Nonenzymatic function of DPP4 in diabetes-associated mitochondrial dysfunction and cognitive impairment.

Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzymatic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetes-associated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/db mice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunction and cognitive impairment both in vivo and in vitro. The results show that increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hippocampus of db/db mice and contributed to mitochondria dysfunction and cognitive impairment. Mechanistically, DPP4 might bind to PAR2 in the hippocampus and trigger GSK-3ß activation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads to mitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.

Association of Plasma DPP4 Activity and Brain-Derived Neurotrophic Factor With Moderate to Severe Depressive Symptoms in Patients With Type 2 Diabetes: Results From a Cross-Sectional Study.

OBJECTIVE: The objective of this study was to assess the association of plasma dipeptidyl peptidase-4 (DPP4) activity, brain-derived neurotrophic factor (BDNF), and the DPP4/BDNF ratio (DBR) with moderate to severe depressive symptoms in patients with type 2 diabetes mellitus. Increased DPP4 activity and decreased BDNF in peripheral circulation have been implicated in the pathophysiology of depression. METHODS: We performed a cross-sectional study using data from 1535 patients with type 2 diabetes mellitus. The main outcome measures were plasma DPP4 activity, BDNF levels, DBR, inflammation markers, and oxidative stress parameters. Depressive symptoms were assessed using the nine-item Patient Health Questionnaire. RESULTS: DPP4 activity and BDNF were negatively correlated in patients with and without moderate to severe depressive symptoms (p < .001). Oxidative stress partially mediated the inverse correlation between DPP4 and BDNF. Nitrotyrosine, 8-iso-PGF2a, interleukin-6, C-reactive protein, and the nine-item Patient Health Questionnaire score increased significantly with rising quartiles of DBR. Patients in the highest quartile of DPP4 activity and DBR and lowest quartile of BDNF more often had moderate to severe depressive symptoms compared with those in the lowest quartile of DPP4 activity and DBR and the highest quartile of BDNF, respectively (p < .05). The likelihood of having moderate to severe depressive symptoms increased more with higher DPP4 activity and lower BDNF. CONCLUSIONS: Our hypothesis-generating study demonstrates that oxidative stress might partially play a mediating role in the negative relationship between DPP4 activity and BDNF. DBR is positively related to moderate to severe depressive symptoms and thus might be used as a novel biological measure associated with depressive symptoms in patients with type 2 diabetes mellitus.

Triglyceride-mediated influence of serum angiopoietin-like protein 8 on subclinical atherosclerosis in type 2 diabetic patients: results from the GDMD study in China.

BACKGROUND: Hypertriglyceridemia, insulin resistance and hyperglycemia are risk factors for atherosclerosis in type 2 diabetes. Angiopoietin-like protein 8 (ANGPTL8) is a newly identified liver-derived hormone related to these risk factors. Hence, we aimed to explore the correlations between serum levels of ANGPTL8 and subclinical atherosclerosis in type 2 diabetes. METHODS: We measured serum ANGPTL8, blood lipids, blood glucose, common carotid artery Intima-Media Thickness (c-IMT) and calculated homeostasis model assessment of insulin resistance in (1) control subjects (n = 100), (2) type 2 diabetic patients without subclinical atherosclerosis (n = 100), and (3) type 2 diabetic patients with subclinical atherosclerosis (n = 100). RESULTS: Serum levels of ANGPTL8 and triglyceride (TG) were significantly increased in type 2 diabetic patients with subclinical atherosclerosis as compared with type 2 diabetic patients without subclinical atherosclerosis and control subjects (P < 0.001). ANGPTL8 was positively associated with age, TG, diabetes duration, and c-IMT in type 2 diabetes. Logistic regression analysis revealed that ANGPTL8 had higher odds of having subclinical atherosclerosis [odds ratio (OR) 2.90, 95% confidence interval (CI) 1.48-5.70, P = 0.002] in type 2 diabetes. Mediation analysis indicated that TG acted as a partial mediator in the relationship between ANGPTL8 and c-IMT. CONCLUSIONS: TG partially mediates the positive relationship between ANGPTL8 and c-IMT. Our data provide the first evidence for a strong link between ANGPTL8 and subclinical atherosclerosis, suggesting ANGPTL8 to be a new biomarker for subclinical atherosclerosis in type 2 diabetes.

The interaction effects of risk factors for hypertension in adults: a cross-sectional survey in Guilin, China.

BACKGROUND: The prevalence of hypertension in adults is increasing each year and has become a main public health issue worldwide. We must consider the impact of both individual factors and interactions among these factors on hypertension in adults. This study was designed to elucidate the clinical and metabolic characteristics of the prevalence of hypertension in adults and to explore the risk factors and interactions among these factors in adults with hypertension. METHODS: We used overall random sampling to conduct a cross-sectional survey of 6660 individuals undergoing a health check from July to November 2012, the subjects were aged 20 to 89 years, including 3480 men and 3180 women. The survey content included a questionnaire, anthropometry, laboratory measurements, and liver Doppler ultrasonography. The clinical and metabolic characteristics were compared between the cases (adult hypertensive patients) and the controls (normotensives). The classification tree model and the non-conditional logistic regression were used to analyze the interactions of risk factors for hypertension in adults. RESULTS: In total, 1623 adult hypertensive patients (940 men and 683 women) were detected. The results showed that adult hypertensive patients were older and had higher levels of systolic blood pressure, diastolic blood pressure, body mass index, fasting plasma glucose, uric acid, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and prevalence of non-alcoholic fatty liver disease (P < 0.001). The classification tree model comprising 5 layers, 39 nodes, and 20 terminal nodes showed that two variables, age and BMI, were closely related to hypertension in adults. The area under the receiver operating characteristic curve for classification tree model was 81.6 % (95 % CI: 80.6 % ~ 82.5 %). Both univariate and multivariate logistic regression analyses revealed that advanced age and high BMI had a significant positive interaction in terms of hypertension in adults. After controlling for confounding factors, the percentage of attributed interaction was 47.62 %. CONCLUSIONS: This study showed that age, BMI, UA, TG, and TC were closely associated with the risk of hypertension in adults, and the positive interaction effect between advanced age and high BMI was an important risk factor for the prevalence of hypertension in adults.

Increased plasma dipeptidyl peptidase 4 activities predict new-onset microalbuminuria in association with its proinflammatory effects in Chinese without diabetes: a four-year prospective study.

BACKGROUND: Recent evidence supports a protective role of dipeptidyl peptidase 4 (DPP4) inhibitors in lowering microalbuminuria (MAU) in diabetes but till now few studies have investigated the associations between DPP4 activity and MAU in nondiabetic Chinese individuals. This study tested whether DPP4 activity could predict new-onset MAU in Chinese without diabetes. METHODS: This was a 4-year prospective study conducted in Sichuan, China. A total of 664 Chinese women and men aged 18-70 years were studied. Circulating DPP4 activity, inflammatory markers and urinary albumin-to-creatinine ratio (ACR) were measured at baseline and 4 years later. RESULTS: The incidence of MAU during follow-up was 33.1 per 1000 patient-years. At baseline, individuals in the highest quartile of DPP4 activity had higher age, body mass index, waist/hip ratio, systolic blood pressure, diastolic blood pressure, fasting insulin, low-density lipoprotein-cholesterol, interleukin-6, high-sensitivity C-reactive protein, urinary albumin-to-creatinine ratio and lower high-density lipoprotein-cholesterol compared with individuals in the lowest quartile. After a 4-year follow-up, 88 individuals developed MAU. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in inflammatory markers and ACR over a 4-year period (all P < 0.05). In multivariable-adjusted models, the odds ratio for incident MAU comparing the highest with the lowest quartiles of DPP4 activity was 3.48 (95% CI: 1.50-8.09) after adjustment for confounding risk factors (P < 0.01). The incidence of MAU owing to DPP4 activity increased by 18.59%. CONCLUSION: DPP4 activity is an important predictor of the onset of inflammation and MAU in Chinese apparently without diabetes. This finding may have important implications for understanding the proinflammatory role of DPP-4 in the pathogenesis of MAU. TRIAL REGISTRATION NUMBER: #TR-CCH-Chi CTR-CCH-00000361.

High glucose impairs cognitive function through inducing mitochondrial calcium overload in Treg cells.

High glucose has been proved to impair cognitive function in type 2 diabetes, but the underlying mechanisms remain elusive. Here, we found that high glucose increased transcription factors' SP1 O-GlcNAcylation in regulatory T (Treg) cells. Glycosylated SP1 further enhanced HDAC2 recruitment and histone deacetylation on Na+/Ca2+/Li+ exchanger (NCLX) promoter, which downregulated NCLX expression and led to mitochondrial calcium overload and oxidative damage, thereby promoting Treg cell dysfunction, M1 microglia polarization, and diabetes-associated cognitive impairment. Importantly, GLP-1 receptor agonist alleviated these deleterious effects via GLP-1-receptor-mediated upregulation of OGA and inhibition of SP1 O-GlcNAcylation in Treg cells. Our study highlighted a link between high-glucose-mediated SP1 O-GlcNAcylation and HDAC2/NCLX signaling in control of mitochondrial calcium concentrations in Treg cells. It also revealed a mechanism for linking Treg cell dysfunction and cognitive impairment in type 2 diabetes and provides an insight into the mechanism underlying the neuroprotective effects of GLP-1 receptor agonist.

Discovery of novel quinoline scaffold selective estrogen receptor degraders (SERDs) for treatment of ER positive breast cancer with enhanced antiproliferative bioactivity through immunogenic cell death (ICD) effects.

Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.

Nonenzymatic function of DPP4 promotes diabetes-associated cognitive dysfunction through IGF-2R/PKA/SP1/ERp29/IP3R2 pathway-mediated impairment of Treg function and M1 microglia polarization.

BACKGROUND: Impairment of regulatory T (Treg) cells function is implicated in the pathogenesis of immune imbalance-mediated cognitive impairment. A complete understanding of whether and how this imbalance affect cognitive function in type 2 diabetes is lacking, and the driver affecting this imbalance remains unknown. METHODS: We examined the impact of enzymatic and non-enzymatic function of DPP4 on Treg cell impairment, microglia polarization and diabetes-associated cognitive defects and identified its underlying mechanism in type 2 diabetic patients with cognitive impairment and in db/db mice. RESULTS: We report that DPP4 binds to IGF2-R on Treg cell surface and activates PKA/SP1 signaling, which upregulate ERp29 expression and promote its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting mitochondria-associated ER membrane formation and mitochondria calcium overload in Tregs. This, in turn, impairs Tregs function and polarizes microglia toward a pro-inflammatory phenotype in the hippocampus and finally leads to neuroinflammation and cognitive impairment in type 2 diabetes. Importantly, inhibiting DPP4 enzymatic activity in type 2 diabetic patients or mutating DPP4 enzymatic active site in db/db mice did not reverse these changes. However, IGF-2R knockdown or blockade ameliorated these effects both in vivo and in vitro. CONCLUSION: These findings highlight the nonenzymatic role of DPP4 in impairing Tregs function, which may facilitate the design of novel immunotherapies for diabetes-associated cognitive impairment.

Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes.

DPP4 has been shown to induce diabetes-associated mitochondrial dysfunction and cognitive impairment through its non-canonical function. Here, we report that enhanced DPP4 expression in diabetes contributes to IP3R2-mediated mitochondria-associated ER membrane (MAM) formation, mitochondria calcium overload, and cognitive impairment, and its knockdown showed opposite effects. Mechanistically, DPP4 binds to PAR2 in hippocampal neurons and activates ERK1/2/CEBPB signaling, which upregulates ERp29 expression and promotes its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting MAM formation, mitochondria calcium overload, and cognitive impairment. Meanwhile, targeting DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling achieved satisfactory therapeutic effects on MAM formation, mitochondria calcium overload, and cognitive impairment. Notably, DPP4 activates this pathway in an enzymatic activity-independent manner, suggesting the non-canonical role of DPP4 in the pathogenesis of mitochondria calcium overload and cognitive impairment in diabetes. Together, these results identify DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling as a promising therapeutic target for the treatment of cognitive impairment in type 2 diabetes.

Relationship between blood lipid profiles and pancreatic islet ß cell function in Chinese men and women with normal glucose tolerance: a cross-sectional study.

BACKGROUND: Dyslipidemia is present in people with diabetes as well as subjects with normal glucose tolerance (NGT). The purpose of this study was to investigate the relationship between lipid profiles and ß cell function in Chinese individuals with NGT but without history of diabetes or prediabetes. METHODS: A total of 893 men and 1454 women aged 18-76 years living in Sichuan, China, who were not being treated with lipid-lowering drugs were enrolled in this study. Insulin sensitivity (IR) was evaluated using the homeostasis model assessment -IR (HOMA-IR), ß-cell function was calculated by the following equation: ΔI30/ΔG30/ HOMA-IR (ΔI30/ΔG30: the ratio of incremental glucose and insulin 30 min after glucose intake). Multivariate linear regression analyses were performed to estimate the relationship between blood lipid and ß cell function as standardized coefficients (ß). RESULTS: ß cell function decreased in men and women with increasing age. We found inverse relationships between ß cell function and total cholesterol (TC) in men and women (ß = -0.157 and -0.113, respectively, both p < 0.001), low-density lipoprotein-cholesterol (LDL-C; ß = -0.130 and -0.068, respectively, both p < 0.001), TC/high-density lipoprotein-cholesterol (HDL-C) ratio (ß = -0.084, p < 0.01 and -0.096, p < 0.001), and triglycerides (TG) (women only; ß = -0.053, p < 0.05). However, ß cell function was not associated with HDL-C in men or women (ß = -0.034 and 0.000, respectively, both p > 0.05) or the TG/HDL-C ratio (ß = -0.035 and -0.013, respectively, both p > 0.05). ß cell function was significantly worse in males than in females in all age groups, except in subjects aged > 70 years. CONCLUSIONS: Dyslipidemia is associated with dysfunction of pancreatic ß cells in subjects with NGT and this is particularly evident in people with elevated TC and LDL-C levels, especially males. TRIAL REGISTRATION NUMBER: #TR-CCH-Chi CTR-CCH-00000361.

Coxsackievirus B5 virus-like particle vaccine exhibits greater immunogenicity and immunoprotection than its inactivated counterpart in mice.

Coxsackievirus B group 5 (CVB5) represents one of the major pathogens that cause diseases such as hand, foot and mouth disease (HFMD) and aseptic meningitis et al. Currently, no specific drugs and vaccines are available, and a safe and effective CVB5 vaccine is of great value for control of the diseases. In this study, CVB5 P1 precursor and 3CD protease were co-expressed in Sf9 cells by using a baculovirus expression system. The P1 was processed by 3CD and self-assembled into CVB5 virus-like particles (VLPs). VP1 and VP3 capsid proteins of CVB5 could be detected by SDS-PAGE and Western blotting. Transmission electron microscopy revealed that the CVB5 VLPs were spherical particles with a diameter of about 30 nm, mimicking wild-type CVB5 virus. Our study showed that the total IgG and neutralizing antibodies induced by CVB5 VLPs were higher than those induced by inactivated vaccine. More importantly, the CVB5 VLPs conferred full protection to the CVB5-challenged suckling mice via passive immunity while protection efficiency of the inactivated vaccine was only 80%. The CVB5 VLPs vaccine could protect the limb muscles, brain, and heart tissues of suckling mice from CVB5-induced damage. These results demonstrated that the CVB5 VLPs vaccine possessed stronger immunogenicity and provided more robust immunoprotection than the inactivated CVB5 vaccine, suggesting that the CVB5 VLPs promise to be a CVB5 vaccine candidate in future.

Association between plasma dipeptidyl peptidase-4 activity to brain-derived neurotrophic factor ratio and depressive symptoms in middle-aged and older adults with normal glucose tolerance: A cross-sectional study.

Objectives: Attenuation of brain-derived neurotrophic factor (BDNF) availability and increased dipeptidyl peptidase-4 (DPP4) activity have both been reported to link to the pathogenesis of depression. The aim of this study was to test the correlation between depressive symptoms and plasma DPP4 activity to BDNF ratio (DBR).Methods: We evaluated DPP4 activity, BDNF, oxidative stress parameters and inflammatory markers and calculated DBR in a cross-sectional sample of 1640 non-diabetic participants.Results: DPP4 activity was negatively related to BDNF in participants with and without depressive symptoms (r= -0.351 and r= -0.404, p<.001). Nitrotyrosine and 8-iso-PGF2a mediated 18.4 and 12.6% of the total effect of DPP4 activity on BDNF, respectively. 8-iso-PGF2a, nitrotyrosine, C-reactive protein, interleukin-6 and PHQ-9 score progressively increased across DBR quartiles. Participants whose DBRs were in the highest quartile had 2.64-fold increased odds (OR = 3.03) of depressive symptoms. The depressive symptoms risk increased more with lower levels of BDNF and higher levels of DPP4 activity (p<.05).Conclusions: Our data suggested inverse correlation between DPP4 activity and BDNF through the oxidative stress mediator. The positive relationship between DBR and depressive symptoms risk raises feasibility of identifying DBR as a novel biological marker or even a possible therapeutic target for depression.

The Relationship Between Plasma DPP4 Activity to BDNF Ratio and Mild Cognitive Impairment in Elderly Population With Normal Glucose Tolerance.

Objective: Since decreased brain-derived neurotrophic factor (BDNF) and increased dipeptidyl peptidase-4 (DPP4) activity have both been implicated in the pathogenesis of mild cognitive impairment (MCI), the aim of our study was to evaluate the association of MCI with plasma DPP4 activity to BDNF ratio (DBR) in an elderly population with normal glucose tolerance. Methods: We cross-sectionally measured C-reactive protein, interleukin-6, nitrotyrosine, 8-iso-PGF2a, DPP4 activity BDNF and calculated the DBR in a total of 1,066 elderly participants in China. MCI was determined by the Montreal Cognitive Assessment and finally confirmed by neurologists. Results: An inverse correlation was found between DPP4 activity and BDNF (r = -0.456, P < 0.001) and this inverse correlation was partly mediated by nitrotyrosine and 8-iso-PGF2a. Across rising quartiles of DBR, nitrotyrosine, 8-iso-PGF2a, C-reactive protein and interleukin-6 progressively increased, whereas the Montreal Cognitive Assessment score progressively decreased. Subjects in the lowest quartile of BDNF and highest quartiles of DBR and DPP4 activity, had higher MCI risk compared with subjects in the highest quartile of the BDNF and lowest quartiles of DBR and DPP4 activity, respectively (all P < 0.05). The odds ratio for MCI became more pronounced with decreased BDNF and increased DPP4. Conclusion: In conclusion, a negative correlation was found between DPP4 activity and BDNF, and this negative correlation was partly mediated by oxidative stress, not inflammation. The DBR was positively associated with MCI and thus may be used as a novel risk biomarker for MCI in an elderly population with normal glucose tolerance.

Oxidative stress-mediated influence of plasma DPP4 activity to BDNF ratio on mild cognitive impairment in elderly type 2 diabetic patients: results from the GDMD study in China.

OBJECTIVE: Increased dipeptidyl peptidase-4 (DPP4) activity and reduced brain-derived neurotrophic factor (BDNF) in peripheral circulation are both associated with a high risk of mild cognitive impairment (MCI) in the elderly. Hence, we aimed to investigate the association between plasma DPP4 activity to BDNF ratio (DBR) and MCI in elderly patients with type 2 diabetes. DESIGN AND METHODS: We measured plasma DPP4 activity, BDNF levels, oxidative stress parameters, inflammatory markers and calculated DBR in 1833 elderly type 2 diabetic patients aged 60 years or older. MCI was diagnosed according to the National Institute on Aging-Alzheimer's Association workgroups criteria. Further, mediation analysis was performed to estimate the mediator role of oxidative stress on the relationship between DPP4 activity and BDNF. RESULTS: DPP4 activity was negatively associated with BDNF (r = -0.408, P < 0.001). Oxidative stress, particularly in male participants, acted as a partial mediator in the relationship between DPP4 activity and BDNF. Participants in the highest quartile of DBR had higher nitrotyrosine, 8-isoPGF2a, interleukin-6, C-reactive protein and lower Montreal Cognitive Assessment score compared with those in the lowest quartile. The odds ratio (5.15, 95% CI 3.64-7.30) for MCI in the highest DBR quartile was significantly higher than in the lowest quartile. The risk for MCI increased with higher levels of DPP4 activity and lower levels of BDNF. CONCLUSIONS: Oxidative stress partially mediates the inverse relationship between DPP4 and BDNF. Our data provide evidence for a strong link between DBR and MCI, suggesting DBR to be a new biomarker for MCI in type 2 diabetic patients.

Association of Serum Angiopoietin-Like Protein 8 With Albuminuria in Type 2 Diabetic Patients: Results From the GDMD Study in China.

Background: Hyperglycemia, insulin resistance and hypertriglyceridesmia are risk factors for albuminuria in type 2 diabetes. Angiopoietin-like Protein 8(ANGPTL8) is a newly identified liver-derived hormone related to these risk factors. Hence, we aimed to explore the relationship between ANGPTL8 and albuminuria in type 2 diabetes. Methods: Serum ANGPTL8 levels were determined in groups of control (n = 50) and type 2 diabetic patients with normoalbuminuria (A1, n = 100), microalbuminuria (A2, n = 45), and macroalbuminuria (A3, n = 33). Results: Serum levels of ANGPTL8 and triglycerides were significantly increased in type 2 diabetic patients with albuminuria as compared with controls (P < 0.001). ANGPTL8 levels were positively correlated with triglycerides, duration of diabetes, and urine albumin-to-creatinine ratio (ACR) and negatively correlated with estimated glomerular filtration rate in type 2 diabetic patients with A2 and A3 (all P < 0.05). Logistic regression analysis indicated that ANGPTL8 had higher odds of having A2 (OR = 2.52, 95% CI 1.16-5.48, P = 0.019) and A3 (OR = 4.89, 95% CI 2.10-11.39, P < 0.001) in type 2 diabetes. Mediation analysis indicated that triglycerides might act as a partial mediator in the relationship between ANGPTL8 and ACR. Conclusions: Triglycerides might partially mediate the correlation between ANGPTL8 and ACR. Our data provide the evidence for a strong link between ANGPTL8 and albuminuria, indicating that ANGPTL8 may be a new biomarker for diabetic kidney disease in type 2 diabetes. TRIAL REGISTRATION NUMBER: ChiCTR-EPC-14005273.

Vitamin D and Incidence of Prediabetes or Type 2 Diabetes: A Four-Year Follow-Up Community-Based Study.

AIM: To examine whether the baseline 25-hydroxyvitamin D [25(OH)D] level was predictive of the onset of prediabetes or type 2 diabetes (T2DM) in the Chinese population. METHODS: This was a 4-year follow-up study that was conducted in the Chengdu region of China as part of the China National Diabetes and Metabolic Disorders Study. The study included 490 participants that were free of prediabetes and type 2 diabetes mellitus (T2DM) at baseline and had complete data by follow-up examinations. Glucose, insulin, and 25(OH)D levels were measured at baseline and at 4 years later. Prediabetes and T2DM were defined by results obtained from an oral glucose tolerance test. RESULTS: Over a 4-year follow-up, 95 (48.5‰) developed prediabetes and 31 (15.8‰) individuals developed diabetes. Low 25(OH)D status was significantly associated with the risk of developing prediabetes [OR 3.01 (95% CI: 1.50-6.06), P = 0.002] and T2DM [OR 5.61 (95% CI: 1.73-18.27), P = 0.004] after adjustment for multiple potential confounders. In a multiple linear regression analysis, low baseline levels of 25(OH)D were an independent predictor of increased insulin resistance over a 4-year period (P < 0.05). CONCLUSIONS: The current prospective study suggests that low 25(OH)D levels might have contributed to the incidence of prediabetes or T2DM in Chinese individuals. This trial is registered with TR-CCH-ChiCTR-OCS-09000361.

Association of plasma dipeptidyl peptidase-4 activity with non-alcoholic fatty liver disease in nondiabetic Chinese population.

OBJECTIVE: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is attributed to a "multi-hits hypothesis" involving insulin resistance, oxidative stress and inflammation. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing the"multi-hits". Hence, we investigated the association between plasma DPP4 activity and NAFLD in nondiabetic Chinese population. DESIGN AND METHODS: We performed a cross-sectional study using data from 1105 subjects (36-79years) in Guilin between 2015 and 2016. Plasma DPP4 activity, homeostatic model assessment of insulin resistance (HOMA-IR), oxidative stress parameters, and inflammatory markers were measured in all participants. NAFLD and its severity were diagnosed by ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS: Participants in the highest quartile of DPP4 activity had higher HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6, CRP, alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase compared with those in the lowest quartile (all P<0.05). Plasma DPP4 activity gradually increased across the groups according to the ultrasonographic severity of steatosis (P<0.001 for the trend). In the highest DPP4 quartile, NAFLD risk was higher (odds ratio 1.88; 95% CI 1.04-3.37) than in the lowest quartile after adjustment for confounders. The risk for NAFLD increased more with higher levels of DPP4 activity, HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6 and CRP. CONCLUSIONS: Plasma DPP4 activity is significantly associated with NAFLD. The underlying mechanisms may be partly attributed to the interactions between insulin resistance, oxidative stress, inflammation, and DPP4.

Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance.

Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT). Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer's Association workgroups criteria. Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile (P < 0.001). The odds ratios (ORs) for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001). In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36-3.76) than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a (P < 0.05), but not with higher IL-6, CRP or lower GLP-1. Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.

Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of diabetic nephropathy in Chinese patients with newly diagnosed type 2 diabetes: A cross-sectional study.

OBJECTIVE: To investigate the association between plasma Dipeptidyl peptidase-4 (DPP4) activities and diabetic nephropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1193 newly diagnosed type 2 diabetic subjects were studied. Plasma DPP4 activity, mannose 6-phosphate receptor, inflammatory markers and oxidative stress parameters were measured in all participants. Diabetic nephropathy was defined as the presence of albuminuria or an estimated glomerular filtration rate < 60 mL/min/1.73 m(2). RESULTS: Participants in the highest quartile of DPP4 activity had higher HbA1c, homeostatic model assessment of insulin resistance, nitrotyrosine, 8-iso-PGF2a, interleukin-6, high-sensitivity C-reactive protein, mannose 6-phosphate receptor, urinary albumin-to-creatinine ratio and lower estimated glomerular filtration rate compared with participants in the lowest quartile (all p < 0.001). DPP4 activities were associated positively with HbA1c, homeostatic model assessment of insulin resistance, nitrotyrosine, 8-iso-PGF2a, interleukin-6, high-sensitivity C-reactive protein, mannose 6-phosphate receptor, urinary albumin-to-creatinine ratio and negatively with estimated glomerular filtration rate (all p < 0.001). In the highest DPP4 quartile, diabetic nephropathy risk was significantly higher (odds ratio: 3.77; 95% confidence interval: 2.34-6.07) than in the lowest quartile after adjustment for potential confounders. This association remained strong (2.85; 1.74-4.68) after further controlling for HbA1c, homeostatic model assessment of insulin resistance, nitrotyrosine and high-sensitivity C-reactive protein. CONCLUSION: This study shows that increased DPP4 activities are strongly and independently associated with diabetic nephropathy in type 2 diabetes. The associations between DPP4 and diabetic nephropathy, although strong, do not imply causality. There are however plausible mechanisms which could explain such a link.