Andrew Sanigorski

Periostin, a novel secreted protein involved in the pathogenesis of obesity and type 2 diabetes.

Insulin resistance of glucose and fat metabolism in T2DM is firmly established whereas that of protein remains controversial. We addressed this in nine lean (L), 11 overweight/obese (O/O) non-diabetic and 10 T2DM male subjects using the hyperinsulinemic (40 mU/m min), euglycemic (5.5 mM), isoaminoacidemic (maintaining post-absorptive plasma amino acids) clamp. [3-3H]glucose and [1-13C]leucine kinetics were measured. BMI in L (21 ± 0.4) was <O/O and T2DM (both 29 ± 1 kg/m, P < 0.001) but FFM did not differ, nor did waist circumference between O/O and T2DM. Fasting glycemia was 10.4 ± 0.5 mM in T2DM, and insulin was higher (126 ± 17) vs. O/O (75 ± 7) and L (63 ± 3 pM, P < 0.05). Clamp insulin was higher in T2DM (663 ± 23) and O/O (647 ± 22) than L (552 ± 30 pM, P < 0.05). The response of protein synthesis (S) to hyperinsulinemia was markedly blunted in T2DM vs. L (P < 0.001), and <O/O. S was stimulated 23 ± 4% in L, only 6 ± 2% in O/O, but not in T2DM (-2 ± 2%), P < 0.001. Breakdown (B) was inhibited comparably in all. Increase in net balance (S-B) was greater in L (48 ± 2) than in O/O (40 ± 2) and T2DM (36 ± 3 lmol/min), P < 0.05. Clamp glucose disposal (Rd) was lower in T2DM (232 ± 19 vs. 486 ± 48 mg/min, in O/O (P < 0.001), vs. 550 ± 48 in L (P < 0.001). Clamp glucose Rd correlated with S (r = 0.408, P = 0.028, n = 30, controlled for FFM) and S-B (r = 0.678, P < 0.001) and anabolic response (DS-B), (r = 0.604, P < 0.001). Thus, (i) T2DM in men is associated with diminished insulin-stimulated protein synthesis and is dramatically impaired compared to L; (ii) Whereas resistance of protein anabolism to insulin parallels that of glucose, sensitivity of breakdown suppression does not appear to be impaired; and (iii) Insulin resistance of protein metabolism in T2DM and its correction have important therapeutic implications.