OBJECTIVE: To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. METHODS: The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. RESULTS: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). CONCLUSION HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.
Animals ; Glucagon-Like Peptide 1/metabolism* ; Diabetes Mellitus, Type 2/metabolism* ; Glucagon-Like Peptide-1 Receptor/metabolism* ; Insulin-Secreting Cells/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Male ; Blood Glucose/metabolism* ; Insulin/blood* ; Mice ; Intestinal Mucosa/pathology* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Islets of Langerhans/pathology*

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

Humans ; Diabetic Nephropathies/pathology* ; Kidney/pathology* ; Biopsy ; Diabetes Mellitus, Type 2/pathology* ; Retrospective Studies ; Glomerular Filtration Rate ; Disease Progression

Objective: To investigate the clinical and pathologic characteristics of obese adults with nonalcoholic fatty liver disease (NAFLD) and to aid the diagnosis of nonalcoholic steatohepatitis (NASH). Methods: A total of 262 patients eligible for inclusion who received volume reduction metabolism surgery and liver biopsy in the First Affiliated Hospital of Nanjing Medical University from June 2018 to September 2019 were selected. HE staining, reticular fiber staining and Masson staining were performed. Statistical analysis was performed using SPSS 20.0. Results: The patients ranged in age from 18 to 66 years. Among the 262 cases, 65 cases (65/262, 24.8%) were male and 197 cases (197/262, 75.2%) were female. Sixty-one cases (61/262, 23.3%) were non-NAFLD, 201 cases (201/262, 76.7%) were NAFLD including 27 cases (27/201, 13.4%) of nonalcoholic fatty live (NAFL) and 174 cases (174/201, 86.6%) of NASH. The main lesions of NAFLD were in hepatic acinus zone 3. There were significant differences in age, alanine aminotransferase (ALT), glutamic oxaloacetic transaminase (AST), body mass index (BMI), fasting blood-glucose (FPG) and apolipoprotein A (APOA) levels among the non-NAFLD group, NAFL group and NASH group (P<0.05). Patients with BMI≥35 m/kg² combined with type 2 diabetes had a higher prevalence of NASH. Multiple logistic regression showed that ALT and APOA were independent predictors of NASH (P<0.001, OR=1.05, 95%CI: 1.020-1.082; P=0.027, OR=0.916, 95%CI: 0.878-0.941). Total cholesterol (CHO) and high-density lipoprotein (HDL) were independent predictors of lobular inflammation (P=0.043, 95%CI: 0.010-0.634; P=0.024, 95%CI:-3.068--0.216). AST and HDL were independent predictors of fibrosis stage (P=0.029, 95%CI: 0.001-0.021; P<0.001, 95%CI:-2.670--0.645). Conclusions: Biochemical indicators of NAFLD are closely related to its pathology. The histological lesions of NAFLD are mainly present in hepatic acinar area 3. The diagnosis of NASH is supported by extensive steatosis and high levels of CHO, ALT, AST and BMI, low levels of HDL and ApoA in biochemical markers, but pathological examination is still the gold standard for it.
Adult ; Humans ; Male ; Female ; Adolescent ; Young Adult ; Middle Aged ; Aged ; Non-alcoholic Fatty Liver Disease/pathology* ; Diabetes Mellitus, Type 2/pathology* ; Liver/pathology* ; Obesity/pathology* ; Apolipoproteins A

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.
Acupuncture Therapy ; Diabetes Mellitus, Type 2/therapy* ; Humans ; Insulin-Secreting Cells/pathology* ; Islets of Langerhans/pathology* ; Macrophages

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

OBJECTIVE: To analyze the changes of blood biochemical index and the pathological changes of myocardium and kidney in type 2 diabetic mouse at different time points, which can provide the basis for the selection of type 2 diabetic modeling time for later research. METHODS: After 6 weeks of feeding with high-fat diet, 24 healthy male ICR mice were injected with streptozocin (STZ, 30 mg/kg) intraperitoneally for 5 days to establish diabetic models. After 9 days, a random blood glucose ≥ 11.1 mmol / L was measured as diabetic mice. 4, 6 and 8 weeks after successfully preparing the diabetic mouse, 8 diabetic mice (a group)would be sacrificed each time. Then the biochemical and pathological conditions were analyzed: ① the indexes of heart and kidney were calculated. ②the serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), creatinine (Cr) and blood urine nitrogen (BUN) were determined. ③ Histopathological changes of myocardium and renal tissues were observed by hematoxylin and eosin (HE) staining. Masson staining was used to observe the fibrosis of myocardium. PAS staining was adopted to observe the pathological changes of renal tissue. In addition, 8 ICR male mice were taken as the control group. RESULTS: At the 4, 6 and 8 week, cardiac organ coefficient, the values of LDH and CK were all increased compared with the control group. Cardiomyocyte hypertrophy and myocardial fibrosis could be observed. Renal organ coefficient, the values of Cr and BUN were increased. Glomerular hypertrophy, basement membrane thickening and atrophy could be perceived. CONCLUSION At the 6 week, related biochemical and pathological changes in diabetic mice were comparatively obvious and breeding time was relatively short. Thus, 6 weeks after the preparation of the diabetic mice would be the optimal time for type 2 diabetes mellitus modeling, proper for inventions of drugs and other research purposes including pathology, physiology, biochemistry, etc.
Animals ; Diabetes Mellitus, Experimental ; pathology ; Diabetes Mellitus, Type 2 ; pathology ; Disease Models, Animal ; Kidney ; pathology ; Male ; Mice ; Mice, Inbred ICR ; Streptozocin

OBJECTIVE: To investigate the intervention of curcumin and its analogue J7 on oxidative stress injury in testis of type 2 diabetic rats. METHODS: Sixty male SD rats, 10 rats were chosen as normal control group (NC), the other 50 rats were assigned to experiment group. Experiment diabetic rats were induced by high-fat food and intraperitoneal injection of steptozotocin (STZ). After the model was established successfully, diabetic rats were divided into four groups randomly: diabetes mellitus group (DM, n=12), curcumin treatment group (CUR, n=10), high dose treatment group of J7 (J+, n=10), low dose treatment group of J7 (J-, n=10). The CUR group were intragastrically administered with curcumin 20 mg/kg daily, in addition, the J+ group and the J- group were intragastrically administered with J7 20 mg/kg and 10 mg/kg daily respectively. After 8 weeks, the fast blood glucose was detected biochemically. The activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) were detected by hydroxylamine method and thiobarbituric acid method respectively. The protein expressions of the nuclear factor-erythroid 2-related factor 2 (tNrf2), phosphorylation of Nrf2 (pNrf2), catalase (CAT), NAD(P)H quinine oxidoreductase 1 (NQO1) were measured by Western blot. The mRNA expressions of CAT, NQO1, hemeoxygenase-1 (HO1) were measured by quantitative real-time PCR (qRT-PCR). Morphological structure of testis was observed by hematoxylin-eosin (HE) staining. The expressions of Nrf2 and CAT were also detected by immunohistochemical method. RESULTS: The levels of fast blood glucose and MDA in DM group were increased significantly(P＜0.05), while the body weight, the activity of SOD, the protein expressions of pNrf2/tNrf2, CAT, NQO1 and the mRNA expressions of CAT, NQO1, HO1 were decreased (P＜0.05). Under light microscope, the DM group showed disrupted histological appearance. Immunohistochemistry showed that the protein expressions of Nrf2 around the nucleus and CAT were decreased. With the treatment of curcumin and J7, the MDA levels in the three treatment groups were decreased (P＜0.05). The activity of SOD, the protein expressions of pNrf2/tNrf2, CAT, NQO1 and the mRNA expressions of NQO1, HO1 were increased (P＜0.05). the levels of fast blood glucose were decreased in the J+ and J- group (P＜0.05), and the mRNA expression of CAT was increased in the J+ group (P＜0.05). The ratio of pNrf2/tNrf2 in the J+ group was significantly higher than that in CUR and J- group (P＜0.05). The protein level of CAT in the J+ group was also significantly higher than that in J- group (P＜0.05). There were no significant differences in other indexes among the three treatment groups. Under light microscope, the morphology was obviously improved in the three treatment groups. Immunohistochemistry showed that the protein expressions of Nrf2 around the nucleus and CAT were increased in the three treatment groups. It was suggested that high dose J7 had better antioxidant stress ability in testis of diabetic rats. CONCLUSION Curcumin and J7 could inhibit the oxidative stress damage of testicular tissue in diabetic rats, which might be related with the activation of the Nrf2-ARE signaling pathway.
Animals ; Blood Glucose ; analysis ; Curcumin ; analogs & derivatives ; pharmacology ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 2 ; Male ; Malondialdehyde ; metabolism ; NF-E2-Related Factor 2 ; metabolism ; Oxidative Stress ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Superoxide Dismutase ; metabolism ; Testis ; drug effects ; pathology

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