Spectrum of Renal Diseases Associated with Extreme Forms of Insulin Resistance

Abstract

Diabetic nephropathy is the leading cause of ESRD in the United States. Why the pathogenic mechanisms lead to nephropathy in certain patients with type 1 and 2 diabetes and spare others is unclear, but it is clear that hyperglycemia and glomerular hyperfiltration are important factors. In patients with syndromes of extreme insulin resistance, proteinuric forms of renal disease are common, but it is surprising to find that the renal pathology usually is not diabetic nephropathy. For instance, in the lipodystrophy syndromes, membranoproliferative glomerulonephritis type 1 and type 2, focal segmental glomerulosclerosis, and also diabetic nephropathy are seen. In the syndromes of autoantibodies to the insulin receptor, the various forms of lupus glomerulonephritis are seen. Even in patients with type 2 diabetes, the renal pathology may not be diabetic nephropathy. Therefore, in patients with syndromic forms of insulin resistance and type 2 diabetes, renal biopsy has an important role in defining the pathology that leads to proteinuric nephropathy and in formulating a therapeutic approach. It is the purpose of this article to review these unusual aspects of proteinuric nephropathy in patients with diabetes.

Efficacy of leptin therapy in the different forms of human lipodystrophy

“…The improvement in glucose tolerance occurred even though most patients had a reduction in their glucose-lowering medications (Table 3). Effect of leptin on urinary protein We have previously reported that generalised lipodystrophy can be associated with clinical and nephrotic-range proteinuria and that this proteinuria can be ameliorated with leptin therapy [12,13]. The decrease in proteinuria with leptin replacement is accompanied by a reduction in creatinine clearance and hyperfiltration [12,13].…”

“…Effect of leptin on urinary protein We have previously reported that generalised lipodystrophy can be associated with clinical and nephrotic-range proteinuria and that this proteinuria can be ameliorated with leptin therapy [12,13]. The decrease in proteinuria with leptin replacement is accompanied by a reduction in creatinine clearance and hyperfiltration [12,13]. In six patients, the nature of the renal dysfunction was determined by renal biopsy [13]; however, the specific aetiology of proteinuria was not known for the majority of patients.…”

“…The decrease in proteinuria with leptin replacement is accompanied by a reduction in creatinine clearance and hyperfiltration [12,13]. In six patients, the nature of the renal dysfunction was determined by renal biopsy [13]; however, the specific aetiology of proteinuria was not known for the majority of patients. In patients with generalised lipodystrophy, urinary protein excretion tended to decline over time with leptin replacement.…”

“…Comorbid conditions The various forms of lipodystrophy represent serious medical conditions [8,12,13]. For instance, two patients whom we evaluated for leptin replacement died of cardiac and pulmonary causes and never received treatment.…”

“…We have previously discussed the issue of renal disease in patients with generalised lipodystrophy [12,13]. Proteinuria is very common in these patients and may have a complex aetiological basis.…”