The insulin-like growth factor system and the progression of renal complications of type 2 diabetes.

aimsChronic kidney disease is associated with dysregulation of the insulin-like growth factor (IGF) system. Alterations in IGF bioavailability, driven by IGF binding proteins (IGFBPs), may influence the decline in renal function. However, the longitudinal relationship between baseline IGF-I, IGF-II, IGFBPs and progression of kidney dysfunction remains unclear. We evaluated how IGF/IGFBP profile relates to longitudinal changes in urinary albumin/creatinine ratio (ACR) and serum creatinine level in people with type 2 diabetes (T2D).

methodsIndividuals' measurements were performed in 436 individuals with T2D recruited from primary and secondary care (2002-2004), from the Salford and Manchester Integrated Care Record (GMCR), for laboratory and clinical data, as well as date of death. Baseline IGF/IGFBP profile was related to 2 primary outcomes: (i) change in albumin-to-creatinine ratio over time (urine ACR trend slope) and (ii) change in serum creatinine over time (creatinine trend slope). Trend slopes were derived for each participant, using repeated measures throughout follow-up for up to 24 years. Associations between IGF axis proteins and outcomes were evaluated with multivariate regression models. Cox proportional hazards models were constructed to determine mortality risk associated with the IGF system proteins studied.

resultsAt baseline, 59.3% of participants were men. Age at baseline was 56.6 ± 9.4 years. Mean follow-up duration was 17.4 ± 5.2 years. IGF-II and IGFBP-3 were strongly correlated (Spearman rho = 0.80), and were therefore not included simultaneously in the multi-variate linear regression model to avoid co-linearity. Higher circulating IGFBP-2 was independently associated with faster rate of ACR progression (normalised beta (Β) = 0.007, p = 0.002), while IGFBP-1 showed an inverse association (B = -0.057, p = 0.009). IGF-II also remained positively associated with ACR trend (B = 0.005, p = 0.013), whereas IGF-I showed no association. IGFBP-1 showed a significant inverse association with creatinine change when adjusted for effects of covariates (unstandardised B = -0.038, p = 0.04). Survival analysis revealed that higher IGFBP-2 levels were independently associated with higher all-cause mortality (hazard ratio [HR] per 1 standard deviation increase 1.306, 95% CI 1.151-1.483 p = 0.0001).

conclusionThis longitudinal study indicated that higher baseline IGF-II, lower IGFBP-1 and higher IGFBP-2 are associated with a greater likelihood of albuminuria progression, independent of standard risk factors; lower IGBFP-1 also associated with greater increase in serum creatinine. Higher circulating IGFBP-2 level was also associated with relatively higher mortality. This study demonstrated the relevance of the IGF system to our understanding of renal complications in diabetes and strongly suggests that further exploration of mechanisms underlying these associations is merited.