). A decline in cerebral glucose metabolism is widely reported in AD (Foster et al., 1984;Blennow et al., 2006;Mosconi et al., 2007). This deterioration in brain fuel supply is progressive, correlates broadly with dementia severity, and may appear during normal aging at which time there can be an approximately 6% reduction in glucose uptake per decade (Petit-Taboué et al., 1998). Reduced brain glucose metabolism can arise before the clinical symptoms of AD (Reiman et al., 2004) and may contribute to neurodegenerative processes leading to AD (Liu 2004(Liu , 2008. As such, an alternative brain fuel to glucose may be therapeutically useful in AD.Physiologically, ketone bodies [or ketones; ␤-hydroxybutyrate (␤-OHB), acetoacetate, and acetone] are the main alternative energy substrate to glucose for brain metabolism and are especially important during periods of glucose deprivation. Ketones can supply up to two thirds of the energy requirement of the brain during starvation (Owen et al., 1967). Mildly increasing ketone synthesis has been proposed as a possible therapeutic approach to correct or bypass brain

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“…Given that lipid oversupply/accumulation leads to insulin resistance, one would expect that lowering lipids with a PPAR-␣ agonist should also attenuate insulin resistance, as does a PPAR-␥ agonist in insulin-resistant states caused by lipid oversupply/accumulation (7). However, studies in humans have been inconclusive, with reports showing both improved (12,13) and unimproved insulin sensitivity (14,15). It might be that the PPAR-␣ agonists, though lowering circulating lipids, have little effect on muscle lipids in those reports in which insulin sensitivity is not improved.…”

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confidence: 94%

Peroxisome Proliferator—Activated Receptor (PPAR)-αActivation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat—Fed Rats

et al. 2001

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Peroxisome proliferator-activated receptor (PPAR)-␣ agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-␣ activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-␥ activation. Threeweek high fat-fed male Wistar rats were untreated or treated with the specific PPAR-␣ agonist WY14643 or the PPAR-␥ agonist pioglitazone (both 3 mg · kg -1 · day -1 ) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced wholebody insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulinmediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-␣ and PPAR-␥ activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation. Diabetes 50:411-417, 2001

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Effects of Gemfibrozil Therapy on Glucose Tolerance, Insulin Sensitivity and Plasma Plasminogen Activator Inhibitor Activity in Hypertriglyceridaemia

Cited by 10 publications

References 19 publications

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Peroxisome Proliferator—Activated Receptor (PPAR)-αActivation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat—Fed Rats

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