Risk Factors for Cognitive Impairment in Patients with Type 2 Diabetes.
ABSTRACT: Objectives:To investigate the risk factors for cognitive impairment in Chinese type 2 diabetes mellitus (T2DM) patients of advanced age and to identify effective biomarkers of mild cognitive impairment (MCI) in these patients. Methods:Chinese T2DM patients (n = 120) aged 50-70 years were divided into groups with impaired (mild, moderate, and severe) and normal cognitive function based on Montreal Cognitive Assessment and Mini-Mental State Examination scores. Data regarding demographic characteristics, clinical features of diabetes, biochemical markers, and metabolomics were collected. Results:Age, educational level, duration of diabetes, fasting blood glucose (FBG), HbA1c, total cholesterol (TC), triglyceride (TG), and 24-hour urine protein were significantly associated with cognitive impairment in T2DM patients of advanced age. The severity of fundus retinopathy and the incidence of macrovascular disease also differed significantly among the groups (P < 0.05). Metabolomics analysis suggested that increased levels of glutamate (Glu), phenylalanine (Phe), tyrosine (Tyr), proline (Pro), and homocysteine (Hcy) and a decreased level of glutamine (Gln) were significantly associated with cognitive impairment in the T2DM patients (P < 0.05). Receiver operating characteristic curve analysis demonstrated that Glu, Gln, Phe, and Pro levels were significant predictors of cognitive impairment in the T2DM patients. Conclusions:Age, educational level, duration of diabetes, and the levels of FBG, HbA1c, TC, TG, and 24-hour urine protein were considered as independent risk factors for cognitive impairment in older T2DM patients. Macrovascular and microvascular diseases also were closely associated with cognitive impairment in these patients. Together, Glu and Gln levels may represent a good predictive biomarker for the early diagnosis of cognitive impairment in T2DM patients.
Project description:People with insulin resistance and type 2 diabetes mellitus (T2DM) are at increased risks of cognitive impairment. We aimed to investigate the association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment (MCI) in T2DM patients.In addition to elevated glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR), T2DM patients with MCI had decreased plasma ghrelin levels compared with their healthy-cognition subjects (all p < 0.05). Further logistic regression analysis showed that ghrelin level was one of independent factors for MCI in T2DM patients (p < 0.05). Moreover, partial correlation analysis demonstrated that ghrelin levels were positively associated with the scores of Montreal Cognitive Assessment (r = 0.196, p = 0.041) and Auditory Verbal Learning Test-delayed recall (r = 0.197, p = 0.040) after adjustment for HbA1c, FBG and HOMA-IR, wherein the latter represented episodic memory functions. No significant differences were found for the distributions of genotype and allele of ghrelin rs4684677 polymorphism between MCI and control group.A total of 218 T2DM patients, with 112 patients who satisfied the MCI diagnostic criteria and 106 who exhibited healthy cognition, were enrolled in this study. Demographic characteristics, clinical variables and cognitive performances were extensively assessed. Plasma ghrelin levels and ghrelin rs4684677 polymorphism were also determined.Our results suggest that decreased ghrelin levels are associated with MCI, especially with episodic memory dysfunction in T2DM populations.
Project description:Patients with type 2 diabetes mellitus (T2DM) have a considerably high risk of developing dementia, especially for those with mild cognitive impairment (MCI). The investigation of the microstructural change of white matter (WM) between T2DM with amnesic MCI (T2DM-aMCI) and T2DM with normal cognition (T2DM-NC) and their relationships to cognitive performances can help to understand the brain variations in T2DM-related amnesic cognitive impairment. In the current study, 36 T2DM-aMCI patients, 40 T2DM-NC patients, and 40 healthy control (HC) individuals underwent diffusion tensor image and T1-weighted MRI scans and comprehensive cognition assessments. All of these cognitive functions exhibited intergroup ranking differences in patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WM integrity. The T2DM-aMCI patients showed disrupted integrity in multiple WM tracts compared with HC and T2DM-NC. Specifically, the damaged WM integrity of the right inferior fronto-occipital fasciculus and the right inferior longitudinal fasciculus exhibited significant correlations with episodic memory and attention function impairment in T2DM patients. Furthermore, cognitive impairment-related WM microstructural damage was associated with the degeneration of cortex connected to the affected WM tract. These findings indicate that degeneration exists extensively in WM tracts in T2DM-aMCI, whereas no brain WM damage is evident in T2DM-NC.
Project description:Type 2 diabetes mellitus (T2DM) may be associated with altered urinary microbiota in female patients. We investigated alterations of urinary microbiota in Chinese female T2DM patients, and explored the associations between urinary microbiota and a patient's fasting blood glucose (FBG), urine glucose (UGLU), age, menstrual status, and body mass index (BMI). Midstream urine was collected from 70 female T2DM patients and 70 healthy females. Microbial diversity and composition were analyzed using the Illumina MiSeq sequencing platform by targeting the hypervariable V3-V4 regions of the 16S rRNA gene. We found that bacterial diversity was decreased in T2DM patients. Increased Actinobacteria phylum was positively correlated with FBG, UGLU, and BMI; Lactobacillus abundance decreased with age and menopause; and increased Lactobacillus correlated positively with FBG and UGLU. Decreased Akkermansia muciniphila was associated with FBG and UGLU. Escherichia coli abundance did not differ between the two cohorts. Carbohydrate and amino acid metabolism was reduced in T2DM patients, which were associated with bacterial richness indices such as Chao1 and ACE. Detailed microbiota analysis of well-characterized T2DM patients and healthy controls indicate that Chinese T2DM female patients exhibit dysbiosis of urinary microbiota.
Project description:Previous studies on the large-scale glycomics of more than 3500 human serum samples revealed that the serum glycoproteins of cancer patients often have more dominant and specific glycoforms, namely, branched tri- and tetra-antennary N-glycans, most cancer patient groups than normal control groups. We herein established an efficient synthetic protocol of glycopeptides having highly complicated N-glycan structures that may be generated by direct tryptic digestion of serum glycoproteins. A preliminary selected reaction monitoring (SRM) assay using the synthetic model glycopeptide <b>1</b>, <sup>40</sup>Ser-Val-Gln-Glu-Ile-Gln-Ala-Thr-Phe-Phe-Tyr-Phe-Thr-Pro-Asn-Lys-Thr-Glu-Asp-Thr-Ile-Phe-Leu-Arg<sup>63</sup> having an asialo tri-antennary N-glycan at the Asn54 residue as a designated calibration standard allowed for the rapid and absolute quantitation of the tryptic fragment derived from the serum ?1-acid glycoprotein carrying a focused N-glycoform of cancer patients and healthy controls in a range between 200 and 1600 fmole ?L<sup>-1</sup> without any enrichment process for the target glycoprotein.
Project description:The holostean fishes are the extant representatives of the primitive ray-finned fishes from which the present-day teleosts may have evolved. The primary structure of insulin from a holostean fish, the bowfin (Amia calva), was established as: A-chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Leu-Lys-Pro-Cys-Thr-Ile-Tyr-Glu-Met-Glu- Lys-Tyr-Cys-Asn B-chain: Ala-Ala-Ser-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Phe-Leu- Val-Cys-Gly-Glu-Ser-Gly-Phe-Phe-Tyr-Asn-Pro-Asn-Lys-Ser This amino acid sequence contains several substitutions (methionine at A16, phenylalanine at B16 and serine at B22) at sites that have been strongly conserved in other vertebrate species and that may be expected to influence biological activity. Consistent with this prediction, bowfin insulin was approx. 14-fold less potent than pig insulin in inhibiting the binding of [125I-Tyr-A14](human insulin) to transfected mouse NIH 3T3 cells expressing the human insulin receptor.
Project description:We have demonstrated that the S'(1) and S'(2) subsites of human tissue kallikrein (hK1) play determinant roles in the recognition and hydrolysis of substrates. The presence of serine at position P'(1) and arginine at P'(2) resulted in the best substrate, Abz-Ala-Ile-Lys-Phe-Phe-Ser-Arg-Gln-EDDnp, which was derived from the kallistatin reactive-centre loop sequence and quencher groups o-aminobenzoic acid (Abz) and N-(2,4-dinitrophenyl)ethylenediamine (EDDnp). Serine and arginine are also the residues at positions P'(1) and P'(2) in human kininogen, from which hK1 releases Lys-bradykinin. Several peptide analogues of Abz-Ala-Ile-Lys-Phe-Phe-Ser-Arg-Gln-EDDnp, in which the Ser and Arg residues were substituted with various other amino acids, were synthesized and tested as substrates. Most of them were hydrolysed slowly, although they showed significant binding to hK1, as demonstrated by their competitive inhibition constants (K(i)). Using this information, six peptides were designed, synthesized and assayed as inhibitors of hK1. Abz-Lys-Phe-Phe-Pro-Arg-Gln-EDDnp, Abz-Lys-Phe-Arg-Pro-Arg-Gln-EDDnp and acetyl-Lys-Phe-Phe-Pro-Leu-Glu-NH(2) inhibited hK1 in the range 20-30 nM (letters in italics denote the D-form of the amino acid). The peptide acetyl-Lys-Phe-Phe-Pro-Leu-Glu-NH(2) was a weak inhibitor for other serine proteases, as indicated by the higher K (i) values compared with hK1, but this peptide was a potent inhibitor of human plasma kallikrein, which has a K (i) value of 8 nM. This result was surprising, since this enzyme is known to be a restricted arginyl-hydrolase. In conclusion, acetyl-Lys-Phe-Phe-Pro-Leu-Glu-NH(2) can be used as a leader compound to design specific inhibitors for hK1, plasma kallikrein, or for both at same time, if the inhibition of kinin release is the main goal.
Project description:NAD+-dependent formate dehydrogenase (FDH) from Candida boidinii was cloned and expressed to a high level in Escherichia coli (20% of soluble E. coli protein). Molecular modelling studies were used to create a three-dimensional model of C. boidinii FDH, based on a known structure of the Pseudomonas sp. 101 enzyme. This model was used for investigating the catalytic mechanism by site-directed mutagenesis. Eleven forms of C. boidinii FDH were characterized by steady-state kinetic analysis: the wild type as well as 10 mutants involving single (Phe-69-Ala, Asn-119-His, Ile-175-Ala, Gln-197-Leu, Arg-258-Ala, Gln-287-Glu and His-311-Gln) and double amino acid substitutions (Asn-119-His/His-311-Gln, Gln-287-Glu/His-311-Gln and Gln-287-Glu/Pro-288-Thr). The kinetic results of the mutant enzymes provide the first experimental support that hydrophobic patches, formed by Phe-69 and Ile-175, destabilize substrates and stabilize products. Also, the key role of Arg-258 in stabilization of the negative charge on the migrating hydride was established. Asn-119, besides being an anchor group for formate, also may comprise one of the hinge regions around which the two domains shift on binding of NAD+. The more unexpected results, obtained for the His-311-Gln and Gln-287-Glu/His-311-Gln mutants, combined with molecular modelling, suggest that steric as well as electrostatic properties of His-311 are important for enzyme function. An important structural role has also been attributed to cis-Pro-288. This residue may provide the key residues Gln-287 and His-311 with the proper orientation for productive binding of formate.
Project description:To determine the prevalence of vascular complications among inpatients with type 2 diabetes mellitus (T2DM) and factors independently associated with vascular complications in a tertiary care department in Ningbo, China, the authors conducted a cross-sectional study using an existing computerised medical records database. A total of 3370 adult patients with T2DM were admitted to this tertiary care department for the first time between 2012 and 2017. Patients were categorised as those (1) with at least one vascular complication, (2) with at least one microvascular complication, and (3) with at least one macrovascular complication. Over 5 years, the prevalence of vascular, microvascular, and macrovascular complications among inpatients with T2DM was 73.2%, 57.5%, and 51.4%, respectively. The odds of vascular, microvascular, and macrovascular complications increased with age and were higher in patients with hypertension. The odds of vascular and microvascular complications were higher in single, divorced, or widowed patients, patients with T2DM for a long time, and patients on advanced T2DM therapeutic regimen. The odds of vascular and macrovascular complications were lower in women. The odds of microvascular complications decreased with education. The odds of macrovascular complications were higher in smokers. In conclusion, in the tertiary care department, more than half of inpatients with T2DM had vascular complications, and factors independently associated with vascular complications were identified. The study findings could be used in future interventional studies to prevent and manage vascular complications among these patients.
Project description:Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. We investigated whether alterations of intranetwork and internetwork functional connectivity with T2DM progression exist, by using resting-state functional MRI. MRI data were analysed from 19 T2DM patients with normal cognition (DMCN) and 19 T2DM patients with cognitive impairment (DMCI), 19 healthy controls (HC). Functional connectivity among 36 previously well-defined brain regions which consisted of 5 resting-state network (RSN) systems [default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL) and sensorimotor network (SMN)] was investigated at 3 levels (integrity, network and connectivity). Impaired intranetwork and internetwork connectivity were found in T2DM, especially in DMCI, on the basis of the three levels of analysis. The bilateral posterior cerebellum, the right insula, the DMN and the CON were mainly involved in these changes. The functional connectivity strength of specific brain architectures in T2DM was found to be associated with haemoglobin A1c (HbA1c), cognitive score and illness duration. These network alterations in intergroup differences, which were associated with brain functional impairment due to T2DM, indicate that network organizations might be potential biomarkers for predicting the clinical progression, evaluating the cognitive impairment, and further understanding the pathophysiology of T2DM.
Project description:Type 2 diabetes mellitus (T2DM) and hypertension are both associated with cognitive impairment and brain function abnormalities. We investigated whether abnormal cerebral blood flow (CBF) patterns exists in T2DM patients and possible relationships between aberrant CBF and cognitive performance. Furthermore, we examined the influence of hypertension on CBF alterations in T2DM patients. T2DM patients (n = 38) and non-T2DM subjects (n = 40) were recruited from clinics, hospitals, and normal community health screenings. Cerebral blood flow images were collected and analyzed using arterial spin labeling perfusion functional magnetic resonance imaging (fMRI). Regions with major CBF differences between T2DM patients and non-T2DM controls were detected via 1-way ANOVA. The interaction effects between hypertension and T2DM for CBF alterations were also examined. Correlation analyses illustrated the association between CBF values and cognitive performance and between CBF and blood pressure. Compared with non-T2DM controls, T2DM patients exhibited decreased CBF, primarily in the visual area and the default mode network (DMN); decreased CBF in these regions was correlated with cognitive performance. There was a significant interaction effect between hypertension and diabetes for CBF in the precuneus and the middle occipital gyrus. Additionally, blood pressure correlated negatively with CBF in T2DM patients.T2DM patients exhibited reduced CBF in the visual area and DMN. Hypertension may facilitate a CBF decrease in the setting of diabetes. T2DM patients may benefit from blood pressure control to maintain their brain perfusion through CBF preservation.