malonyl-coenzyme-a and Diabetes-Mellitus--Type-1

Diabetic ketoacidosis is still today a medical emergency in pediatrics. Despite the latest great sensibilization of the population and the doctors, the risk of DKA has not yet been completely eliminated and this pathology is still occurring in 25 to 40% of diabetes onset cases, in already diagnosed patients with poor compliance, or in patients undergoing acute medical or surgical events. In affected patients, missed recognition can influence morbility and mortality rates. Despite the improvement in DKA management and therapy, a lot of controversies have been encountered through a careful review of the most recent literature in the sector (guidelines in Pediatrics). Particularly as far as DKA pathophysiology and its complications (cerebral oedema) are concerned. In terms of insulin therapy the latest progress has underlined the advantages and disadvantages of the therapeutical choices that have modified in time. A wide consent exists on the need to use small doses of regular insulin for continuous intravenous administration as therapy of choice for pediatric DKA (0.1-0.05 U/Kg/h). The success of the treatment is nevertheless tightly connected to a correct management of rehydratation, of metabolic acidosis and of electrolyte deficit replacement more than on insulin therapy, aimed at avoiding the most dangerous complication of DKA: cerebral oedema.

Topics: Adolescent; Bicarbonates; Child; Child, Preschool; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Electrolytes; Emergencies; Female; Fluid Therapy; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Infant; Insulin; Ketone Bodies; Male; Malonyl Coenzyme A; Mitochondria, Liver; Practice Guidelines as Topic; Recurrence

The regulation of hepatic mitochondrial carnitine palmitoyltransferase-I (CPT-I) was studied in rats during starvation and insulin-dependent diabetes and in rat H4IIE cells. The Vmax. for CPT-I in hepatic mitochondrial outer membranes isolated from starved and diabetic rats increased 2- and 3-fold respectively over fed control values with no change in Km values for substrates. Regulation of malonyl-CoA sensitivity of CPT-I in isolated mitochondrial outer membranes was indicated by an 8-fold increase in Ki during starvation and by a 50-fold increase in Ki in the diabetic state. Peroxisomal and microsomal CPT also had decreased sensitivity to inhibition by malonyl-CoA during starvation. CPT-I mRNA abundance was 7.5 times greater in livers of 48-h-starved rats and 14.6 times greater in livers of insulin-dependent diabetic rats compared with livers of fed rats. In H4IIE cells, insulin increased CPT-I sensitivity to inhibition by malonyl-CoA in 4 h, and sensitivity continued to increase up to 24 h after insulin addition. CPT-I mRNA levels in H4IIE cells were decreased by insulin after 4 h and continued to decrease so that at 24 h there was a 10-fold difference. The half-life of CPT-I mRNA was 4 h in the presence of actinomycin D or with actinomycin D plus insulin. These results suggest that insulin regulates CPT-I by inhibiting transcription of the CPT-I gene.

Topics: Animals; Carnitine O-Palmitoyltransferase; Cell Line; Dactinomycin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Enzyme Inhibitors; Hypoglycemic Agents; Insulin; Intracellular Membranes; Male; Malonyl Coenzyme A; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; RNA, Messenger; Starvation