OBJECTIVE: To explore the role of 5-hydroxytryptamine (5-HT) in type 2 diabetes mellitus (T2DM)-related hepatic inflammation and fibrosis. METHODS: Male C57BL/6J mice were used to establish T2DM model by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. Then, the mice with hyperglycemia were still fed with high-fat diet for nine weeks, and treated with or without 5-HT_2A receptor (5-HT_2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (alone or in combination). To observe the role of 5-HT in the myofibroblastization of hepa-tic stellate cells (HSCs), human HSCs LX-2 were exposed to high glucose, and were treated with or without SH, CDP or monoamine oxidase A (MAO-A) inhibitor clorgiline (CGL). Hematoxylin & eosin and Masson staining were used to detect the pathological lesions of liver tissue section, immunohistochemistry and Western blot were used to analyze protein expression, biochemical indicators were measured by ELISA or enzyme kits, and levels of intracellular reactive oxygen species (ROS) were detected by fluorescent probe. RESULTS: There were up-regulated expressions of 5-HT_2AR, 5-HT synthases and MAO-A, and elevated levels of 5-HT in the liver of the T2DM mice. In addition to reduction of the hepatic 5-HT levels and MAO-A expression, treatment with SH and CDP could effectively ameliorate liver lesions in the T2DM mice, both of which could ameliorate hepatic injury and steatosis, significantly inhibit the increase of hepatic ROS (H₂O₂) levels to alleviate oxidative stress, and markedly suppress the production of transforming growth factor β1 (TGF-β1) and the development of inflammation and fibrosis in liver. More importantly, there was a synergistic effect between SH and CDP. Studies on LX-2 cells showed that high glucose could induce up-regulation of 5-HT_2AR, 5-HT synthases and MAO-A expression, increase intracellular 5-HT level, increase the production of ROS, and lead to myofibroblastization of LX-2, resulting in the increase of TGF-β1 synthesis and production of inflammatory and fibrosis factors. The effects of high glucose could be significantly inhibited by 5-HT_2AR antagonist SH or be markedly abolished by mitochondrial 5-HT degradation inhibitor CGL. In addition, SH significantly suppressed the up-regulation of 5-HT synthases and MAO-A induced by high glucose in LX-2. CONCLUSION Hyperglycemia-induced myofibroblastization and TGF-β1 production of HSCs, which leads to hepatic inflammation and fibrosis in T2DM mice, is probably due to the up-regulation of 5-HT_2AR expression and increase of 5-HT synthesis and degradation, resulting in the increase of ROS production in mitochondria. Among them, 5-HT_2AR is involved in the regulation of 5-HT synthases and MAO-A expression.
Male ; Mice ; Humans ; Animals ; Hepatic Stellate Cells/pathology* ; Transforming Growth Factor beta1/pharmacology* ; Serotonin/metabolism* ; Reactive Oxygen Species/metabolism* ; Diabetes Mellitus, Type 2/complications* ; Hydrogen Peroxide/metabolism* ; Mice, Inbred C57BL ; Liver Cirrhosis/etiology* ; Hyperglycemia/pathology* ; Monoamine Oxidase/metabolism* ; Inflammation ; Glucose/metabolism* ; Cytidine Diphosphate/pharmacology*

To investigate the association of pancreatic steatosis with coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who underwent coronary computed tomography angiography(CCTA)in our center due to chest pain were enrolled from January 2016 to February 2019. According to the CCTA findings,patients were divided into normal group,mild-to-moderate coronary atherosclerosis group and severe coronary atherosclerosis group. CT attenuation of pancreas and spleen was measured on abdominal non-enhanced CT,and the CT attenuation indexes including the difference between pancreatic and splenic attenuation (P-S) and the ratio of pancreas-to-spleen attenuation (P/S) were calculated. Analysis of variance or Kruskal-Wallis rank test were used to assess differences among each group. Logistic regression analysis was used to analyze the risk factors of severe coronary stenosis. The accuracy of P/S in predicting severe coronary artery stenosis was assessed by receiver operator characteristic (ROC) curve analysis. A total of 173 consecutive T2DM patients were enrolled. These patients included 27 patients with normal coronary artery (15.6%),124 patients with mild to moderate stenosis (71.7%),and 22 patients with severe stenosis (12.7%). There were significant differences in CT attenuation of pancreas (=11.543,=0.003),P-S (=11.152,=0.004) and P/S (=11.327,=0.004) among normal coronary artery group,mild and moderate stenosis group,and severe stenosis group. The CT attenuation of pancreatic head,body,and tail significantly differed in patients with coronary artery stenosis (=14.737,=0.001). After adjusting for confounding factors,multiple Logistic regression showed that P/S (=0.062,95%=0.008-0.487,=0.008) was still significantly associated with the severe coronary artery stenosis. The area under the ROC curve of P/S for the diagnosis of severe coronary artery stenosis was 0.701,and the optimal cutoff point was 0.660. CT attenuation of pancreas and CT attenuation indexes are associated with the severity of coronary stenosis in T2DM patients,suggesting that pancreatic steatosis may be used as one of the indicators for predicting severe coronary artery stenosis.
Coronary Angiography ; Coronary Artery Disease ; complications ; Coronary Stenosis ; Diabetes Mellitus, Type 2 ; complications ; Humans ; Pancreas ; pathology ; Predictive Value of Tests

Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical characteristics of animal models that could help to better understand molecular mechanisms underlying the increased risk of CVD and AD in patients with prediabetes or T2D.
Alzheimer Disease ; Amyloid ; Blood Vessels ; Cerebrovascular Disorders ; Dementia ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Humans ; Islet Amyloid Polypeptide ; Models, Animal ; Neurologic Manifestations ; Pathology ; Prediabetic State ; Rodentia

OBJECTIVETo develop a risk model for predicting later development of diabetic nephropathy (DN) in Chinese people with type 2 diabetes mellitus (T2DM) and evaluate its performance with independent validation.

METHODSWe used data collected from the project 'Comprehensive Research on the Prevention and Control of Diabetes', which was a community-based study conducted by the Jiangsu Center for Disease Control and Prevention in 2013. A total of 11,771 eligible participants were included in our study. The endpoint was a clear diagnosis of DN. Data was divided into two components: a training set for model development and a test set for validation. The Cox proportional hazard regression was used for survival analysis in men and women. The model's performance was evaluated by discrimination and calibration.

RESULTSThe incidence (cases per 10,000 person-years) of DN was 9.95 (95% CI; 8.66-11.43) in women and 11.28 (95% CI; 9.77-13.03) in men. Factors including diagnosis age, location, body mass index, high-density-lipoprotein cholesterol, creatinine, hypertension, dyslipidemia, retinopathy, diet control, and physical activity were significant in the final model. The model showed high discrimination and good calibration.

CONCLUSIONThe risk model for predicting DN in people with T2DM can be used in clinical practice for improving the quality of risk management and intervention.

Aged ; Asian Continental Ancestry Group ; Diabetes Mellitus, Type 2 ; complications ; Diabetic Nephropathies ; pathology ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Reproducibility of Results ; Risk Factors ; Urban Population

PURPOSE: Diabetic nephropathy is a serious complication of type 2 diabetes mellitus, and delaying the development of diabetic nephropathy in patients with diabetes mellitus is very important. In this study, we investigated inflammation, oxidative stress, and lipid metabolism to assess whether curcumin ameliorates diabetic nephropathy. MATERIALS AND METHODS: Animals were divided into three groups: Long-Evans-Tokushima-Otsuka rats for normal controls, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats for the diabetic group, and curcumin-treated (100 mg/kg/day) OLETF rats. We measured body and epididymal fat weights, and examined plasma glucose, adiponectin, and lipid profiles at 45 weeks. To confirm renal damage, we measured albumin-creatinine ratio, superoxide dismutase (SOD), and malondialdehyde (MDA) in urine samples. Glomerular basement membrane thickness and slit pore density were evaluated in the renal cortex tissue of rats. Furthermore, we conducted adenosine monophosphate-activated protein kinase (AMPK) signaling and oxidative stress-related nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling to investigate mechanisms of lipotoxicity in kidneys. RESULTS: Curcumin ameliorated albuminuria, pathophysiologic changes on the glomerulus, urinary MDA, and urinary SOD related with elevated Nrf2 signaling, as well as serum lipid-related index and ectopic lipid accumulation through activation of AMPK signaling. CONCLUSION: Collectively, these findings indicate that curcumin exerts renoprotective effects by inhibiting renal lipid accumulation and oxidative stress through AMPK and Nrf2 signaling pathway.
Albuminuria ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Curcumin/*pharmacology ; Diabetes Mellitus, Type 2/*metabolism/urine ; Diabetic Nephropathies/complications/*drug therapy/metabolism/pathology ; Gene Expression/drug effects ; Inflammation ; Kidney/drug effects/metabolism/physiopathology ; Kidney Glomerulus/metabolism/physiopathology ; Lipid Metabolism/*drug effects ; Male ; Malondialdehyde/metabolism/urine ; Oxidative Stress/*drug effects ; Rats ; Rats, Inbred OLETF ; Rats, Long-Evans ; Superoxide Dismutase/metabolism

Chemerin is a recently identified adipokine suggested to play a role in obesity and its metabolic complications. The relationship between visceral obesity and serum chemerin levels in type 2 diabetes (T2DM) is unknown and may differ from that of subjects without diabetes. Therefore, we evaluated whether serum chemerin was associated with visceral abdominal obesity in patients with T2DM. A total of 218 Korean patients with T2DM were enrolled and metabolic parameters, abdominal visceral and subcutaneous fat areas, and serum chemerin levels were measured. Serum chemerin level showed positive correlation with fasting insulin, HOMA-IR, serum triglyceride, serum creatinine, urine albumin/creatinine ratio, high-sensitivity C-reactive protein (hsCRP), fibrinogen, abdominal visceral fat area, visceral to subcutaneous fat area ratio, and negatively correlation with high density lipoprotein cholesterol and creatinine clearance (CCr) after adjusting for age, gender and body mass index. Multiple linear stepwise regression analysis showed that abdominal visceral fat area (β = 0.001, P < 0.001), serum triglyceride (β = 0.001, P < 0.001), CCr (β = -0.003, P = 0.001), hsCRP (β = 0.157, P = 0.001), fibrinogen (β = 0.001, P < 0.001) and BMI (β = 0.02, P = 0.008) independently affected log transformed serum chemerin levels. Higher serum chemerin level was associated with higher level of abdominal visceral fat area, serum triglyceride, hsCRP and fibrinogen and lower level of CCr in patients with T2DM. Serum chemerin may be used as a biomarker of visceral adiposity and chemerin may play a role in inflammation, decreased renal function, and increased cardiovascular risk in T2DM.
Adult ; Biomarkers/blood ; Body Mass Index ; C-Reactive Protein/analysis ; Chemokines/*blood ; Creatinine/blood/urine ; Diabetes Mellitus, Type 2/*blood/diagnosis ; Female ; Humans ; Insulin/blood ; Intercellular Signaling Peptides and Proteins/*blood ; Intra-Abdominal Fat/*pathology ; Linear Models ; Lipocalins/blood ; Male ; Middle Aged ; Obesity/complications ; Triglycerides/blood

The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases.
Diabetes Mellitus, Type 2/complications/epidemiology/metabolism/*pathology ; Humans ; Hyperglycemia/pathology ; Insulin/metabolism ; Insulin Resistance ; Insulin-Like Growth Factor I/metabolism ; Pancreatic Neoplasms/epidemiology/*etiology ; Risk Factors

PURPOSE: The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS: Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS: Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ=0.407) or fasting C-peptide (ρ=0.402) were demonstrated. CONCLUSION: Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.
Adult ; Aged ; Biomarkers/metabolism ; C-Peptide/metabolism ; Case-Control Studies ; Diabetes Mellitus, Type 2/*complications/metabolism ; Female ; Hemoglobin A, Glycosylated/metabolism ; Humans ; Insulin Resistance ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*epidemiology/metabolism/pathology ; Odds Ratio ; Prevalence

Both diabetic retinopathy (DR) and coronary heart disease (CHD) are clinically significant in diabetic patients. We investigated the correlation between the severity of DR and the presence and severity of CHD among type 2 diabetic patients. A total of 175 patients who were examined at the DR clinic and underwent dual-source computed tomography (DSCT) angiography within 6 months were included. The degree of DR was graded as no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). The severity of CHD and the numbers of significant stenotic coronary artery on DSCT angiography according to DR grade were assessed. The mean Agatston Calcium Score (ACS) in patients with PDR was significantly higher than other groups (P < 0.001). The overall odds of an ACS increase were about 4.7-fold higher in PDR group than in no DR group (P < 0.001). In PDR group, in comparison with in no DR, the odds of having 1 or 2 arterial involvement were 3-fold higher (P = 0.044), and those of having 3 were 17-fold higher (P = 0.011). The c-index, one of the predictability values in regression analysis model, was not significantly increased when PDR was added to classical CHD risk factors (0.671 to 0.706, P = 0.111). Conclusively, patients with PDR develop a greater likelihood of not only having CHD, but being more severe nature. PDR has no additional effect to classical CHD risk factors for predicting CHD.
Aged ; Angiography ; Coronary Artery Disease/complications/*pathology ; Coronary Vessels/diagnostic imaging ; Diabetes Mellitus, Type 2/*complications ; Diabetic Retinopathy/complications/*diagnosis/diagnostic imaging ; Female ; Glomerular Filtration Rate ; Humans ; Linear Models ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Severity of Illness Index ; Tomography, X-Ray Computed

Both diabetic retinopathy (DR) and coronary heart disease (CHD) are clinically significant in diabetic patients. We investigated the correlation between the severity of DR and the presence and severity of CHD among type 2 diabetic patients. A total of 175 patients who were examined at the DR clinic and underwent dual-source computed tomography (DSCT) angiography within 6 months were included. The degree of DR was graded as no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). The severity of CHD and the numbers of significant stenotic coronary artery on DSCT angiography according to DR grade were assessed. The mean Agatston Calcium Score (ACS) in patients with PDR was significantly higher than other groups (P < 0.001). The overall odds of an ACS increase were about 4.7-fold higher in PDR group than in no DR group (P < 0.001). In PDR group, in comparison with in no DR, the odds of having 1 or 2 arterial involvement were 3-fold higher (P = 0.044), and those of having 3 were 17-fold higher (P = 0.011). The c-index, one of the predictability values in regression analysis model, was not significantly increased when PDR was added to classical CHD risk factors (0.671 to 0.706, P = 0.111). Conclusively, patients with PDR develop a greater likelihood of not only having CHD, but being more severe nature. PDR has no additional effect to classical CHD risk factors for predicting CHD.
Aged ; Angiography ; Coronary Artery Disease/complications/*pathology ; Coronary Vessels/diagnostic imaging ; Diabetes Mellitus, Type 2/*complications ; Diabetic Retinopathy/complications/*diagnosis/diagnostic imaging ; Female ; Glomerular Filtration Rate ; Humans ; Linear Models ; Male ; Middle Aged ; Odds Ratio ; Risk Factors ; Severity of Illness Index ; Tomography, X-Ray Computed