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Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis.

ABSTRACT: 1. The infusion of sodium dichloroacetate into rats with severe diabetic ketoacidosis over 4h caused a 2mM decrease in blood glucose, and small falls in blood lactate and pyruvate concentrations. Similar findings had been reported in normal rats (Blackshear et al., 1974). In contrast there was a marked decrease in blood ketone-body concentration in the diabetic ketoacidotic rats after dichloroacetate treatment. 2. The infusion of insulin alone rapidly decreased blood glucose and ketone bodies, but caused an increase in blood lactate and pyruvate. 3. Dichloroacetate did not affect the response to insulin of blood glucose and ketone bodies, but abolished the increase of lactate and pyruvate seen after insulin infusion. 4. Neither insulin nor dichloroacetate stimulated glucose disappearance after functional hepatectomy, but both agents decreased the accumulation in blood of lactate, pyruvate and alanine. 5. Dichloroacetate inhibited 3-hydroxybutyrate uptake by the extra-splachnic tissues; insulin reversed this effect. Ketone-body production must have decreased, as hepatic ketone-body content was unchanged by dicholoracetate yet blood concentrations decreased. 6. It was concluded that: (a) dichloroacetate had qualitatively similar effects on glucose metabolism in severely ketotic rats to those observed in non-diabetic starved animals; (b) insulin and dichloroacetate both separately and together, decreased the net release of lactate, pyruvate and alanine from the extra-splachnic tissues, possibly through a similar mechanism; (c) insulin reversed the inhibition of 3-hydroxybutyrate uptake caused by dichloroacetate; (d) dichloroacetate inhibited ketone-body production in severe ketoacidosis.

SUBMITTER: Backshear PJ

PROVIDER: S-EPMC1165323 | biostudies-other | 1975 Feb

REPOSITORIES: biostudies-other

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Project description:ImportanceStandard diabetic ketoacidosis care in the US includes intravenous insulin treatment in the intensive care unit. Subcutaneous (SQ) insulin could decrease intensive care unit need, but the data are limited.ObjectiveTo assess outcomes after implementation of an SQ insulin protocol for treating diabetic ketoacidosis.Design, setting, and participantsThis cohort study is a retrospective evaluation of a prospectively implemented SQ insulin protocol. The study was conducted at an integrated health care system in Northern California. Participants included hospitalized patients with diabetic ketoacidosis at 21 hospitals between January 1, 2010, and December 31, 2019. The preimplementation phase was 2010 to 2015, and the postimplementation phase was 2017 to 2019. Data analysis was performed from October 2020 to January 2022.ExposureAn SQ insulin treatment protocol for diabetic ketoacidosis.Main outcomes and measuresDifference-in-differences evaluation of the need for intensive care, mortality, readmission, and length of stay at a single intervention site using an SQ insulin protocol from 2017 onward compared with 20 control hospitals using standard care.ResultsA total of 7989 hospitalizations for diabetic ketoacidosis occurred, with 4739 (59.3%) occurring before and 3250 (40.7%) occurring after implementation. The overall mean (SD) age was 42.3 (17.7) years, with 4137 hospitalizations (51.8%) occurring among female patients. Before implementation, SQ insulin was the first insulin used in 40 intervention (13.4%) and 651 control (14.7%) hospitalizations. After implementation, 98 hospitalizations (80.3%) received SQ insulin first at the intervention site compared with 402 hospitalizations (12.8%) at control sites. The adjusted rate ratio for intensive care unit admission was 0.43 (95% CI, 0.33-0.56) at the intervention sites, a 57% reduction compared with control sites, and was 0.50 (95% CI, 0.25-0.99) for 30-day hospital readmission, a 50% reduction. There were no significant changes in hospital length of stay and rates of death.Conclusions and relevanceThese findings suggest that a protocol based on SQ insulin for diabetic ketoacidosis treatment was associated with significant decreases in intensive care unit need and readmission, with no evidence of increases in adverse events.

Project description:ImportanceIntravenous (IV) insulin infusion is the standard of care for treating diabetic ketoacidosis (DKA) worldwide. Subcutaneous (SC) insulin aspart could decrease the use of health care resources.ObjectiveTo compare the cost-effectiveness of mild uncomplicated DKA management with SC insulin aspart vs IV insulin infusion among pediatric patients from the perspective of a public health care payer using clinical data.Design, setting, and participantsThis economic evaluation included children aged 2 to 14 years presenting to the emergency department of a single academic medical center with mild DKA between January 1, 2015, and March 15, 2020. The medical records for DKA treatment course and its associated hospitalization costs were reviewed. Data were analyzed from January 1, 2015, to March 15, 2020.ExposuresSubcutaneous insulin aspart vs IV regular insulin infusion.Main outcomes and measuresThe incremental cost-effectiveness ratio (US dollars per hour), duration of DKA treatment, and length of hospital stay.ResultsA total of 129 children with mild DKA episodes (mean [SD] age, 9.9 [3.1] years; 72 girls [55.8%]) were enrolled in the study. Seventy children received SC insulin aspart and 59 received IV regular insulin. Overall, the length of hospital stay in the SC insulin group was reduced (mean, 16.9 [95% CI, -31.0 to -2.9] hours) compared with the IV insulin group (P = .005). The mean (SD) cost of hospitalization in the SC insulin group (US $1071.99 [US $523.89]) was less than that in the IV insulin group (US $1648.90 [US $788.03]; P = .001). The incremental cost-effectiveness ratio was -34.08 (95% CI, -25.97 to -129.82) USD/h. The use of SC insulin aspart was associated with a lower likelihood of prolonged hospital stay (β = -17.22 [95% CI, -32.41 to -2.04]; P = .03) than IV regular insulin when controlling for age and sex.Conclusion and relevanceFindings of this economic evaluation suggest that SC insulin aspart is dominant vs IV regular insulin in the management of mild uncomplicated DKA in children.

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Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis.

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