Background: Insulin sensitivity and insulin clearance are compromised in end-stage renal disease but it has not been fully established whether they are altered in earlier stages of diabetic nephropathy.
Design: We studied three groups of patients with type 1 diabetes; 10 with no sign of nephropathy, 11 with albuminuria (> 20 microg min-1) but normal glomerular filtration rate (GFR) and eight with a small reduction in GFR, (43-73 mL min-1 1.73 m-2). The groups were matched for age (range 36-61 years), body mass index (BMI), diabetes duration and glycaemic control. The euglycaemic hyperinsulinaemic clamp technique was utilized to study insulin sensitivity (M-value) and metabolic clearance rate for insulin. Needle biopsies from abdominal subcutaneous fat tissue were obtained to study insulin binding, insulin degradation, insulin-stimulated glucose uptake and anti-lipolysis in adipocytes in vitro.
Results: Patients with reduced GFR were more insulin-resistant (M-value 5.7 +/- 0.7 mg kg LBM-1 min-1) than those without nephropathy (9.6 +/- 0.7, P = 0.001) and those with only albuminuria (8.9 +/- 1.2, P = 0.044). In all subjects taken together there was a strong association between insulin sensitivity and GFR (r = 0.46, P = 0.012). Patients with reduced GFR displayed no significant difference in insulin clearance (12.2 +/- 1.6 mL kg-1 min-1) compared to controls (13.8 +/- 1.3) but a slightly lower insulin clearance than patients with only albuminuria (16.6 +/- 1.0, P = 0.027). There were no significant differences between patient groups in the adipocyte studies in vitro, i.e. with respect to insulin binding, insulin degradation and the effects of insulin on glucose uptake and lipolysis. This is compatible with humoral factors causing whole-body insulin resistance and in the group with reduced GFR, we found that serum parathyroid hormone, interleukin-6 and tumour necrosis factor-alpha levels were elevated whereas the morning cortisol was decreased.
Conclusions: In type 1 diabetes, the appearance of albuminuria does not seem to alter insulin sensitivity and clearance. A marked insulin resistance but no consistent impairment in insulin clearance seems to accompany progression to a stage with a slight reduction in GFR. These alterations are not accompanied by general defects in insulin target cells. Instead, alterations in the regulation of insulin-antagonistic hormones and cytokines could potentially contribute to the development of insulin resistance in diabetic nephropathy.