The insulin-like growth factor system : Effects of circulating proteases

摘要: The insulin-like growth factor-I and –II (IGF-I/ -II) are peptide hormones important for metabolism. They stimulate cell proliferation differentiation inhibit apoptosis. In addition, they have effects on glucose amino acid A large quantity of IGFs is synthesized in the liver subsequently transported to circulation act as endocrine factors. produced extra hepatic tissues may locally paracrine/ autocrine serum most IGF circulate a ternary complex with IGF-binding protein-3 (IGFBP-3) labile subunit (ALS). affinity between IGFBP-3 exceeds that type 1 receptor demonstrating circulating unavailable receptor. However, slight decrease binding within increases bioavailability IGFs. Post-translational modifications IGFBPs common proteolytic cleavage represents one example. IGFBP proteolysis results reduced increased bioavailability. Increased found several clinical conditions associated insulin resistance, e.g. critical illness, postoperatively 2 diabetes. partly compensate resistance by increasing availability thereby also effects. present licentiate thesis we studied mechanisms vivo humans. We attempted evaluate molecular consequences proteolysis. first (paper I) whether cannulation and/ or venous stasis activating fibrinolytic thrombogenic enzymes. These enzymes capacity cleave vitro. limited vascular damage blood flow response did not affect Furthermore, elevated levels after surgery. This does exclude extensive activation myocardial infarction, thrombosis wound healing result further demonstrates current methods detect valid if our sampling recommendations followed. then investigated II) cytokine interleukin-6 (IL-6) IGFBP-1 healthy adults. was since IL-6 inflammatory diseases 3-hour infusion increase up 5 hours post-infusion compared saline infusion. finding should target resulting changes IGF-system during inflammation resistance. Based these cannot higher (>0.1 ng/ ml) immediately prolonged exposure IGFBP-3. Interestingly, end mechanism independent insulin. change total free IGF-I. Finally, (project report) isolate major fragment human postoperative order 1) obtain sequence data site unravel protease 2) examine from cleavage. By using IGF-I chromatography, isolated 30 kDa post-operative serum. N-terminal sequencing revealed GASS. identical low recovery allow us identify Cterminal enough material studies. Alternative purification strategies were explored including an attempt raise antibodies chromatography. summary this provides abdominal surgery but it affected canulation short-term IL6. currently established can be used potential inductors demonstrate more potent regulator significance unknown level unchanged. suggest development procedures characterize fragments helpful identifying proteases fragmentation vivo. provide useful information about alterations