Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness.
ABSTRACT In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now investigated the impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity.
Prospective, randomized laboratory investigation.
Three-month-old male rabbits.
After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required alloxan administration, immediately followed by intravenous insulin and glucose infusions titrated to the respective targets.
In liver, the reduced damage by glucose lowering was not explained by better perfusion/oxygen delivery. Abnormal mitochondrial ultrastructure and function was present in the two hyperglycemic groups, most pronounced with concomitant HI. Affected mitochondrial respiratory chain enzyme activities were reduced to 25% to 62% of values in healthy rabbits, in the presence of up to five-fold increased tissue levels of glucose. This was accompanied by elevated levels of dicarbonyls, which may mediate direct toxicity of cellular glucose overload and accelerated glycolysis. The abnormalities were also present in myocardium, although to a lesser extent, and absent in skeletal muscle.
In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage.
- SourceAvailable from: stroke.ahajournals.org[show abstract] [hide abstract]
ABSTRACT: Hyperglycemia following acute stroke is strongly associated with subsequent mortality and impaired neurological recovery, but it is unknown whether maintenance of euglycemia in the acute phase improves prognosis. Furthermore, the safety of such intervention is not established. In an explanatory, randomized, controlled trial to test safety, 53 acute (within 24 hours of ictus) stroke patients with mild to moderate hyperglycemia (plasma glucose between 7.0 and 17.0 mmol/L) were randomized to receive either a 24-hour infusion of 0.9% (154 mmol/L) saline or a glucose potassium insulin (GKI) infusion at 100 mL/h. The GKI consisted of 16 U human soluble insulin and 20 mmol potassium chloride in 500 mL 10% glucose. Blood glucose was measured every 2 hours with Boehringer Mannheim Glycaemie test strips, pulse and blood pressure were measured every 4 hours, and plasma glucose samples were taken every 8 hours. Insulin concentration in the GKI was altered according to BM glucose values. There were no statistically significant differences between the 2 groups at baseline. Twenty-five patients received GKI, 1 of whom required intravenous glucose for symptomatic hypoglycemia. Plasma glucose levels were nonsignificantly lower in the GKI group throughout the infusion period. Four-week mortality in the GKI group was 7 (28%), compared with 8 (32%) in the control group. GKI infusions can be safely administered to acute stroke patients with mild to moderate hyperglycemia producing a physiological but attenuated glucose response to acute stroke, the effectiveness of which remains to be elucidated.Stroke 05/1999; 30(4):793-9. · 6.16 Impact Factor
Article: Fluorimetric assay of D-lactate.[show abstract] [hide abstract]
ABSTRACT: A fluorimetric assay for D-lactate in human blood samples was developed using an endpoint enzymatic assay with D-lactate dehydrogenase from Staphylococcus epidermidis. The intrabatch and interbatch coefficients of variance were 8.7% (n = 4) and 16.6% (n = 4), respectively. The limit of detection in blood was 3.73 nmol/ml. The assay suffers minor interference from S-D-lactoylglutathione, which was also present in the blood samples. The concentration of D-lactate in blood was (mean +/- SE, nmol/ml) normal healthy individuals, 11.0 +/- 1.2 (n = 7); and diabetic patients, 20.0 +/- 1.3 (n = 55) (a significant increase in diabetes mellitus; P < 0.01, Mann-Whitney U test).Analytical Biochemistry 10/1992; 206(1):12-6. · 2.58 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium (GIK) solution in diabetic coronary artery bypass graft (CABG) patients would improve perioperative outcomes. One hundred forty-one diabetic patients undergoing CABG were prospectively randomized to tight glycemic control (serum glucose, 125 to 200 mg/dL) with GIK or standard therapy (serum glucose <250 mg/dL) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery. GIK patients had lower serum glucose levels (138+/-4 versus 260+/-6 mg/dL; P<0.0001), a lower incidence of atrial fibrillation (16.6% versus 42%; P=0.0017), and a shorter postoperative length of stay (6.5+/-0.1 versus 9.2+/-0.3 days; P=0.003). GIK patients also showed a survival advantage over the initial 2 years after surgery (P=0.04) and decreased episodes of recurrent ischemia (5% versus 19%; P=0.01) and developed fewer recurrent wound infections (1% versus 10%, P=0.03). Tight glycemic control with GIK in diabetic CABG patients improves perioperative outcomes, enhances survival, and decreases the incidence of ischemic events and wound complications.Circulation 04/2004; 109(12):1497-502. · 15.20 Impact Factor