The hemodynamic abnormalities in short-term insulin deficiency: the role of prostaglandin inhibition.
It has been suggested that the hemodynamic derangements present in diabetic ketoacidosis are the results not only of profound volume depletion but also of the effects of increased production of vasodilating prostaglandins (PGs), principally PGI2, released by adipose tissue. In animal and in vitro models, prostaglandin synthesis is increased during insulin deficiency. We assessed the effects of short-term ketosis on the metabolic and hemodynamic variables of 10 IDDM patients free from long-term complications and of 9 normal control subjects after a 7-day randomized double-blind indomethacin (INDO) (50 mg q.i.d.) or placebo treatment period. Calf blood flow (CBF), postocclusive reactive hyperemia (PORH), and recovery half-time (an index of overall perfusion) after PORH were measured by plethysmography. Left ventricular and myocardial functions were also studied in each different condition during placebo and INDO treatment in IDDM patients. During placebo treatment, the increase in CBF during ketosis was higher (1.75 +/- 0.29 ml / min / 100 ml muscle) than during INDO (0.85 +/- 0.17 ml / min) / 100 ml muscle; P = 0.007). PORH was similar in baseline conditions, during ketosis, and in recovery in both the placebo and INDO arms. Recovery half-time significantly increased during placebo (10 +/- 2; 200%; P < 0.01) but not during INDO (1 +/- 1; 106%; NS) treatment. In normal control subjects, insulin deficiency did not induce any significant effect on hemodynamic variables. In IDDM patients, during placebo treatment, ketosis increased both the cardiac index (from 3.4 +/- 0.7 to 4.1 +/- 0.81 / min / m; P < 0.01) and the stroke index (from 42 +/- 8 to 49 +/- 7 ml/m2; P < 0.01) without changes in left ventricular ejection fraction but with a significant increase in both left and right ventricular end-diastolic volumes. Metabolic recovery induced a normalization of these parameters. INDO treatment significantly blunted these alterations. In summary, we showed that during acute insulin deficiency, INDO-sensitive mechanisms mediate vascular disturbances. Moreover, INDO treatment was capable of completely preventing the cardiac venous return and the left ventricular alterations. INDO does not interfere with the overall ketogenetic process or with insulin-induced metabolic recovery.
Avogaro
A
A
Department of Clinical Medicine, Azienda Ospedaliera di Padova, Padua, Italy.
Crepaldi
C
C
Piarulli
F
F
Milan
D
D
Valerio
A
A
Pavan
P
P
Sacerdoti
D
D
Calabrò
A
A
Macdonald
I
I
Crepaldi
G
G
Scognamiglio
R
R
Tiengo
A
A
D020155:3-Hydroxybutyric Acid; D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000090:Acetoacetates / Q000097:blood; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology*; D016883:Diabetic Ketoacidosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D004311:Double-Blind Method; D004452:Echocardiography / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000627:therapeutic use; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D009638:Norepinephrine / Q000097:blood; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
D000090:Acetoacetates; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007328:Insulin; C016635:acetoacetic acid; D015121:6-Ketoprostaglandin F1 alpha; D005934:Glucagon; D020155:3-Hydroxybutyric Acid; D009638:Norepinephrine; D007213:Indomethacin; D004837:Epinephrine