title: Preclinical characterization of recombinant human tissue kallikrein-1 as a novel treatment for type 2 diabetes mellitus.
abstract: Modulation of the kallikrein-kinin system (KKS) has been shown to have beneficial effects on glucose homeostasis and several other physiological responses relevant to the progression of type 2 diabetes mellitus (T2D). The importance of bradykinin and its receptors in mediating these responses is well documented, but the role of tissue kallikrein-1, the protease that generates bradykinin in situ, is much less understood. We developed and tested DM199, recombinant human tissue kallikrein-1 protein (rhKLK-1), as a potential novel therapeutic for T2D. Hyperinsulinemic-euglycemic clamp studies suggest that DM199 increases whole body glucose disposal in non-diabetic rats. Single-dose administration of DM199 in obese db/db mice and ZDF rats, showed an acute, dose-dependent improvement in whole-body glucose utilization. Sub-acute dosing for a week in ZDF rats improved glucose utilization, with a concomitant rise in fasting insulin levels and HOMA1-%B scores. After cessation of sub-acute dosing, fasting blood glucose levels were significantly lower in ZDF rats during a drug wash-out period. Our studies show for the first time that DM199 administration results in acute anti-hyperglycemic effects in several preclinical models, and demonstrate the potential for further development of DM199 as a novel therapeutic for T2D.
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Kolodka
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Charles
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Raghavan
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Ilian A
authors.initials: IA
authors.lastname: Radichev
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Amatya
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellefson
authors.affiliation: Sanford Project/Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America.
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Savinov
authors.affiliation: Invitek, Inc., Hayward, California, United States of America.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Nag
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Robbins
mesh_terms: D000818:Animals; D001786:Blood Glucose; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D020840:Tissue Kallikreins / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; D020840:Tissue Kallikreins
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