RESUMEN
UNLABELLED: Acetyl-L-Carnitine (ALC), an activator of carnitine, can accelerate nerve regeneration after experimental surgical injury in rats. In this study, we examined the ability of ALC to improve nerve conduction velocity and its effect on intravenous glucose tolerance test in streptozotocin-induced diabetic rats. Diabetic (blood glucose > 200 mg%) and normal animals were treated intraperitoneally for four weeks with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction velocity was measured by direct exposure of sural nerve. Two-hour IVGTT was studied by measuring plasma glucose, insulin and free fatty acids after intravenous injection of glucose, 1.75 gm/Kg/body weight in animals treated either with ALC 150 md/Kg/d or saline alone. Six weeks of STZ-induced diabetes resulted in impairment of nerve conduction velocity in animals injected with saline (16.05 +/- 1.09 m/s), as compared to saline-treated normals who did not receive streptozotocin (31.0 +/- 0.84 m/s, p<0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d, preserved near normal nerve conduction (27.10 +/- 1.42 m/s), compared with the saline-treated diabetic animals (p < 0.0005), but diabetic animals treated with ALC, 50 mg/Kg/d, had a non-significant increase in nerve conduction (23.68 +/- 1.6). ALC treatment had no effect on fasting or post-intravenous plasma glucose in normal or diabetic rats, although it moderately reduced baseline and 40 minute insulin levels (p < 0.02) in normal rats as compared with their saline-treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p < 0.04) and diabetic (p < 0.03) animals, and the 60 minute levels in the normal group only (p < 0.003). CONCLUSION: ALC at a dose of 150 mg/Kg/d given for one month, produced near normalization of nerve conduction velocity in streptozotocin-induced diabetes with no adverse effects on glucose, insulin or free fatty acid levels.
Asunto(s)
Acetilcarnitina/farmacología , Glucemia/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/tratamiento farmacológico , Conducción Nerviosa/efectos de los fármacos , Animales , Neuropatías Diabéticas/fisiopatología , Evaluación Preclínica de Medicamentos , Prueba de Tolerancia a la Glucosa , Masculino , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacosRESUMEN
OBJECTIVES: New treatment options are needed for glycemic control in NIDDM. We evaluated the effects of bedtime or morning insulin treatment, combined with daytime glyburide or given alone. RESEARCH DESIGN AND METHODS: Twenty-nine male patients with NIDDM, mean age 63 +/- 1.7 yr, body weight 124 +/- 2.98% of DBW, received a maximum glyburide dose (20 mg/day) for a minimum of 6 wk, to confirm sulfonylurea failure. Human lente insulin was added for 12 wk either AM (n = 14) or HS (n = 15) and adjusted to obtain fasting euglycemia (FPG; combination treatment phase). Glyburide was then stopped, and insulin was continued for 6 wk, aiming for normal FPG (insulin phase). RESULTS: After combination treatment phase, FPG decreased (P < 0.02) from 12.43 +/- 0.68 to 5.73 +/- 0.65 mM (AM) and from 12.68 +/- 0.76 to 5.51 +/- 0.48 mM (HS) (AM vs. HS, NS). Postbreakfast, presupper, and 0200 AM plasma glucose levels fell equally (P < 0.02) except for 1-h postprandial (AM 12.46 +/- 0.51 mM, HS 10.88 +/- 0.62 mM, AM vs. HS, P < 0.1). Mean HBA1c fell similarly in both AM and HS groups. At 2 wk of the insulin phase, FPG was higher in AM than HS, 9.8 +/- 0.76 vs. 7.56 +/- 0.7 mM (P < 0.1). At the end of insulin phase, plasma glucose levels were similar to the end of combination treatment phase, but the insulin dose had to be raised in AM by 39% (P < 0.02) and HS by 30% (P < 0.05). After the combination treatment phase, fasting C-peptide was significantly suppressed in HS group only, from 1.22 +/- 0.12 to 0.82 +/- 0.09 nM (P < 0.02). At the end of insulin phase, fasting C-peptide was further suppressed in both groups, but 2-h postprandial C-peptide levels decreased significantly in AM group only, from 1.85 +/- 0.23 to 1.42 +/- 0.13 nM (P < 0.02). Triglycerides and total and HDL cholesterol did not change significantly after either combination treatment phase or insulin phase. Mean weight gain was 6.5 lb during combination treatment phase (NS from baseline), without further change during insulin phase. Hypoglycemic reactions, all mild, were recorded at a rate of 1.35/patient in the AM group and 0.4/patient in the HS group (P < 0.025). CONCLUSIONS: Normal fasting glycemia and near-normal postprandial glucose profile could be obtained with combination therapy in NIDDM. Results were similar if insulin, alone or in combination with glyburide, was given before breakfast or at bedtime, but hypoglycemic reactions were more common with conventional morning insulin injections.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliburida/uso terapéutico , Insulina de Acción Prolongada/administración & dosificación , Insulina de Acción Prolongada/uso terapéutico , Adulto , Anciano , Péptido C/sangre , Diabetes Mellitus Tipo 2/sangre , Esquema de Medicación , Quimioterapia Combinada , Ayuno , Gliburida/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Insulina de Acción Prolongada/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Factores de TiempoRESUMEN
Staub Effect or improved glucose disposal after repetitive glucose loads does not occur in untreated diabetes. In non-insulin dependent diabetes (NIDDM) there is impaired insulin response to intravenous (i.v.) glucose injection, especially in early insulin release (EIR) and the lesser known post EIR suppression of insulin levels below basal, or acute insulin decrement (AID). To test the ability of a second generation sulfonylurea, glyburide, to affect glucose primed glucose disposal and insulin secretory patterns, sixteen NIDDM male subjects received three hourly intravenous glucose loads while untreated and again after six months of glyburide therapy. After treatment there was a fall of fasting glycemia from 204 +/- 11 to 147 +/- 8 mg/dl (p less than 0.001), of all glucose levels during the i.v. glucose tolerance tests (p less than 0.025) and glycosylated hemoglobin from 8 +/- 0.3% to 7.6 +/- 0.3% (p less than 0.005). Before treatment i.v. glucose disposal (K value) changed very little after successive glucose challenges, but after glyburide all mean K values were higher, and glucose primed glucose disposals were faster after the second (K2) and third (K3) glucose injection than after the first (K1) (p less than 0.025 and p less than 0.01 respectively). In the untreated state, there was higher and significant EIR by the third glucose load, (p less than 0.025) while AID was clearly more pronounced after the second load (p less than 0.001). After glyburide treatment EIR was significantly higher than before in all loads, and mean AID was no longer demonstrable. Insulin summation (S) after successive i.v. loads maintained a stepwise increase both before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)