A two-chain insulin analogue contains a modified A-chain polypeptide and a modified B-chain polypeptide. The A-chain polypeptide comprises one or more of: a His or Glu substitution at position A8, a Glu substitution at position A14； and a Gln or Arg substitution at positon A17. The B-chain polypeptide comprises one or more of: a deletion of the amino acids at position B1, B1-B2, B1-B3, B30 or a combination thereof； an Ala or Glu substitution at position B2； a Glu substitution at position B3. The insulin analogue exhibits thermodynamic stability in a zinc-free solution, decreased self-association, maintains biological potency, and does not exhibit enhanced mitogenicity. The insulin analogue exhibits resistance to chemical degradation and resistance to physical degradation. A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.本發明係關於一種雙鏈胰島素類似物，其含有經改造之A-鏈多肽及經改造之B-鏈多肽。該A-鏈多肽包含以下中之一或多者：在位置A8處之His或Glu取代，在位置A14處之Glu取代；及在位置A17處之Gln或Arg取代。該B-鏈多肽包含以下中之一或多者：在位置B1、B1-B2、B1-B3、B30處之胺基酸缺失或其組合；在位置B2處之Ala或Glu取代；在位置B3處之Glu取代。該胰島素類似物展現於無鋅溶液中之熱力學穩定性、減少自我締合、維持生物效力、及沒有增強之絲裂原活性。該胰島素類似物展現抗化學降解及抗物理降解。一種治療患有糖尿病或肥胖症之患者之方法包括對患者投與生理上有效量之胰島素類似物或其生理上可接受之鹽。
