Insulin, ketone bodies, and mitochondrial energy transduction.
Level 5 - mechanism / opinion, no new human data
Ex vivo animal tissue experiment (isolated perfused rat hearts) without human clinical data.
PubMed 7768357 · doi:10.1096/fasebj.9.8.7768357
What was done
Researchers perfused isolated working rat hearts with buffer containing 10 mM glucose alone, with insulin, with a physiological ratio of ketone bodies, or with both in combination. They measured cardiac efficiency (hydraulic work per oxygen consumed), tissue metabolite levels (acetyl CoA, TCA cycle intermediates), mitochondrial redox states (free NAD and coenzyme Q couples), and intracellular pH values using 31P-NMR spectroscopy and bicarbonate distribution.
What was found
Addition of either insulin or ketone bodies increased cardiac efficiency by 25%, and the combination increased it by 36%. Acetyl CoA content rose 9- to 18-fold, while metabolites of the first third of the TCA cycle increased 2- to 5-fold; succinate, oxaloacetate, and aspartate decreased 2- to 3-fold, and succinyl CoA, fumarate, and malate remained essentially unchanged. Free mitochondrial NAD couples became 2- to 10-fold more reduced (Eh7 shift from -280 to -300 mV) and coenzyme Q couples became 2- to 4-fold more oxidized (Eh7 shift from -4 to +12 mV), increasing energy yield in the NADH dehydrogenase reaction from -53 kJ to -60 kJ/2 mol electrons. Cytosolic pH remained constant at approximately 7.0, whereas mitochondrial pH increased from 7.1 with glucose alone to 7.2 with insulin, 7.5 with ketones, and 7.4 with both.
Why it matters
This study defines a thermodynamic mechanism whereby ketone bodies and insulin augment myocardial mechanical efficiency by increasing the redox span across mitochondrial Complex I and raising the free energy of ATP hydrolysis.
Limits
The study was conducted entirely ex vivo in isolated rodent hearts under artificial perfusion conditions, lacking systemic hormonal and vascular feedback. The abstract does not report the total sample size or variance metrics.
Cited by
- supports Langendorff perfused heart preparations show that the heart has greater hydraulic efficiency and generates proportionately more ATP per oxygen consumed in the presence of ketones.