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Mechanisms of kidney protection by intensive insulin therapy during critical illness
Critical Care volume 12, Article number: P151 (2008)
To study the underlying mechanisms, we independently manipulated blood glucose (G) and insulin (I) to normal (N) or high (H) levels in our rabbit model of prolonged critical illness , resulting in four experimental groups: NI/NG, HI/NG, NI/HG and HI/HG.
Plasma creatinine levels were elevated in the two HG compared with the two NG groups. Light microscopy showed severe renal structural abnormalities in HG rabbits, with formation of tubular casts. These effects of blood glucose control on kidney function and structure were not explained by an effect on blood flow or oxygen delivery to the kidney. In contrast, in the renal cortex of HG rabbits, the activities of the mitochondrial respiratory chain enzymes were reduced to below 50% to 30% of the values observed in controls and NG rabbits, a finding that was independent of insulin. No significant correlations were found between respiratory chain complex activities and blood flow or oxygen delivery to the cortex. Strongly significant inverse correlations were found between the enzyme activities and plasma levels of creatinine, suggesting that mitochondrial protection by intensive insulin therapy mediated at least part of the prevention of kidney injury. The glucose content in the renal cortex was more than fourfold higher in the HG than the NG groups and correlated directly with creatinine levels and inversely with enzyme activities, supporting glucose toxicity as the mediator of renal mitochondrial damage. The dicarbonyls glyoxal, methylglyoxal and 3-deoxyglucosone were elevated in plasma of the HG groups and strongly correlated with glucose in the cortex and plasma creatinine, suggesting a possible contribution of these toxic metabolites of glucose.
Intensive insulin therapy during critical illness confers renal protection by prevention of hyperglycemia-induced mitochondrial damage rather than by improving perfusion and oxygen delivery.
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Vanhorebeek, I., Ellger, B., Gunst, J. et al. Mechanisms of kidney protection by intensive insulin therapy during critical illness. Crit Care 12, P151 (2008). https://doi.org/10.1186/cc6372
- Critical Illness
- Oxygen Delivery
- Renal Cortex