Circulating levels of insulin-like growth factor-II/mannose-6-phosphate receptor in obesity and type 2 diabetes

Objective: The extracellular domain of the insulin-like growth factor II/mannose-6-phosphate receptor (IGF-II/M6P-R) is present in the circulation, but its relationship with plasma IGF-II is largely unknown. As ICF-II appears to be nutritionally regulated, we studied the impact of obesity, type 2 diabetes (T2D) and weight loss on circulating levels of ICF-II and its soluble receptor. Methods: Twenty-three morbidly obese non-diabetic subjects were studied before and after gastric banding (GB), reducing their BMI from 59.3 +/- 1.8 to 52.7 +/- 1.6 kg/m(2). Lean controls (n = 10, BMI 24.2 +/- 0.5 kg/m(2)), moderately obese controls (n = 21, BMI 31.8 +/- 1.0 kg/m(2)) and obese T2D patients (n = 20, BMI 32.3 +/- 0.8 kg/m(2)) were studied before and after a hyperinsulinaemic euglycaemic clamp. Results: Morbidly obese subjects had elevated IGF-II/M6P-R and IGF-II levels, which both decreased following GB (IGF-II/M6P-R: from 0.97 +/- 0.038 to 0.87 +/- 0.030 nmol/l, P = 0.001; IGF-II: from 134 +/- 7 to 125 6 nmol/l, P = 0.01), as did fasting plasma glucose and insulin (P < 0.05). However, the metabolic parameters correlated with neither IGF-II nor IGF-II/M6P-R. Obese diabetics had increased IGF-II/M6P-R as compared with lean and obese controls (0.82 +/- 0.031 vs. 0.70 +/- 0.033 vs. 0.74 +/- 0.026 nmol/l; P < 0.03) and levels were unaffected by clamp. In the latter cohort, IGF-II/M6P-R but not IGF-II correlated with HbA1c, and fasting plasma C-peptide, insulin and glucose (0.34 < r < 0.45; P < 0.05). In all subjects, BMI correlated with IGF-II/M6P-R (r = 0.57; P < 0.001) and IGF-II (r = 0.39: P < 0.005). IGF-II/M6P-R and IGF-II were not associated. Conclusion: Serum IGF-II/M6P-R is up-regulated in morbid obesity, down-regulated by weight loss and elevated in moderately obese T2D. However, although plasma was also reduced following GB, the two peptides were not statistically correlated. No acute effect of insulin was seen. These findings indicate that the IGF-II/M6P-R is nutritionally regulated, independently of IGF-II. (C) 2010 Elsevier Ltd. All rights reserved.