Abstract
Diabetes in the elderly increases cognitive impairment, but the underlying mechanisms are still far from fully understood. A non-targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was performed to screen out the serum biomarkers of diabetic mild cognitive impairment (DMMCI) in rats. Total 48 SD rats were divided into three groups, Normal control (NC) group, high-fat diet (HFD) fed group and type 2 diabetes mellitus (T2DM) group. The T2DM rat model was induced by intraperitoneal administration of streptozotocin (STZ, 35 mg/kg) after 6 weeks of high-fat diet (HFD) feeding. Then each group was further divided into 4-week and 8-week subgroups, which were calculated from the time point of T2DM rat model establishment. The novel object recognition test (NORT) and the Morris water maze (MWM) method were used to evaluate the cognitive deficits in all groups. Compared to the NC-8w and HFD-8w groups, both NOR and MWM tests indicated significant cognitive dysfunction in the T2DM-8w group, which could be used as an animal model of DMMCI. Serum was ultimately collected from the inferior vena cava after laparotomy. Metabolic profiling analysis was conducted using ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to verify the stability of the model. According to variable importance in the project (VIP > 1) and the p-value of t-test (P < 0.05) obtained by the OPLS-DA model, the metabolites with significant differences were screened out as potential biomarkers. In total, we identified 94 differentially expressed (44 up-regulated and 50 down-regulated) endogenous metabolites. The 10 top up-regulated and 10 top down-regulated potential biomarkers were screened according to the FDR significance. These biomarkers by pathway topology analysis were primarily involved in the metabolism of sphingolipid (SP) metabolism, tryptophan (Trp) metabolism, Glycerophospholipid (GP) metabolism, etc. Besides, SP metabolism, Trp metabolism and GP metabolism mainly belonging to the lipid metabolism showed marked perturbations over DMMCI and may contribute to the development of disease. Taken collectively, our results revealed that T2DM could cause cognitive impairment by affecting a variety of metabolic pathways especially lipid metabolism. Besides, serum PE, PC, L-Trp, and S1P may be used as the most critical biomarkers for the early diagnosis of DMMCI.
Highlights
Increasing numbers of people are suffering from diabetes mellitus (DM), with the improvement of living standards and lifestyle changes
T2DM Rat Model Induced by HFD and STZ Diabetic SD rat models induced by the administration of STZ in the 6th week were confirmed through monitoring body weights (BW), random blood glucose (RBG) levels, Glycated serum protein (GSP) levels, and insulin levels
Persistent high glucose and GSP, as well as low insulin levels suggested the establishment of a diabetic rat model (Figure 2)
Summary
Increasing numbers of people are suffering from diabetes mellitus (DM), with the improvement of living standards and lifestyle changes. According to the eighth edition of the International Diabetes Federation (IDF), Diabetes Atlas in 2017, about 425 million people worldwide have diabetes, and the number is expected to rise to 700 million by 2045 [1]. DM is considered to be a major disease associated with cognitive decline and dementia, another most common chronic disabling disease among the elderly, with a 1.5–2.5-fold higher risk of dementia than the general population [2, 3]. As dementia is an irreversible disease, early diagnosis and detection of dementia are critical for its prevention and treatment. There is still a lack of accurate and reliable diagnostic criteria for DCD, making early detection of diabetic cognitive impairment more difficult
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