Insulin sensitivity predicts cognitive decline in individuals with prediabetes

Abstract

Introduction: Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).

Research design and methods: We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3: 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.

Results: Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.

Conclusions: Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

Keywords: diabetes complications; insulin resistance.

Figure 1

Presented are the regression lines from the statistical models. The linear trend lines show the association of age and the CERAD sum score for different levels of insulin sensitivity (mean±1 SD). CERAD, Consortium to Establish a Registry for Alzheimer’s Disease.

Figure 2

Presented are the regression lines from the statistical models. The linear trend lines show the association of age and the cognitive memory tests ‘world list learn’ (left) and ‘word list recall’ (right) for different levels of insulin sensitivity (mean±1 SD).

Figure 3

Risk of cognitive decline (assessed by CERAD sum score) >5% using Kaplan-Meier estimators. Subjects were stratified by the median of insulin sensitivity. Insulin-resistant subjects are represented in the lower curve, insulin-sensitive subjects in the upper curve. CERAD, Consortium to Establish a Registry for Alzheimer’s Disease.