title: Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.
abstract: Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Danny Hung-Chieh
authors: DH
authors: Chou
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Matthew J
authors: MJ
authors: Webber
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Benjamin C
authors: BC
authors: Tang
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Amy B
authors: AB
authors: Lin
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Lavanya S
authors: LS
authors: Thapa
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: David
authors: D
authors: Deng
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;
authors: Jonathan V
authors: JV
authors: Truong
authors: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors: Abel B
authors: AB
authors: Cortinas
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139 rlanger@mit.edu dgander@mit.edu.
authors: Robert
authors: R
authors: Langer
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139 rlanger@mit.edu dgander@mit.edu.
authors: Daniel G
authors: DG
authors: Anderson
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D013311:Streptozocin
chemical_list: D001897:Boronic Acids; D007328:Insulin; D013311:Streptozocin; D005947:Glucose; C010686:benzeneboronic acid
keywords: diabetes; glucose sensing; molecular engineering; protein modification; smart therapy