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Insulin reverses the protection given by diabetes against gentamicin nephrotoxicity in the rat
1Research Service, Veterans Affairs Medical Center, Miami, Florida 33125.
Abstract:
Rats with untreated diabetes mellitus are protected from gentamicin-induced nephrotoxicity. In order to evaluate the role of hyperglycemia, glycosuria, and polyuria in this phenomenon, miniosmotic pumps filled with insulin were implanted for 15 days in seven female Sprague-Dawley rats with streptozotocin-induced diabetes mellitus. Plasma glucose levels were successfully maintained under 126 mg/dl. To serve as the control group, eight age-matched diabetic (plasma glucose > 400 mg/dl) rats had miniosmotic pumps placed delivering only Ringer's solution. Six days after placement of the pumps, gentamicin (40 mg/Kg/day) was administered to all animals for 9 days. The insulin-treated diabetic rats exhibited clear signs of nephrotoxicity by Day 6 of gentamicin, whereas the diabetic control group remained free from any functional or morphological evidence of proximal tubular damage throughout the 9 days of the aminoglycoside administration. At the end of the experiment, the creatinine clearance in the insulin-treated diabetic group was 45% lower than in the untreated diabetic group (P < 0.005). In addition, there was a rise in plasma creatinine (P < 0.02), muramidase appeared in the urine, and mild patchy acute tubular necrosis of the renal cortex was observed by light microscopic examination. The insulin-treated group also accumulated more gentamicin in the renal cortex than the untreated animals (P < 0.005). It is concluded that protection against the nephrotoxic effects of gentamicin is a feature of untreated experimental diabetes mellitus in the rat and that correction of the hyperglycemic state with insulin reverses this resistance.
Insights
Untreated diabetes mellitus protects rats from gentamicin nephrotoxicity. However, correcting hyperglycemia with insulin reverses this protective effect, leading to kidney damage.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Diabetes mellitus is associated with protection against gentamicin-induced nephrotoxicity in rats.
- The exact mechanisms underlying this protective phenomenon, particularly the roles of hyperglycemia, glycosuria, and polyuria, require further investigation.
Purpose of the Study:
- To investigate the role of hyperglycemia in the protective effect of untreated diabetes mellitus against gentamicin nephrotoxicity.
- To determine if correcting hyperglycemia in diabetic rats with insulin reverses their resistance to gentamicin-induced kidney damage.
Main Methods:
- Streptozotocin-induced diabetic rats were divided into two groups: insulin-treated (maintained normoglycemic) and untreated diabetic controls (hyperglycemic).
- Both groups received gentamicin administration for 9 days.
- Kidney function (creatinine clearance, plasma creatinine), urinary markers (muramidase), and renal cortical gentamicin accumulation were assessed.
Main Results:
- Insulin-treated diabetic rats showed significant signs of nephrotoxicity, including reduced creatinine clearance and elevated plasma creatinine, by day 6 of gentamicin treatment.
- Untreated diabetic rats remained protected from functional and morphological evidence of proximal tubular damage throughout the gentamicin administration period.
- Insulin-treated rats accumulated significantly more gentamicin in the renal cortex compared to untreated diabetic rats.
Conclusions:
- The protective effect of untreated experimental diabetes mellitus against gentamicin nephrotoxicity in rats is confirmed.
- Correction of hyperglycemia via insulin treatment abolishes this protective effect, rendering diabetic rats susceptible to gentamicin-induced kidney damage.
- Hyperglycemia, a hallmark of untreated diabetes, plays a crucial role in conferring resistance to aminoglycoside nephrotoxicity.