Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy
Autor: | Raghavendra G. Mirmira, Bernhard Maier, Sarah A. Tersey, Stephanie C. Colvin |
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Rok vydání: | 2013 |
Předmět: |
Male
medicine.medical_specialty Eflornithine Clinical Biochemistry Inflammation Nod Biochemistry Article Streptozocin Diabetes Mellitus Experimental Mice chemistry.chemical_compound Mice Inbred NOD Peptide Initiation Factors Internal medicine Polyamines medicine Animals Deoxyhypusine synthase Mice Knockout Hypusine Oxidoreductases Acting on CH-NH Group Donors Type 1 diabetes geography geography.geographical_feature_category Dose-Response Relationship Drug biology Organic Chemistry RNA-Binding Proteins medicine.disease Streptozotocin Islet Mice Inbred C57BL Disease Models Animal Diabetes Mellitus Type 1 Endocrinology chemistry Ornithine Decarboxylase Inhibitor biology.protein Female medicine.symptom medicine.drug |
Zdroj: | Amino Acids. 46:633-642 |
ISSN: | 1438-2199 0939-4451 |
Popis: | The underlying pathophysiology of type 1 diabetes involves autoimmune-mediated islet inflammation, leading to dysfunction and death of insulin-secreting islet β cells. Recent studies have shown that polyamines, which are essential for mRNA translation, cellular replication, and the formation of the hypusine modification of eIF5A may play an important role in the progression of cellular inflammation. To test a role for polyamines in type 1 diabetes pathogenesis, we administered the ornithine decarboxylase inhibitor difluoromethylornithine to two mouse models--the low-dose streptozotocin model and the NOD model--to deplete intracellular polyamines, and administered streptozotocin to a third model, which was haploinsufficient for the gene encoding the hypusination enzyme deoxyhypusine synthase. Subsequent development of diabetes and/or glucose intolerance was monitored. In the low-dose streptozotocin mouse model, continuous difluoromethylornithine administration dose-dependently reduced the incidence of hyperglycemia and led to the preservation of β cell area, whereas in the NOD mouse model of autoimmune diabetes difluoromethylornithine reduced diabetes incidence by 50%, preserved β cell area and insulin secretion, led to reductions in both islet inflammation and potentially diabetogenic Th17 cells in pancreatic lymph nodes. Difluoromethylornithine treatment reduced hypusinated eIF5A levels in both immune cells and islets. Animals haploinsufficient for the gene encoding deoxyhypusine synthase were partially protected from hyperglycemia induced by streptozotocin. Collectively, these studies suggest that interventions that interfere with polyamine biosynthesis and/or eIF5A hypusination may represent viable approaches in the treatment of diabetes. |
Databáze: | OpenAIRE |
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