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      Autoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1

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          The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.

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          Most cited references 40

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          Epidemiology of type 1 diabetes.

          This article describes the epidemiology of type 1 diabetes mellitus (T1D) around the world and across the lifespan. Epidemiologic patterns of T1D by demographic, geographic, biologic, cultural, and other factors in populations are presented to gain insight about the causes, natural history, risks, and complications of T1D. Data from large epidemiologic studies worldwide indicate that the incidence of T1D has been increasing by 2% to 5% worldwide and that the prevalence of T1D is approximately 1 in 300 in the United States by 18 years of age. Research on risk factors for T1D is an active area of research to identify genetic and environmental triggers that could potentially be targeted for intervention. Although significant advances have been made in the clinical care of T1D with resultant improvements in quality of life and clinical outcomes, much more needs to be done to improve care of, and ultimately find a cure for, T1D. Epidemiologic studies have an important ongoing role to investigate the complex causes, clinical care, prevention, and cure of T1D. Copyright 2010 Elsevier Inc. All rights reserved.
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            Type 1 diabetes

             Denis Daneman (2006)
            Type 1 diabetes accounts for only about 5-10% of all cases of diabetes; however, its incidence continues to increase worldwide and it has serious short-term and long-term implications. The disorder has a strong genetic component, inherited mainly through the HLA complex, but the factors that trigger onset of clinical disease remain largely unknown. Management of type 1 diabetes is best undertaken in the context of a multidisciplinary health team and requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal planning, and screening for comorbid conditions and diabetes-related complications. These complications consist of microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type 1 diabetes. Newer treatment approaches have facilitated improved outcomes in terms of both glycaemic control and reduced risks for development of complications. Nonetheless, major challenges remain in the development of approaches to the prevention and management of type 1 diabetes and its complications.
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              NOD mouse colonies around the world--recent facts and figures.

              Non-obese diabetic (NOD) mice are commonly used in autoimmune research. However, the diversity of these mice in developing autoimmune disease under different conditions prompted a group of researchers to compile a questionnaire on this subject. Here Paolo Pozzilli and colleagues comment on the results of this survey.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                26 September 2014
                : 9
                : 9
                [1 ]Sanford Project/Children’s Health Research Center, Sanford Research, Sioux Falls, South Dakota, United States of America
                [2 ]DiaMedica USA, Inc., Minneapolis, Minnesota, United States of America
                Bristol Heart Institute, University of Bristol, United Kingdom
                Author notes

                Competing Interests: MLC, MSW and MSR are employees and shareholders of Diamedica USA, Inc. AR is a consultant for Diamedica USA, Inc. The authors (indicated in parentheses) are inventors on the following patents covering compositions and/or the use of human tissue kallikrein for treating diabetes: PCT/ CA2010/000413, ‘Tissue kallikrein for the treatment of pancreatic beta cell dysfunction’ (MSW); PCT/US2012/036556, ‘Compositions and methods for treating diabetes' (MLC and MSW); PCT/CA2013/050395, ‘Formulations of human tissue kallikrein-1 for parenteral delivery and related methods’ (MLC). DM199 is currently in clinical trials for the treatment of type 2 diabetes. There are no further relevant patents, products in development or marketed products to declare. These competing interests do not alter the authors' adherence to all the PLOS ONE policies on sharing data and/or materials.

                Conceived and designed the experiments: LM-R MSW MLC AYS. Performed the experiments: LM-R CA CP JE IR. Analyzed the data: LM-R CA IR AR MLC MSW MSR AYS. Contributed reagents/materials/analysis tools: MSW MLC AYS. Wrote the paper: LM-R AR MSW MSR AYS.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                All funding for the study and supply of the therapeutic test article, DM199, was provided by Diamedica, Inc. The funder provided support in the form of salaries for authors MLC, AR, MSW and MSR, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Research Article
                Biology and Life Sciences
                Immune Suppression
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Type 1 Diabetes
                Drug Research and Development
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are included within the paper.



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