Simulation model of defective insulin receptors as byproducts of receptor recycling.
Our simulation model assumes that the defective insulin-binding receptors in non-insulin-dependent diabetes (NIDDM) patients result from functional receptor recycling. The model is a short program written in MS DOS 5.0 Qbasic. MODEL DESIGN: Receptors with intracellular portions damaged in the process of recycling are considered defective since they bind insulin but do mediate insulin effects, or recycle. Their occurrence depends on the average activation rate of functional receptors. The insulin-binding receptors (defective and functional) are objects of slow and time-dependent turnover defined by the turnover rate. Recycled receptors rejoin functional receptors or enter the pool of defective receptors. The waste in the functional receptors' pool is covered by a limited amount of newly synthesized receptors. The defective receptors often accumulate in cases of increased activation of functional receptors. SIMULATION RESULTS: The insulin-binding receptor quantity is determined, in the model, only by the number of newly synthesized receptors, reflecting the intensity of insulin stimulation. Synthesis is increased following variable insulin stimulations and decreased after sustained, intensive insulin stimulation. The number of functional receptors inversely reflects the average activation rate of functional receptors compared with the insulin-binding receptors turnover rate. High activation rates can diminish the proportion of functional receptors to less than 5% of that of all insulin-binding receptors. The model predicts that cells bearing only functional receptors show progressively shortened half-lives of receptors, reflecting the receptor activation intensity. On the other hand, cells bearing both defective and functional receptors show stable receptors' half-lives (20-36% of the defective receptors' half-life). Simulation results suggest that reduced functional receptor proportions in NIDDM patients might reflect the imbalance between the activation of functional receptors and the slow catabolism of defective receptors.
Kurbel
B
B
Department of Anaesthesiology, University Hospital Dubrava, Zagreb, Croatia.
Kurbel
S
S
Kristek
Z
Z
Jakić
M
M
Jurić
M
M
Sulava
D
D
D000818:Animals; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008954:Models, Biological; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000378:metabolism*; D012984:Software
D011972:Receptor, Insulin