Low alpha-synuclein levels in the blood are associated with insulin resistance

Mutations in the protein alpha-synuclein (SNCA) have been linked to Parkinson’s disease. We recently reported that non-mutated SNCA enhanced glucose uptake through the Gab1-PI3 kinase-Akt pathway and elucidated its effects on glucose regulation. Here, we examined the association of SNCA with insulin resistance (IR), a condition that is characterized by decreased tissue glucose uptake. Our observations include those from a population study as well as a SNCA-deficient mouse model, which had not previously been characterized in an IR scenario. In 1,152 patients, we found that serum SNCA levels were inversely correlated with IR indicators—body mass index, homeostatic model assessment for IR (HOMA-IR) and immunoreactive insulin (IRI)—and, to a lesser extent, with blood pressure and age. Additionally, SNCA-deficient mice displayed alterations in glucose and insulin responses during diet-induced IR. Moreover, during euglycemic clamp assessments, SNCA knock-out mice fed a high-fat diet (HFD) showed severe IR in adipose tissues and skeletal muscle. These findings provide new insights into IR and diabetes and point to SNCA as a potential candidate for further research.