Effect of the fatty acid oxidation inhibitor methyl palmoxirate (methyl 2-tetradecylglycidate) on recovery from insulin-induced hypoglycemia in diabetic dogs.

Methyl palmoxirate, an effective hypoglycemic agent administered p.o., has been shown to decrease hepatic glucose production secondary to inhibition of mitochondrial fatty acid oxidation.

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

1. The hypoglycaemic and hypoketonaemic effects of orally administered methyl palmoxirate were studied in streptozotocin/alloxan-induced diabetic dogs. 2.

Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid (TDGA) on glucose and fatty acid oxidation in isolated rat soleus muscle.

1. The effect of 2-tetradecylglycidic acid (TDGA), a potent, specific inhibitor of long-chain fatty acid oxidation, on fatty acid and glucose oxidation by isolated rat soleus muscle was studied. 2.

Resolution of (+/-)-2-tetradecyloxiranecarboxylic acid. Absolute configuration and chiral synthesis of the hypoglycemic R enantiomer and biological activity of enantiomers.

The resolution of the hypoglycemic agent (+/-)-2-tetradecyloxiranecarboxylic acid (3) as its d- and l-ephedrine salts is presented. The active enantiomer (R)-(+)-3 was also synthesized by the Sharpless chiral epoxidation procedure and its methyl ester (R)-(+)-4 was shown to be identical with the corresponding ester from the resolved acid. Single-crystal X-ray structure analysis of the diastereomeric salt of (+)-3 and (-)-ephedrine allowed assignment of (+)-3 as the R configuration.

Influence of the oral hypoglycemic agent linogliride (McN-3935) on insulin secretion from isolated rat islets of Langerhans.

The influence of a new orally effective hypoglycemic compound, linogliride (McN-3935), on insulin release from isolated perifused rat islets was investigated. At a concentration of 100 microM, linogliride was without effect on insulin secretion in the absence of glucose. While 5.

Alkylglycidic acids: potential new hypoglycemic agents.

A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to transport long-chain fatty acids into the mitochondria for subsequent beta-oxidation, was determined for the series. Structure-activity relationships using in vitro inhibition of [1-14C]palmitic acid oxidation in rat hemidiaphragm muscle indicate that potent activity resides mainly in 2-alkyl (C12-C16) glycidates.

Highly purified human growth hormone fails to stimulate lipolysis in rabbit adipocytes in vitro or in rabbits in vivo.

To determine whether the rapid lipolytic effect observed with human growth hormone (hGH) preparations in rabbits and rabbit adipose tissue is an intrinsic property of the hormone, we examined the lipolytic effects in vivo and in vitro of clinical grade preparations, hGH purified by DEAE cellulose chromatography, and hGH prepared by recombinant DNA techniques. Using isolated rabbit perirenal adipocytes, ACTH and clinical-grade hGH preparations both stimulated glycerol release to the same maximal rate with half-maximal hGH effects observed between 8 and 50 micrograms/mL. Purification of the most potent lipolytic preparation of clinical grade hGH by DEAE cellulose chromatography yielded a preparation (2 IU/mg of growth activity that retained insulinlike effects on rat fat pad [U-14C] glucose metabolism) that, at concentrations up to 0.

Inhibition of mitochondrial carnitine palmitoyl transferase A in vivo with methyl 2-tetradecylglycidate (methyl palmoxirate) and its relationship to ketonemia and glycemia.

The oral hypoglycemic agent, methyl 2-tetradecylglycidate (Me-TDGA), which inhibits in vitro mitochondrial carnitine palmitoyl transferase A (CPT-A) was used to study the relationship of CPT inhibition to changes in ketonemia and glycemia in normal and diabetic rats. After oral administration of Me-TDGA, the CPT activity of isolated rat liver mitochondria was substantially reduced with only the presumed outer enzyme fraction CPT-A released by digitonin treatment showing reduced activity. Mitochondrial fatty acyl-CoA synthetase was not inhibited.

Mechanism of hyperglycemia and response to treatment with an inhibitor of fatty acid oxidation in a patient with insulin resistance due to antiinsulin receptor antibodies.

Severe hyperglycemia and insulin resistance due to antiinsulin receptor antibodies developed over a period of 3 months in a 50-yr-old insulin-requiring diabetic patient. The hyperglycemia resulted from overproduction of glucose due to excessive rates of glycogenolysis and gluconeogenesis rather than decreased glucose utilization. Treatment with methyl-2-tetradecylglycidate, an inhibitor of fatty acid oxidation, resulted in a decrease in plasma glucose concentration.

Identification of 2-tetradecylglycidyl coenzyme A as the active form of methyl 2-tetradecylglycidate (methyl palmoxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine palmitoyltransferase A in isolated rat liver mitochondria.

Methyl-2-tetradecylglycidic acid (MeTDGA) has been hypothesized to inhibit fatty acid oxidation by irreversible, active site-directed inactivation of carnitine palmitoyltransferase A after being converted to TDGA-CoA. Using synthetic TDGA-CoA, this hypothesis has been confirmed. Assessing enzyme inhibition in an isolated rat liver mitochondrial system, TDGA-CoA (synthetic or enzyme prepared) was more potent than TDGA or MeTDGA and retained activity in the absence of CoA or Mg2+-ATP.

Effects of the oral hypoglycemic agent methyl palmoxirate on exercise capacity of rats.

The effect of the oral hypoglycemic agent methyl palmoxirate (methyl 2-tetradecylglycidate, McN-3716), a selective inhibitor of long chain fatty acid oxidation, on the exercise capacity of normal rats was evaluated. Daily administration of 2.5 mg/kg for 7 days, or of a single dose of 10 mg/kg, of methyl palmoxirate did not affect the ability of rats to perform strenuous exercise of an intensity that caused exhaustion in less than 30 min.

Alloxan analogues as potential pancreatic-imaging radiopharmaceuticals.

Three families of alloxan derivatives, 5-arylthiobarbituric, 5-aryliminobarbituric, and 5-aryldialuric acids, were prepared as prospective radioiodine-transporting radiopharmaceuticals for the delineation of pancreatic insulinomas. Members of each class were screened for effects on blood sugar levels in a rat glucose tolerance assay. Transient hyperglycemia was observed with 5-(2,4-dichlorophenyl)iminobarbituric acid.

Effect of the oral hypoglycemic agent pirogliride (McN-3495) on glycogen levels of normal and diabetic rats.

Pirogliride, a new oral hypoglycemic agent unrelated structurally or mechanistically to either the sulfonylureas or biguanides, produced a dose-dependent increase in liver but not muscle glycogen levels of fasted non-diabetic rats and produced at 100 mg/kg, p.o. a modest increase in liver but not gastrocnemius muscle glycogen of fasted streptozotocin diabetic rats.

Relation of oxidation of long-chain fatty acids to gluconeogenesis in the perfused liver of the guinea pig: effect of 2-tetradecylglycidic acid (McN-3802).

1. The potent, specific inhibitor of long-chain fatty acid oxidation, 2-tetradecylglycidic acid (McN-3802), at 10 microM totally abolished ketogenesis from endogenous substrates in the isolated perfused guinea pig liver. This effect was accompanied by a marked inhibition of gluconeogenesis from lactate plus pyruvate and by a shift toward a more oxidized state of the mitochondrial (3-hydroxybutyrate/acetoacetate ratio) and cytoplasmic (lactate/pyruvate ratio) compartments.

Metabolic control of prevention of nephropathy by 2-tetradecylglycidate in the diabetic mouse (db/db).

The genetically diabetic mouse (db/db) exhibits hyperphagia, progressive weight gain, hyperglycemia, and hyperinsulinemia during the first few months of life during which time characteristic pathologic changes occur in several organ systems including the kidney. The extent to which long chain fatty acid oxidation (LCFAO) contributes to excessive gluconeogenesis and hyperglycemia in these animals in unknown. Therefore, the synthetic fatty acid analogue 2-tetradeclyglycidate (TDHA), a potent inhibitor of LCFAO, was given orally to db/db mice to evaluate its capacity to control the blood glucose and prevent their diabetic nephropathy.

Hyperglycemic activity of the 20,000-dalton variant of human growth hormone.

The 20,000-dalton structural variant of human growth hormone was inactive as a hyperglycemic agent in dogs when injected 10 h prior to a glucose tolerance test. Limited digestion with subtilisin did not generate hyperglycemic activity. These results are in contrast to those obtained with human growth hormone where subtilisin treatment potentiated the weak hyperglycemic activity of the undigested hormone.