A single-chain insulin analog containing a basic side chain at position A8 (Arginine, Histidine, Lysine, or Ornithine), a basic side chain at position B29 (Arginine, Histidine, Lysine, or Ornithine), and a foreshortened C-domain of length 6-11 residues is provided. Residues C1 and C2 of the C-domain have a net negative charge of −1 or −2； C3 is chosen from a group consisting of Gly, Ala, Pro, or Ser； and the remaining C-domain segment is successively derived from the C-domain of IGF-II (RRSR (SEQ ID NO: 18), SRRSR (SEQ ID NO: 17), VSRRSR (SEQ ID NO: 16), RVSRRSR (SEQ ID NO: 15), or SRVSRRSR SEQ ID NO: 13). A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analog or a physiologically acceptable salt thereof to a patient.
