Genetics and diet explain sex differences in glucose metabolism and cognitive function

Abstract

AbstractBackgroundDiabetes and cognitive impairment occur together more often than would be expected by chance [1–6]. Individuals diagnosed with type 2 diabetes have a 1.4–2.2‐fold higher risk of dementia than those without diabetes [2,6,7]. Epidemiological research has demonstrated shared risk factors, metabolic disorders, and comorbidities[5,8], shared genetics[9], and evidence of causality assessing glycemic traits [4,10–12]. We set out to determine how glucose metabolism modifies normal aging‐related cognitive decline in comparison to Alzheimer’s Disease (AD)‐related decline, given genetic diversity and controlled diet (GxD).MethodWe studied an innovative, genetically diverse mouse population (AD‐BXDs, Fig. 1) to determine GxD effects on metabolic function and the transition to cognitive impairment [13]. The data were collected longitudinally from a cohort of ∼650 AD‐BXD mice (39 unique strains) fed either a low‐fat chow diet or a high‐fat, high sucrose diet (HFD:45% fat,17.5% sucrose). Glucose metabolism was assessed by measuring the area under the curve of an intraperitoneal glucose tolerance test (IPGTT). In general, faster clearance of glucose (smaller area under the curve) reflects better glycemic control. Contextual fear memory (CFM) at 6 and 14 months of age was the measure of cognitive function. We used multivariable linear regression to model the relationship between overall CFM and an IPGTT by strain effect.ResultWe found that there was heterogeneity in IPGTT by sex, strain, and diet, accounting for more than 50% of the variation explained (Fig. 2). Females generally exhibit faster glucose metabolism than males (Fig.2, left), while the magnitude of the effect of sex and diet on IPGTT differs by strain (Fig. 2, x‐axis). For our research question of how glucose metabolism affects cognitive function, we identified strains that exhibited resilience to cognitive dysfunction as predicted by their glucose metabolism, with a broad‐sense heritability of 0.81 (Fig. 3). These early findings establish a foundation to identify quantitative trait loci (QTLs) and GxD‐type QTLS based on glucose tolerance and cognitive function associations.ConclusionBy examining the effect of diet on AD‐BXD strains and incorporating metabolic measures associated with diabetes, we will be able to evaluate and validate cause in these relationships for the first time.