Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes.

INTRODUCTION: Associations of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) with cardiovascular risk have been inadequately studied. We hypothesized that IGF-II and IGFBP-2 associate with longitudinal trends in lipid profiles in type 2 diabetes patients. SUBJECTS AND METHODS: Four hundred and eighty nine subjects with type 2 diabetes (age 27-87 years) from the Salford Diabetes Cohort were studied. Longitudinal clinical information was extracted for an eight-year period (2002-2009) from an integrated electronic dataset of primary care and hospital data. RESULTS: There were 294 male subjects and mean age was 62.9 years. At baseline, IGF-II concentration was 602 ng/mL. HDL cholesterol at baseline was associated with log-IGF-II concentration in a model adjusted for age, gender, baseline body-mass index (BMI), estimated glomerular filtration rate (eGFR) and lipid-lowering therapy. IGFBP-1 and IGFBP-2 were associated with high HDL-cholesterol. A higher circulating IGF-II concentration at baseline was also associated with longitudinal increase in HDL-cholesterol in mixed-effects regression analyses independent of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, age, gender, eGFR, BMI and lipid-lowering therapy. Log-transformed baseline concentrations of IGFBP-1 and IGFBP-2 were also associated with longitudinal elevation in HDL-cholesterol. No association was observed for IGF-II or IGFBP-2 with longitudinal LDL cholesterol trends. CONCLUSION: Our analyses based on 'real world' data demonstrate that higher baseline IGF-II and IGFBP-2 predict increased HDL concentration over time, implicating IGF-II in modulation of circulating HDL-cholesterol concentrations.

Variability in parathyroid hormone assays confounds clinical practice in chronic kidney disease patients.

BACKGROUND: Intact parathyroid hormone (iPTH) measurements are used to guide therapy in renal patients, but variability in results can occur depending on the assay used. This study has investigated iPTH assay variation in North West England and paired data with regional audit data to determine clinical relevance of assay variability. METHODS: Thirty-seven haemodialysis patients had blood taken (EDTA plasma, and serum), and samples were processed at 17 laboratories that analyse iPTH for North West dialysis patients. Correction factors were calculated and applied to the iPTH assay results to enable direct comparisons. These correction factors were also applied to Regional Audit data to determine if iPTH assay variability explains the variation in unit performance in achieving PTH targets. RESULTS: The iPTH results from the 37 patients were significantly different when either analysed by different assays and/or different laboratories (P < 0.001). The Abbott Architect method consistently produced the highest iPTH results. Of the 37 patients, between 49% and 65% would achieve the Kidney Disease: Improving Global Outcomes (KDIGO) iPTH target depending on the assay used. When results were adjusted using correction factors, 21% of the patients would require a change of management according to guidelines. Data from all haemodialysis units submitted for the regional audit were adjusted to the Roche assay and this led to a small change in achievement of KDIGO iPTH targets in individual units when compared to each other. CONCLUSIONS: A combination of iPTH assay variability and diversity in clinical management leads to variation in achieving iPTH targets. Both need to be improved and/or standardized to improve patient care.

Atorvastatin administration is associated with dose-related changes in IGF bioavailability.

OBJECTIVE: IGF levels, their binding proteins (IGFBPs) and high-dose statin therapy have been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins. DESIGN AND METHODS: We measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 and 12 months in Protection Against Nephropathy in Diabetes with Atorvastatin trial participants with type 2 diabetes randomised to 10 mg (n=59) vs 80 mg (n=60) of atorvastatin (n=119; mean (S.D.): age 64 (10) years; 83% male; HbA1c 61 (10) mmol/mol; blood pressure 131/73 mmHg). RESULTS: Atorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations (P<0.05 for all changes). The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for IGF1: -3 (-21 to 14) ng/ml; IGF2: -23 (-65 to 18) ng/ml and IGFBP3: -0.34 (-0.71 to 0.03) µg/ml, negative values indicating numerically greater lowering with high dose. The IGFBP1 concentration did not change with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant -0.41 (-0.69 to 0.13, P=0.004). CONCLUSION: IGF1, IGF2 and IGFBP3 concentrations decreased following atorvastatin therapy. A differential effect of low- vs high-dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.

IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes.

OBJECTIVE: Insulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes. DESIGN AND METHODS: IGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes. RESULTS: High IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (ß=-0.02, (95% confidence interval -0.03 to -0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration. CONCLUSION: This study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.