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.
Highlights
According to the World Health Organization (2012) there are more than 340 million people affected by diabetes worldwide, of which 90% suffer from type 2 diabetes mellitus (T2D)
The effect of DM199 on insulin sensitivity and glucose utilization was tested in a hyperinsulinemic euglycemic clamp (HEC) model in non-diabetic male Sprague-Dawley (SD) rats
The area under the curve (AUC) glucose infusion rates (GIR) was significantly increased with the two doses of DM199 compared to control
Summary
According to the World Health Organization (2012) there are more than 340 million people affected by diabetes worldwide, of which 90% suffer from type 2 diabetes mellitus (T2D). New classes of therapeutics such as glucagon-like 1 peptide receptor (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transport (SGLT2) inhibitors have been recently approved, there is still a need for therapies with novel mechanisms of action that can reduce hyperglycemia and ameliorate the complications of diabetes [1]. The kallikrein-kinin system (KKS) includes the serine protease tissue kallikrein-1 (KLK-1), its natural biological substrates, kininogens, and the peptide cleavage products, bradykinin (BK) and lys-bradykinin. The KKS is best characterized by its role in mediating inflammation, the regulation of blood pressure and cardiovascular function (reviewed in [2,3,4,5]). In the context of T2D pathogenesis and progression, several reports suggest a role for the KKS in insulin sensitization and glucose homeostasis.
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