Protective effects of polyamine depletion in mouse models of type 1 diabetes

Implications for therapy

Sarah A. Tersey, Stephanie C. Colvin, Bernhard Maier, Raghu Mirmira

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)633-642
Number of pages10
JournalAmino Acids
Volume46
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Eflornithine
Polyamines
Streptozocin
Medical problems
Type 1 Diabetes Mellitus
Inflammation
Islets of Langerhans
Hyperglycemia
Gene encoding
Th17 Cells
Inbred NOD Mouse
Glucose Intolerance
Incidence
Insulin-Secreting Cells
Protein Biosynthesis
Therapeutics
Insulin
Genes
Lymph Nodes
Biosynthesis

Keywords

  • Diabetes
  • Hypusine
  • Islet
  • Mouse
  • Polyamine

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry
  • Medicine(all)

Cite this

Protective effects of polyamine depletion in mouse models of type 1 diabetes : Implications for therapy. / Tersey, Sarah A.; Colvin, Stephanie C.; Maier, Bernhard; Mirmira, Raghu.

In: Amino Acids, Vol. 46, No. 3, 2014, p. 633-642.

Research output: Contribution to journalArticle

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