Renal hyperinsulinemia causes thickening of glomerular basement membrane independent of hypertension and hyperglycemia
Authors: Monu Sumit 
Published: April 2020

Introduction

Glomerular basement membrane (GBM) thickening is one of the earliest detectable pathological features of obesity‐related kidney damage. Kidney damage observed in obesity or pre‐diabetic condition is almost always preceded with hyperinsulinemia but its role in the kidney damage is largely overlooked. Our unpublished preliminary data in ex‐vivo preparation of rabbit afferent‐arteriole suggests that insulin causes afferent‐arteriole dilation that may lead to glomerular hyperfiltration. Additionally, in humans insulin increases renal blood flow and glomerular filtration rate indicating potential role of insulin in renal pathology.

Hypothesis

Chronic renal hyperinsulinemia increases GBM thickness and this detrimental effect of insulin is independent of hyperglycemia and hypertension.

Materials and methods

To test this hypothesis, we infused insulin (1.8 IU/kg.bw/day) directly to the left kidney of male sprague dawley (SD) rats by custom made subcapsular catheter attached with osmotic minipumps for 6 weeks. Contralateral right kidney was also inserted with subcapsular catheter but without insulin infusion and served as internal control. Normal SD rats without any insulin infusion in any of its kidneys were also included in this study as a separate group for the comparison of various parameters. Blood glucose level was measured every week until 6 weeks of insulin infusion. At the end of the 6 weeks study, mean arterial pressure (MAP) was measured in inactin‐anesthetized rats using femoral artery catheter. Kidneys were perfused with normal saline and fixed by gluteraldehyde for the GBM thickness measurement using electron microscope.

Results

Blood glucose levels in the left‐kidney‐insulin‐infused rats were similar throughout the study including at the end of 6 weeks study to the normal non‐insulin infused SD rats group indicating no significant leakage of insulin (Normal SD rats: 104.5 ±10.3 vs. Insulin infused SD rats: 111.9±4.3mmol/L, p>0.05). MAP was also similar in both of these groups (Normal SD rats: 104.8±6.3 vs. Insulin infused SD rats: 99.7±5.5mmHg, p>0.05). GBM thickness was significantly increased in the insulin infused left kidney compared with contralateral non‐insulin infused right kidney (Insulin‐infused‐left kidney: 199.40±17.0 vs. contralateral non‐insulin infused right kidney: 149.57±5.12 nm, n=4, p<0.05) indicating renal hyperinsulinemia causes GBM thickening. Additionally, GBM thickness of normal SD rat’s kidney was similar to non‐insulin infused right kidney (Normal SD rat’s kidney: 145.53±3.58, n=3 vs. non‐insulin‐infused‐right kidney: 149.57±5.12 nm, n=4, p>0.05) and was significantly less compared to the insulin‐infused left kidney (Normal SD rat’s kidney: 145.53±3.58, n=3 vs. insulin‐infused‐left kidney: 199.40±17.0, n=4, p<0.05).

Conclusion

Renal hyperinsulinemia per se increases GBM thickness that is independent of systemic factors such as hyperglycemia and hypertension. To our knowledge, this is the first study that directly establishes the role of hyperinsulinemia in the initiation of kidney damage.

Perspective

Hyperinsulinemia observed in obesity or prediabetic conditions may be a significant initiating factor in the renal damage possibly via glomerular hyperfiltration.

Support or Funding Information

Fund for Henry Ford Hospital (Monu,S).