194-OR: Lower Insulin Sensitivity before the Onset of Type 2 Diabetes Is Associated with Increased Risk of Albuminuria after Diabetes Onset

Background: Reduced renal insulin signaling is implicated in the pathogenesis of albuminuria, a marker of kidney failure, cardiovascular disease, and mortality. We sought to investigate whether insulin action and secretion, measured prior to diabetes onset, are associated with development of albuminuria after diabetes onset.

Methods: Baseline body composition, insulin sensitivity by hyperinsulinemic-euglycemic clamp at submaximal and max insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test (acute insulin response, AIR) were measured in 166 Indigenous American adults who subsequently developed diabetes. After diabetes onset and during median follow-up of 12.3 years, 44 participants (27%) developed albuminuria. The separate associations of M-low, M-high, and AIR (per 1-SD change) with risk of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) were identified by Cox regression models adjusted for age, sex, and body fat (%).

Results: Participants who developed albuminuria were of similar age (26.8 ± 5.6 vs. 27.1 ± 6.0 years), sex distribution (50% vs. 46% male), body fat (36.6 ± 6.0 vs. 35.8 ± 8.0%), and AIR (3.1 ± 0.3 vs. 3.0 ± 0.3, pmol/L [log]) as those who did not develop albuminuria, but had lower insulin sensitivity (M-low: 0.32 ± 0.06 vs. 0.36 ± 0.11, p = 0.007, M-high: 0.85 ± 0.11 vs. 0.90 ± 0.12, p = 0.03; mg/kg-metabolic body size/min [log]). In separate adjusted models, lower M-low and M-high (i.e., lower insulin sensitivity) were both associated with increased risk for albuminuria (HR 1.67, 95% CI 1.12, 2.50, p = 0.01; HR 1.35, 95% CI 1.03, 1.79, p = 0.03), whereas AIR was not (HR 1.18, 95% CI 0.79, 1.75, p = 0.42).

Conclusion: Lower insulin sensitivity is associated with development of albuminuria, suggesting a role for insulin signaling in the pathogenesis of proteinuria and is a potential therapeutic target for prevention of cardiovascular and kidney disease.