Abstract

Background: Rhesus monkeys have a high prevalence of obesity and spontaneous type 2 diabetes mellitus after the age of 10 years. These monkeys go through a defined, sequential set of metabolic phases, including fasting hyperinsulinemia, impaired glucose tolerance, and fasting hyperglycemia. Using these monkeys, we addressed the hypothesis that renal structural features characteristic of diabetic nephropathy might precede the appearance of overt diabetes. Methods: We carried out a quantitative analysis of renal tissue, using light microscopy and electron microscopy, from 6 metabolically normal young monkeys, 7 metabolically normal aged monkeys, 7 hyperinsulinemic monkeys, and 18 diabetic monkeys. Results: Glomerular volume was increased significantly in hyperinsulinemic monkeys and diabetic monkeys compared with aged normal monkeys. In the normal monkey, glomerular basement membrane (GBM) width rises with age but reaches a plateau at about 20 years of age; the presence of diabetes was associated with markedly increased GBM width. Glomerular tuft volume and GBM width were correlated most closely with age and with glucose tolerance. Conclusion: Diabetic monkey kidneys are characterized by glomerular enlargement, glomerulosclerosis, and thickening of the GBM. Glomerular hypertrophy begins in the prediabetic hyperinsulinemic phase. This finding suggests that early intervention may be required in human patients to preserve normal glomerular structure.

Keywords: Diabetes, glomerulosclerosis, glomerular basement membrane (GBM), electron microscopy (EM), insulin

Fig. 1. Renal histology. (A) A young normal monkey, aged 6.9 years, exhibits normal-sized glomeruli, with glomerular tuft volume measured as 1.035 _ 10_6 _m3. Glomerular architecture appears normal, with a delicate mesangial stalk; the glomerulosclerosis score was 1. (B) An old normal monkey, aged 21.5 years, exhibits slightly enlarged glomeruli, with a glomerular tuft volume of 1.214 _ 10_6 _m3, and a slightly more pronounced mesangial stalk, yielding a glomerulosclerosis score of 2. (C) A hyperinsulinemic monkey, aged 25.5 years, has further increased glomerular size, with a mean volume of 3.685 _ 10_6 _m3, and a normal mesangial matrix, with a glomerulosclerosis score of 1. (D) A diabetic monkey, aged 20.7 years and studied after 12 months of diabetes, shows enlarged glomeruli, with a mean glomerular tuft volume of 5.406 _ 10_6 _m3, and strikingly increased mesangial regions, with a glomerulosclerosis score of 3. (PAS stain, _50.)

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