BM 17.0744: A structurally new antidiabetic compound with insulin-sensitizing and lipid-lowering activity

Pill, Johannes; Kühnle, H.F.

doi:10.1016/s0026-0495(99)90007-0

Cited by 23 publications

(12 citation statements)

References 32 publications

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“…This outcome is consistent with those of previous studies (9,20,39) that showed no rhabdomyolysis after BEZ treatment at the same dosage. We found that BEZ, like other fibrates, can induce hepatomegaly in mice (data not shown), which is consistent with previous studies (40), and may be attributable to its capacity to induce peroxisome proliferation (41). Peroxisomal proliferation is species specific (42,43) because fibrate treatment does not cause hepatomegaly and peroxisomal proliferation in primates and humans (44)(45)(46).…”

Section: Discussionsupporting

confidence: 88%

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

et al. 2016

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Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

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Section: Discussionsupporting

confidence: 88%

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

et al. 2016

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“…Treating db/db mice with the PPAR-␣ ligand BM 17.0744 resulted in a reduction in blood glucose consistent with previous investigations (7,37,38). BM 17.0744 also normalized plasma lipids (free fatty acids and TG) and reduced plasma insulin levels (7).…”

Section: Figsupporting

confidence: 89%

Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From db/db Mice

et al. 2003

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Glucose and palmitate metabolism and contractile function were measured with ex vivo perfused working hearts from control (db/؉) and diabetic (db/db) female mice at 6, 10 -12, and 16 -18 weeks of age. Palmitate oxidation was increased by 2.2-fold in 6-week-old db/db hearts and remained elevated in 10-to 12-and 16-to 18-week-old hearts. Carbohydrate oxidation was normal at 6 weeks but was reduced to 27 and 23% of control at 10 -12 and 16 -18 weeks, respectively. At 6 weeks, db/db hearts exhibited a slight reduction in mechanical function, whereas marked signs of dysfunction were evident at 10 -12 and 16 -18 weeks. Mechanical function after ischemia-reperfusion was examined in hearts from male mice; at 6 weeks, db/db hearts showed normal recovery, whereas at 12 weeks it was markedly reduced. Fatty acid oxidation was the predominant substrate used after reperfusion. Thus, diabetic db/db hearts exhibit signs of a progressive cardiomyopathy; increased fatty acid oxidation preceded reductions in carbohydrate oxidation. Postischemic recovery of function was reduced in db/db hearts, in parallel with age-dependent changes in normoxic contractile performance. Finally, peroxisome proliferator-activated receptor-␣ treatment (3 weeks) did not affect sensitivity to ischemiareperfusion, even though carbohydrate oxidation was increased and palmitate oxidation was decreased. Diabetes 52:434 -441, 2003 N on-insulin-dependent (type 2) diabetes is a prevalent disease that results in a marked increase in cardiovascular complications (1) that are in part due to a specific cardiomyopathy, characterized by ventricular dysfunction in the absence of atherosclerotic coronary heart disease or hypertension (2,3).Diabetic db/db mice provide an animal model of type 2 diabetes, with obesity and insulin resistance (4,5). Recently, we have reported that isolated perfused hearts from db/db mice at 10 -14 weeks of age exhibited characteristics of a diabetic cardiomyopathy, with decreased contractile performance and altered cardiac metabolism (6,7).The natural history of db/db mice follows a distinct pattern (8,9). Initially, peripheral insulin resistance is overcome by increased insulin secretion, so hyperinsulinemia produces normoglycemia. Hyperglycemia develops when enhanced insulin secretion can no longer compensate for insulin resistance. The maximal extent of hyperinsulinemia occurs at 2-3 months of age. Subsequently, insulin levels fall rapidly as ␤-cells exhibit a severe secretory defect, resulting in a progressive increase in hyperglycemia. Thus, the metabolic features of db/db mice are similar to the pathogenesis of type 2 diabetes in humans (10).The first objective of this investigation was to study age-dependent changes of cardiac function and metabolism in db/db mice assessed with ex vivo perfused hearts (7,11,12). Of particular interest was to establish whether the onset of metabolic alterations coincided with contractile dysfunction. Previously, evidence for contractile dysfunction in perfused db/db hearts has been obtained from norm...

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“…None of the organs showed any weight changes, apart from the liver and kidneys, which showed an increase. These effects were quantitatively comparable with those of bezafibrate (36).…”

Section: Pharmacokineticssupporting

confidence: 66%

“…Lipid lowering by BM 17.0744 was associated with elevated carnitine acetyl transferase (CAT) activity in the livers of rats (36). Enhancement of CAT may be an indication of an increase in fatty acid catabolism.…”

Section: Mode Of Actionmentioning

confidence: 99%

Reduction of Risk Factors for Cardiovascular Complications by BM 17.0744

Pill

Meyer

1999

Cardiovascular Drug Reviews

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BM 17.0744: A structurally new antidiabetic compound with insulin-sensitizing and lipid-lowering activity

Cited by 23 publications

References 32 publications

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From db/db Mice

Reduction of Risk Factors for Cardiovascular Complications by BM 17.0744

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