α-Synuclein Regulates Peripheral Insulin Secretion and Glucose Transport

Nadeeja Wijesekara; Rosemary Ahrens; Ling Wu; Tammy Langman; Anurag Tandon; Paul E Fraser

doi:10.3389/fnagi.2021.665348

α-Synuclein Regulates Peripheral Insulin Secretion and Glucose Transport

Front Aging Neurosci. 2021 Jul 30:13:665348. doi: 10.3389/fnagi.2021.665348. eCollection 2021.

Authors

Nadeeja Wijesekara¹, Rosemary Ahrens¹, Ling Wu¹, Tammy Langman¹, Anurag Tandon^{1

2}, Paul E Fraser^{1

3}

Affiliations

¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
² Department of Medicine, University of Toronto, Toronto, ON, Canada.
³ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Abstract

Aim: Population based studies indicate a positive association between type 2 diabetes (T2D) and Parkinson's disease (PD) where there is an increased risk of developing PD in patients with T2D. PD is characterized by the abnormal accumulation of intraneuronal aggregated α-synuclein (α-syn) in Lewy bodies, which negatively impact neuronal viability. α-syn is also expressed in both pancreatic islets and skeletal muscle, key players in glucose regulation. Therefore, we examined the functional role of α-syn in these tissues.

Methods: Using mice lacking, overexpressing or transiently injected with α-syn, effects on glucose and insulin tolerance and insulin secretion were determined, with further characterization of the effects on GLUT4 translocation using GLUT4myc myotubes.

Results: Mice genetically ablated for α-syn became glucose intolerant and insulin resistant with hyperinsulinemia and reduced glucose-stimulated insulin secretion (GSIS). Mice overexpressing human α-syn are more insulin senstive and glucose tolerant compared to controls with increased GSIS. Injection of purified α-syn monomers also led to improved glucose tolerance and insulin sensitivity with hightened GSIS. α-syn monomer treatments increased surface GLUT4 levels in myotubes but without any significant change in Akt phosphorylation. The increase in cell surface GLUT4 was largely due to a large reduction in GLUT4 endocytosis, however, with a compensatory reduction in GLUT4 exocytosis.

Conclusion: Cumulatively, this data suggests that α-syn modulates both pancreatic beta cell function and glucose transport in peripheral tissues, thereby playing a pivitol role in the maintenance of normal glucose homeostasis.

Keywords: GLUT4; Parkinson’s disease; diabetes; insulin secretion; α-synuclein.