A two chain insulin analogue contains an A chain modified by (i) a monomeric glucose binding element at or near its N terminus and (ii) a B chain modified by at or near its C terminus by an element that reversibly binds to the monomeric glucose binding element such that this linkage is displaceable by glucose. The monomeric glucose binding element may be phenylboronic acid derivative (optionally halogenated). The B chain may be modified by a diol containing element derived from a monosaccharide disaccharide or oligosaccharide a non saccharide diol containing moiety or a a hydroxycarboxylate containing moiety. The analogue can be manufactured by trypsin mediated semi synthesis. Formulations can be at strengths U 10 to U 1000 in soluble solutions at pH 7.0 8.0 with or without zinc ions at a molar ratio of 0.0 3.0 ions per insulin analogue monomer. A patient with diabetes mellitus may be treated with subcutaneous intraperitoneal or oral administration of a physiologically effective amount of the insulin analogue.
