Effects of the PPARγ agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus

Nagashima, Kazunori; López, Carlos; Donovan, Daniel S.; Ngai, Colleen; Fontanez, Nelson; Bensadoun, André; Fruchart‐Najib, Jamila; Holleran, Steve; Cohn, Jeffrey S.; Ramakrishnan, Rajasekhar; Ginsberg, Henry N.

doi:10.1172/jci23219

Cited by 104 publications

(97 citation statements)

References 108 publications

(101 reference statements)

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“…These results are consistent with the concept that the insulin-sensitising effect of PPAR-γ agonists, at least in part, are indirect and mediated via a reduction in plasma NEFA and intramyocellular concentration of toxic lipid metabolites [1,35]. In a recent study [36], PIO was shown to enhance the clearance of very-low-density-lipoprotein (VLDL) triacylglycerol-rich particles from the circulation. However, since substrate (plasma NEFA and glucose) delivery to the liver plays an important role in hepatic triacylglycerol synthesis [37], one could hypothesise that part of PIO's triacylglycerol-lowering effect could be related to the reduction in plasma NEFA and/or glucose concentrations.…”

Section: Discussionsupporting

confidence: 87%

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Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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Section: Discussionsupporting

confidence: 87%

“…In contrast, PIO does not alter APOA5 expression in patients with type 2 diabetes [36]. Despite the widespread use of PPAR-α agonists (i.e.…”

Section: Discussionmentioning

confidence: 93%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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“…Apolipoprotein C-III is an inhibitor of LPL and its absence is known to accelerate the disposal of dietary lipid [35]. A recent study on the effect of treatment with pioglitazone in a group of eight type 2 diabetic patients has shown a decrease in apolipoprotein C-III levels, although this is not thought to be mediated through the PPAR-γ receptor [36]. Some influence of insulin resistance on C-III levels can be inferred from the finding that its concentration in plasma correlates strongly with the level of production and concentration of VLDL triglyceride and also with the HOMA score of insulin sensitivity [37].…”

Section: Discussionmentioning

confidence: 99%

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

et al. 2006

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Aims/hypothesis: Insulin resistance is thought to be central to the pathogenesis of diabetic dyslipidaemia. We hypothesised that improving insulin sensitivity would improve fasting and postprandial triglyceride metabolism in patients with type 2 diabetes. To this aim we studied fasting and postprandial lipaemia in type 2 diabetic patients before and after sensitisation to insulin with pioglitazone, compared with that observed in patients on an insulinproviding regime. Methods: In a double-blind placebo-controlled protocol, 22 patients with type 2 diabetes were randomly allocated to receive either pioglitazone (45 mg/day) or glibenclamide (5 mg/day), for a 20-week period. Fasting and postprandial lipid metabolism were investigated at baseline and at the end of the treatment period. A group of non-diabetic subjects was also studied. Results: Compared with glibenclamide treatment, pioglitazone treatment decreased fasting triglyceride, glucose and insulin levels and the homeostasis model assessment score of insulin resistance. Decreased fasting triglyceride after pioglitazone treatment was due to reduced VLDL triglyceride, particularly VLDL-2. Lipoprotein lipase activity was unchanged by pioglitazone treatment but hepatic lipase showed a significant decrease. Pioglitazone treatment lowered total postprandial triglyceride, as well as chylomicron-and chylomicron-remnant retinyl palmitate levels to normal. Glucose disposal improved but remained abnormal. Conclusions/interpretation: Insulin sensitisation with pioglitazone has major effects in restoring postprandial lipaemia to normal, while also correcting fasting hypertriglyceridaemia; both factors may have consequences for atherogenic risk in diabetes.

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“…In diabetic humans, pioglitazone lowers triglycerides by increasing clearance of very low‐density lipoproteins (VLDL), ostensibly through enhanced activity of lipoprotein lipase, an insulin‐regulated enzyme that mediates VLDL‐triglyceride hydrolysis 29. A similar mechanism may have been responsible for the decrease in triglycerides in the obese cats.…”

Section: Discussionmentioning

confidence: 99%

“…A similar mechanism may have been responsible for the decrease in triglycerides in the obese cats. With regard to cholesterol, the effects of pioglitazone differ between humans and cats: pioglitazone increases high‐density lipoprotein (HDL) cholesterol in humans, but does not affect total cholesterol 20, 29. This difference may relate to the fact that (1) cats carry most of their cholesterol in HDL, and (2) activity of cholesteryl ester transfer protein, which catalyzes the exchange of cholesterol between HDL and other lipoproteins, appears to be very low in cats 30.…”

Section: Discussionmentioning

confidence: 99%

Effects of Pioglitazone on Insulin Sensitivity and Serum Lipids in Obese Cats

Clark

Thomaseth

Dirikolu

et al. 2013

Veterinary Internal Medicne

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BackgroundPioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. Therapeutic options for diabetes in cats are limited.ObjectiveTo evaluate the effects of pioglitazone in obese cats, which are predisposed to insulin resistance, to assess its potential for future use in feline diabetes mellitus.AnimalsA total of 12 obese purpose‐bred research cats (6 neutered males and 6 spayed females, 5–7 years of age, weighing 5.4–9.8 kg).MethodsRandomized, placebo‐controlled 3‐way crossover study. Oral placebo or pioglitazone (Actos™; 1 or 3 mg/kg) was administered daily for 7‐week periods, with IV glucose tolerance testing before and after each period.ResultsThree mg/kg pioglitazone significantly improved insulin sensitivity (geometric mean [95% CI] 0.90 [0.64–1.28] to 2.03 [1.49–2.78] min −1pmol−1L; P = .0014 versus change with placebo), reduced insulin area under the curve during IVGTT (geometric mean [range] 27 [9–64] to 18 [6–54] min∙nmol/L; P = .0031 versus change with placebo), and lowered serum triglyceride (geometric mean [range] 71 [29–271] to 48 [27–75] mg/dL; P = .047 versus change with placebo) and cholesterol (geometric mean [range] 187 [133–294] to 162 [107–249] mg/dL; P = .0042 versus change with placebo) concentrations in the obese cats. No adverse effects attributable to pioglitazone were evident in the otherwise healthy obese cats at this dosage and duration.Conclusions and Clinical ImportanceResults of this study support a positive effect of pioglitazone on insulin sensitivity and lipid metabolism in obese cats, and suggest that further evaluation of the drug in cats with diabetes mellitus or other metabolic disorders might be warranted.

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Effects of the PPARγ agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus

Cited by 104 publications

References 108 publications

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

Effects of Pioglitazone on Insulin Sensitivity and Serum Lipids in Obese Cats

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