Metabolic Control of Prevention of Nephropathy by 2-Tetradecylglycidate in the Diabetic Mouse (db/db)

Lee, Stanly M; Tutwiler, Gene F.; Bressler, Rubin; Kircher, Charles H.

doi:10.2337/diab.31.1.12

Cited by 21 publications

(4 citation statements)

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“…In the BLKS background hyperinsulinemia develops at 10 days of age, blood glucose levels are slightly elevated at 4 weeks of age and with frank hyperglycemia at 8 weeks. The hyperglycemia increases gradually until bodyweight and blood glucose levels begin to fall at 5-6 months due to β-cell destruction [202,203]. After 4 months of age there is a 3-fold increase in mesangial matrix expansion [204].…”

Section: T2dm Modelsmentioning

confidence: 99%

Pericytes regulate the blood–brain barrier

Armulik

Genové

Mäe

et al. 2010

Nature

2,314

2,310

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The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.

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Section: T2dm Modelsmentioning

confidence: 99%

Pericytes regulate the blood–brain barrier

Armulik

Genové

Mäe

et al. 2010

Nature

2,314

2,310

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“…Another compound analogue to 43, compound 47 (S15176), has been reported to be a more potent CPT1 inhibitor (IC 50 = 16.8 μM in heart and 51 μM in liver mitochondria, confirmed in ex vivo studies). 147 Perhexiline (44), frequently prescribed as an antianginal agent in the 1970s, is currently used almost exclusively in Australia. 148…”

Section: ' Cpt Inhibitorsmentioning

confidence: 99%

“…209 The potential combination of antidiabetic and cardioprotective effects suggests CPT1B inhibitors as the optimal intervention in advanced NIDD, complicated by cardiovascular liabilities. Oxirane carboxylic acids, with their additional effects on circulating lipids and expression of key cardiac genes, as well as renal protective effects observed in rodent models of diabetes, 44,210 represent an extremely interesting molecular entity whose medicinal chemistry and therapeutic potential has not been exhaustively explored.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Carnitine Palmitoyltransferase (CPT) Modulators: A Medicinal Chemistry Perspective on 35 Years of Research

et al. 2011

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PERSPECTIVEhomology in the active site. These data would point a medicinal chemist to expect that it should be relatively easy to gain selectivity between CPT2 and CPT1 inhibitors, while it might prove to be a daunting task for a competitive inhibitor to differentiate CPT1A from CPT1B. An alternative option is to achieve tissue selective distribution of an unspecific inhibitor via permeability and pharmacodynamic properties.The homology between human, rat, and mouse enzymes, on the other hand, is rather high (see Table 3b), and species differences at the in vitro level are not likely to be significant (the rate of FAO in different species and the level of CPT activity control can be considerably different). 22 CPT1 is subject to multiple controlling factors. Expression level and basal activity of CPT1 depend on fasting state, 23 exercise, 24 type of diet, 25 exposure to cold, infections, metabolic disease, and enzyme inhibition. 9 Diabetes does not affect CPT1B activity 26 but increases CPT1A activity. 27 Malonyl-CoA, the first committed step of fatty acid synthesis, whose concentration is in turn highly regulated by multiple mechanisms, is a potent inhibitor of CPT1B (∼0.03 μM IC 50 for the rat enzyme) and a less potent inhibitor (by about 2 orders of magnitude) of CPT1A. 28,29 The sensitivity of CPT1A to allosteric inhibition by malonyl-CoA varies under different physiological conditions, amplifying the effect of the cellular malonyl-CoA concentration. In particular, declining malonyl-CoA concentrations reduce the sensitivity of the enzyme to allosteric inhibition (and vice versa). Mitochondrial outer membrane composition also affects sensitivity of CPT1A to malonyl-CoA. Studies regarding the binding of malonyl-CoA and other active-site directed inhibitors have shown that there are two separate binding sites for malonyl-CoA: a high-affinity binding site located on the cytoplasmic side of the protein and a second low-affinity site that corresponds to the catalytic site and where also CoA exerts a product-inhibition action. 30 It is postulated that one of these binding sites is a contact interaction between the N-and C-terminal segments of the protein, which explains the sensitivity to membrane fluidity as well as the loss of sensitivity to malonyl-CoA if the N-terminal portion of the protein is deleted (which also leads to loss of function) or by specific single point mutations in this region. The N-terminal domain is also responsible for the targeting of the enzyme to the outer mitochondrial membrane. 31 There is evidence that CPT activity is controlled by phosphorylation 32 and nitration, 33 although the hypothesis has been advanced that CPT is constitutively phosphorylated. 28

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“…Methyl palmoxirate (Me-TDGA, methyl 2tetradecylglycidate), is a potent, specific, irreversible inhibitor of the mitochondrial enzyme carnitine palmitoyltransferase (CPT-A) (Tutwiler & Ryzlak, 1980;Kiorpes et al, 1984) and of long-chain fatty acid oxidation (Tutwiler et al, , 1981Tutwiler & Dellevigne, 1979). Me-TDGA is an orally effective hypoglycaemic and hypoketonaemic agent in fasted nondiabetic and diabetic animals (Tutwiler et al, 1978;1981;1983; Lee et al, 1982) and in preliminary studies in diabetic patients (Mandarino et al, 1984;Verhaegen et al, 1984). In 48-h fasted nondiabetic rats, plasma ketones and liver mitochondrial CPT-A activity were previously shown to be significantly decreased following single oral doses of Me-TDGA (0.05-0.25mgkg-1) that were 10 to 25 fold less than those required for consistent inhibition 1 Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Hypoglycaemic and hypoketonaemic effects of single and repeated oral doses of methyl palmoxirate (methyl 2‐tetradecylglycidate) in streptozotocin/alloxan‐induced diabetic dogs

Tuman

Tutwiler

Joseph

et al. 1988

British J Pharmacology

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1 The hypoglycaemic and hypoketonaemic effects of orally administered methyl palmoxirate were studied in streptozotocin/alloxan-induced diabetic dogs. 2 Single oral 50mg doses (-7.5mgkg-1) of methyl palmoxirate produced statistically significant reductions of plasma glucose (32 + 6% maximum reduction from baseline) and ketones (74 + 12% maximum reduction from baseline), with the peak effect on plasma ketones (3.5 h) preceding that for plasma glucose (6.0 h). 3 Lower doses (0.7-2.0mg kg' daily) of methyl palmoxirate given repeatedly for seven days produced reductions of blood glucose and ketones equivalent to those produced with the higher single dose. Maximal reductions of plasma ketones were generally observed following the first dose of drug, whereas significant lowering of plasma glucose required several days of continuous dosing. 4 Repeated daily doses of methyl palmoxirate markedly reduced the overnight fasting ketone levels but not glucose levels of diabetic dogs. 5 In conclusion, administration of the fatty acid oxidation inhibitor methyl palmoxirate, in the absence of concomitant insulin therapy, was able to lower the plasma glucose and ketone levels of insulin-deficient streptozotocin/alloxan diabetic dogs. Only the plasma ketones were decreased to normal by this treatment.

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Metabolic Control of Prevention of Nephropathy by 2-Tetradecylglycidate in the Diabetic Mouse (db/db)

Cited by 21 publications

References 0 publications

Pericytes regulate the blood–brain barrier

Pericytes regulate the blood–brain barrier

Carnitine Palmitoyltransferase (CPT) Modulators: A Medicinal Chemistry Perspective on 35 Years of Research

Hypoglycaemic and hypoketonaemic effects of single and repeated oral doses of methyl palmoxirate (methyl 2‐tetradecylglycidate) in streptozotocin/alloxan‐induced diabetic dogs

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