Impaired Insulin Sensitivity Relates to Preclinical Biomarkers of Neurodegenerative Disease in Young Adults With and Without Type 1 Diabetes (T1D)

In adults with diabetes, impaired insulin sensitivity (IS) has been implicated in the risk for neurodegenerative diseases, namely Alzheimer's Disease and its related dementias (AD/ADRD). However, the link between diabetes pathophysiology and AD/ADRD in youth-onset T1D is unknown. Thus, we examined the relationships between IS and preclinical biomarkers of AD/ADRD in 30 young adults with T1D (age 23±3 years, diabetes duration 13±5 years, 53% female, HbA1c 7.9±1.1%, BMI 25±3 kg/m2) and 20 age-similar healthy controls (age 25±3, 50% female, HbA1c 5.2±0.3%, BMI: 23±2). Whole-body (M-value mg/kg/min) and adipose (free fatty acid [%FFA] suppression) IS were measured by hyperinsulinemic-euglycemic clamps (80 mU/m2/min). Preclinical biomarkers of AD/ADRD including Neurofilament Light (NfL), Glial Fibrillary Acidic Protein (GFAP), Amyloid-β40 (Aβ40), Amyloid-β42 (Aβ42), and total Tau were measured in plasma via ultra-sensitive immunoassays (SIMOA Quanterix). Pearson correlations were run to examine the relationships among preclinical biomarkers, M-value and %FFA suppression across all participants. Young adults with T1D had higher NfL (2.14 [1.72, 2.56] vs. 1.40 [0.83, 1.97] pg/mL, p=0.046), Aβ40 (50.8 [47.6, 54.1] vs. 45.4 [41.2, 49.6] pg/mL, p=0.048) and Aβ42 (2.50 [2.36, 2.65] vs. 2.23 [2.04, 2.41] pg/mL, p=0.026) compared to healthy controls. No differences were observed in total Tau or GFAP between the two groups. Across all participants, M-value was inversely correlated with Aβ40 (r: -0.36, p=0.018), Aβ42 (r:-0.33, p=0.030) and NfL (r:-0.31, p=0.045). %FFA suppression inversely correlated with NfL (r: -0.70, p<0.0001). Preclinical biomarkers of AD/ADRD were altered in young adults with T1D, compared to healthy young adults, and in all young adults, were related to impaired whole body and adipose IS. Ongoing longitudinal studies will examine the clinical impact of these findings with brain imaging and cognitive testing. Disclosure A.Shapiro: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. R.G.Nelson: None. L.Pyle: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. C.Coughlan: None. C.Vinovskis: None. T.B.Vigers: None. M.E.Pauley: None. J.K.Snell-bergeon: None. A.A.Macdonald: None. K.L.Tommerdahl: None. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc.