Abstract
The link between type 2 diabetes and cognitive dysfunction appears to start in the prediabetic state. Although cross sectional studies have linked insulin resistance to impaired cognition, this mechanism has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its treatment). We investigated participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ (TREND) study longitudinally. Subjects underwent a comprehensive neurocognitive assessment battery at baseline and every 2 years afterwards (median follow-up 4.0 q1-3: 2.2-4.3 y). Subjects with an HbA1c of 5.6-6.5% without known diabetes were metabolically investigated by a five-point 75g oral glucose tolerance test (OGTT) with assessment of insulin sensitivity and insulin secretion (N=175). Subjects with newly diagnosed diabetes or with depression (BDI >20) were excluded (N=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time between measurements were used as random effects. Insulin sensitivity was negatively associated with the CERAD sum score (Consortium to Establish a Registry for Alzheimer's Disease) in a time-dependent manner (p=0.0057). This result is mainly driven by a worse performance in the memory domain due to declining insulin sensitivity (p=0.029). These interactions remained significant after adjusting for glycemia (p<0.04). No interactions between time and insulin sensitivity for executive, visuospatial or language domains were found. There was no association with insulin secretion. In summary, insulin resistance predicts cognitive decline, specifically memory impairment in prediabetic persons. Therefore, insulin resistance rather than sole elevation of blood glucose predispose neuro-cognitive impairment. Diabetes treatments that improve insulin sensitivity might therefore have the potential to postpone/prevent cognitive decline in diabetes. Disclosure C. Willmann: None. K. Brockmann: None. R. Wagner: Other Relationship; Self; Lilly Diabetes, Novo Nordisk A/S. S. Kullmann: None. H. Preissl: None. W. Maetzler: None. T. Gasser: Research Support; Self; National Institute on Aging. Other Relationship; Self; AbbVie Inc. G.W. Eschweiler: None. F.G. Metzger: None. A.J. Fallhgatter: None. H. Haering: None. A. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi.
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