Objective: To correlate brain insulin signalling with peripheral insulin resistance using neuronally derived blood exosomes in patients with Parkinson’s Disease (PD)

Background: Insulin signaling abnormalities may contribute to PD pathogenesis, both promoting and being driven by the deposition of alpha-synuclein. It is unknown whether peripheral insulin resistance and prediabetes are associated with dysfunctional central insulin signalling in PD. Extracellular Vesicles, or exosomes, can be separated to identify those that come specifically from brain neurons implicated in insulin resistance. While this method has primarily been used in AD, its utility has been proven in PD as well.

Method: Fasting insulin, fasting glucose, and HbA1c were recorded 37 non-diabetic and non-demented PD patients in order to determine peripheral IR status. IR was measured using the HOMA-IR method, defined as fasting glucose (mg/dl) × fasting insulin (mU/l)/405. HoMA-IR values ≥ 2.0 and/or HbA1c ≥5.7 were used to define peripheral IR. Plasma exosomes were precipitated and bound to a biotinylated CD-171 antibody, allowing to enrich for neuronal exosomes. This allowed for the determination of the ratio of pSer312-IRS-1 to pan-Tyr phosphorylated IRS-1 (IR index) for each subject. The significance of differences between PD patients with and without IR was calculated with non-parametric tests (Mann Whitney U).

Results: Of 37 non diabetic PD subjects included in the study, 18 (48.6%) had peripheral IR. Mean levels of P-serine 312-IRS-1 were 22.7 ± 0.86 U/ml in non-IR PD patients and 22.3 ± 0.89 U/ml in PD patients with IR (NS). P-pan-tyrosine-IRS-1 levels were 0.153 ± 0.06 AU (absorbance units at 450 nm) for non-IR PD and 0.156 ± 0.06 AU for PD with IR (NS). Mean IR index values were 159.2 ± 48.3 for PD with IR and 167.3 ± 55.1 for non-IR PD (NS).

Conclusion: Comparison of the results for PD patients with and without peripheral IR showed no differences in the exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, or IR index, suggesting that brain insulin resistance is independent of peripheral IR status in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/central-insulin-resistance-index-is-independent-of-peripheral-insulin-resistance-in-parkinsons-disease/