GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.

Abstract

CONTEXT:

Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking.

OBJECTIVE:

Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA).

DESIGN AND SETTING:

A case report and in vitro mechanistic studies.

PATIENT AND METHODS:

We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of β-cell dysfunction and the effects of GLP-1-RA.

RESULTS:

Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects.

CONCLUSION:

NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

• Authors: Liron Danielpur, Yang-Sung Sohn, Ola Karmi, Chen Fogel, Adar Zinger, Abdulsalam Abu-Libdeh, Tal Israeli, Yael Riahi, Orit Pappo, Ruth Birk, David H Zangen, Ron Mittler, Zvi-Ioav Cabantchik, Erol Cerasi, Rachel Nechushtai, Gil Leibowitz
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 101 Issue 10 Pg. 3592-3599 (10 2016) ISSN: 1945-7197 [Electronic] United States
• PMID: 27459537 (Publication Type: Case Reports, Journal Article)

Chemical References

• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Peptides
• Venoms
• Exenatide

Topics

• Aging, Premature (drug therapy)
• Animals
• Exenatide
• Female
• Glucagon-Like Peptide-1 Receptor (agonists)
• Hearing Loss, Sensorineural (drug therapy)
• Humans
• Hypoglycemic Agents (administration & dosage, pharmacology)
• Insulin-Secreting Cells (drug effects)
• Mitochondria (drug effects)
• Mitochondrial Diseases (drug therapy)
• Optic Atrophy (drug therapy)
• Peptides (administration & dosage, pharmacology)
• Rats
• Venoms (administration & dosage, pharmacology)