Tests in mice of recombinant human tissue kallikrein-1 show promise….
Previous reports suggest that the kallikrein-kinin system (KKS) could be involved in insulin sensitization and glucose homeostasis. The KKS system consists of serine protease tissue kallikrein-1 (KLK-1), kinogens, bradykinin (BK) and lys-bradykinin. BK has been showed to increase insulin sensitivity and glucose uptake in rat models; however, the role of KLK-1 is still not well known.
KLK-1 is a "ubiquitous 238 amino acid glycoprotein, exists as a heterogenous mixture of glycoforms due to variable glycosylation at three potential sites." In preclinical studies, KLK-1 had been shown to significantly decrease blood pressure, insulin level, glucose level, plasma triglycerides and cholesterol level. However, these benefits of KLK-1 were not characterized in terms of dose, glycoform profile or activity. To further investigate the characteristics and benefits of KLK-1 for T2DM, Dr. Kolodka and colleagues designed a preclinical study involving DM199, a recombinant human tissue kallikrein-1 protein (rhKLK-1).
In this study, DM199 was produced from Chinese hamster ovary cells. Its specific activity was measured in vitro by cleavage of the substrate D-Val-Leu-Arg-7 amido-4-trifluoromethylcoumarin, and compared to the activity of porcine kininogenase standard acquired from the National Institute for Biological Standards and Control. After the purification process, DM199 was injected in the mice for fasting blood glucose and oral glucose tolerance tests.
The results from hyperinsulinemic-euglycemic clamp studies indicated that DM199 helped increase glucose infusion rates (GIR) and glucose disposal in non-diabetic rats. In obese db/db rats, a single dose of 360 µg/kg DM199 could significantly reduce FBG level and post-prandial glucose level. In ZDF rats, sub-acute dosing of DM199 for 7 days also increased fasting insulin levels and HOMA1-%B scores significantly. After the sub-acute dosing period, FBG levels in ZDF rats remained lower than controls during the wash-out period. According to the authors, the low FBG levels observed in the rats after medium and high doses of DM199 might be due to a protective effect on beta cell function or the stimulation effect on insulin secretion.
Based on the results of this study, DM199 could be a potential novel therapy for type 2 diabetes patients due to its anti-hyperglycemic effect.
- DM199 could be a novel treatment for type 2 diabetes patients.
- DM199 could produce acute anti-hyperglycemic effects in rats.
- DM199 has not been tested in humans.
Kolodka T, Charles ML, Raghavan A, et al. Preclinical characterization of recombinant human tissue kallikrein-1 as a novel treatment for type 2 diabetes mellitus. PLoS One 2014; 9(8): e103981.Endocrinol. 2014 August 13