A 37-residue of human islet amyloid polypeptide (hIAPP or amylin) is a main component of amyloid plaques found in the pancreas of similar to 90% of type PE diabetes patients. It is reported that hIAPP oligomers, rather than mature fibrils, are major toxic species responsible for pancreatic islet beta-cell dysfunction and even cell death, but molecular structures of these oligomers remain elusive. In this work, on the basis of recent solid-state NMR and mass-per-length (MPL) data, we model a series of hIAPP oligomers with different beta-layers (one, two, and three layers), symmetries (symmetry and asymmetry), and associated interfaces using molecular dynamics simulations. Three distinct interfaces formed by C-terminal beta-sheet and C-terminal beta-sheet (CC), N-terminal beta-sheet and N-terminal beta-sheet (NN), and C-terminal beta-sheet and N-terminal beta-sheet (CN) are identified to drive multiple cross-beta-layers laterally associated together to form different amyloid organizations via different intermolecular interactions, in which the CC interface is dominated by polar interactions, the NN interface is dominated by hydrophobic interactions, and the CN interface is dominated by mixed polar and hydrophobic interactions. Overall, the structural stability of the proposed hIAPP oligomers is a result of delicate balance between maximization of favorable peptide-peptide interactions at the interfaces and optimization of solvation energy with globular structure. Different hIAPP oligomeric models indicate a general and intrinsic nature of amyloid polymorphism, driven by different interfacial side-chain interactions. The proposed models are compatible with recent experimental data in overall size, cross-section area, and molecular weight. A general hIAPP aggregation mechanism is proposed on the basis of our simulated models and experimental data.