Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle.
Animals ; Blood Glucose ; drug effects ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Female ; Glucose Tolerance Test ; Glucose Transporter Type 4 ; metabolism ; Hypoglycemic Agents ; pharmacology ; Insulin ; blood ; Insulin Resistance ; Liver ; drug effects ; pathology ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; drug effects

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

PURPOSE: The aim of this study was to examine the effects of all-trans retinoic acid (ATRA) on diabetic nephropathy. MATERIALS AND METHODS: We measured amounts of urinary albumin excretion (UAE) after administrating ATRA to Otsuka Long-Evans Tokushima Fatty (OLETF) rats. In order to understand the mechanism of action for ATRA, we administrated ATRA to examine its inhibitory action on the production of transforming growth factor-beta1 (TGF-beta1), protein kinase C (PKC), and reactive oxidative stress (ROS) in cultured rat mesangial cells (RMCs). RESULTS: After 16 weeks of treatment, UAE was lower in the ATRA-treated OLETF rats than in the non-treated OLETF rats (0.07+/-0.03 mg/mgCr vs. 0.17+/-0.15 mg/mgCr, p<0.01). After incubation of RMCs in media containing 30 or 5 mM of glucose, treatment with ATRA showed time- and dose-dependent decreases in TGF-beta1 levels and ROS. Moreover, ATRA treatment showed a dose-dependent decrease in PKC expression. CONCLUSION: ATRA treatment suppressed UAE and TGF-beta1 synthesis, which was mediated by significant reductions in PKC activity and ROS production. Our results suggest that ATRA has a potential therapeutic role for diabetic nephropathy.
Animals ; Diabetes Mellitus, Type 2/*complications ; Diabetic Nephropathies/*complications/*drug therapy/pathology ; Mesangial Cells/*metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Inbred OLETF ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/analysis/pharmacology ; Tretinoin/*pharmacology/therapeutic use

The Goto-Kakizaki (GK) rat is a spontaneous type 2 diabetic animal model, which is characterized by a progressive loss of beta islet cells with fibrosis. In the present study, the hypoglycemic effect of asiatic acid (AA) in GK rats was examined. GK rats receiving AA at a daily dose of 25 mg·kg(-1) for four weeks showed a significant reduction in blood glucose levels. Age-matched normal Wistar rats were given 0.5% sodium carboxymethyl cellulose (CMC-Na) solution for the same periods and used as control. Compared to the normal Wistar rats, GK rats treated with AA showed improvement in insulin resistance partially through decreasing glucose level (P < 0.01) and insulin level (P < 0.05). Furthermore, the results of immunohistochemistry indicate that AA treatment reduced islet fibrosis in GK rats. Fibronectin, a key protein related to islet fibrosis, was over-expressed in GK rats, which was reversed significantly by AA treatment (P < 0.05). These findings suggest that AA has a beneficial effect on lowering blood glucose levels in GK rats and improves fibrosis of islets in diabetes, which may play a role in the prevention of islets dysfunction.
Animals ; Blood Glucose ; metabolism ; Centella ; chemistry ; Diabetes Mellitus, Type 2 ; drug therapy ; pathology ; Disease Models, Animal ; Fibronectins ; metabolism ; Fibrosis ; Glucose Tolerance Test ; Hyperglycemia ; drug therapy ; pathology ; Insulin ; blood ; Insulin Resistance ; Islets of Langerhans ; drug effects ; pathology ; Male ; Pancreatic Diseases ; metabolism ; pathology ; prevention & control ; Pentacyclic Triterpenes ; pharmacology ; therapeutic use ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Rats, Inbred Strains

OBJECTIVETo study the effects of Meilian Xiaoke capsule (a traditional Chinese medicinal preparation) combined with metformin for protecting islet cells and lowering blood glucose in diabetic rats.

METHODSRat models with type 2 diabetes, established by high-fat and high-glucose diet combined with streptozotocin (STZ) injection, were treated with a low dose of metformin, Meilian Xiaoke capsule, or both for 4 weeks by gavage. Blood glucose level was tested in the rats, and islet pathologies and changes in islet β cell number after the treatment were observed with HE staining and aldehyde fuchsin staining, respectively.

RESULTSTreatment with metformin or Meilian Xiaoke capsule alone for 2 or 4 weeks did not produce significant improvement of blood glucose in the diabetic rats. Their combined treatment for 4 weeks resulted in significantly lowered blood glucose level and improved glucose tolerance with also obviously increased islet β cell number and lessened islet pathologies.

CONCLUSIONSMeilian Xiaoke capsule and metformin show a synergistic effect to significantly enhance the therapeutic effect in rats with type 2 diabetes.

Animals ; Blood Glucose ; drug effects ; Diabetes Mellitus, Experimental ; drug therapy ; Diabetes Mellitus, Type 2 ; drug therapy ; Drug Synergism ; Drugs, Chinese Herbal ; pharmacology ; Hypoglycemic Agents ; pharmacology ; Insulin-Secreting Cells ; pathology ; Metformin ; pharmacology ; Rats ; Streptozocin

BACKGROUNDIntensive insulin therapy has been found to lessen the progress of diabetic retinopathy (DR) to some extent, while it has also been implicated to be responsible for decrease of DR. We investigated visual function and morphological changes in the macular area in short-term follow-up of patients with type 2 diabetes mellitus after intensive insulin therapy.

METHODSThis was a prospective clinical study of nonproliferative DR patients (102 eyes, 120 patients) undergoing intensive insulin therapy. The Contrast Glare Tester (Takagi CGT-1000) was used to examine contrast sensitivity (CS) and Heidelberg Retina Tomograph (HRT) II and Stratus Model 3000 OCT were used to observe the changes of morphology in the macular area. Follow-up times were pre-intensive therapy, 3 and 6 months post-intensive therapy.

RESULTSCS at low and middle frequencies was higher at 3 and 6 months post-therapy compared with pre-therapy (P < 0.05). Significant differences in CS at low frequency were found between 6 and 3 months post-therapy (P < 0.05). Macular edema index was lower in the first, second, and third rings of the macular area after intensive therapy compared with pre-therapy (P < 0.05). Compared with 3 months post-therapy, the macular edema index was lower in the first, second, and third rings of the macular area at 6 months post-therapy (P > 0.05). No significant differences in the thickness of the first, second, and third rings of the macular area were detected between 3 and 6 months post-therapy and pre-therapy (P > 0.05).

CONCLUSIONCS and macular edema indexes were significantly improved in nonproliferative diabetic retinopathy patients after intensive insulin therapy, but thickness of the macular area was unchanged.

Diabetes Mellitus, Type 2 ; drug therapy ; pathology ; physiopathology ; Follow-Up Studies ; Humans ; Insulin ; therapeutic use ; Macula Lutea ; pathology ; Middle Aged ; Prospective Studies ; Tomography, Optical Coherence ; Vision, Ocular ; physiology

OBJECTIVETo analyze the impact of atorvastatin on blood lipids and arterial media thickness (IMT) in new-onset type 2 diabetes patients.

METHODS333 patients, 30-70 years old and diagnosed within one year as type 2 diabetes, were selected from the Chinese Diabetes Complication Prevention Study (CDCPS) to take part in this study. Changes of blood lipids and IMT of carotid, femoral and iliac artery pre and post the administration of atorvastatin were tested and followed for 24 months.

RESULTSTotal cholesterol, triglycerides and low-density lipoprotein decreased significantly (P = 0.000) and maintained at a low level. The carotid artery IMT decreased significantly (P = 0.022) at the end of this study, but the femoral and iliac artery IMT did not show any obvious change. There were no serious adverse events noticed, during the study period.

CONCLUSIONLong-term use of atorvastatin seemed to be safe and effective in reducing blood lipids in patients with type 2 diabetes thus could delay the development of atherosclerosis.

Adult ; Aged ; Atorvastatin Calcium ; Diabetes Mellitus, Type 2 ; drug therapy ; Female ; Follow-Up Studies ; Heptanoic Acids ; therapeutic use ; Humans ; Lipids ; blood ; Male ; Middle Aged ; Pyrroles ; therapeutic use ; Tunica Media ; pathology

OBJECTIVETo observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism.

METHODSRats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting.

RESULTSCompared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin.

CONCLUSIONSaxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.

Adamantane ; analogs & derivatives ; pharmacology ; Animals ; Blood Glucose ; Diabetes Mellitus, Type 2 ; drug therapy ; Dipeptides ; pharmacology ; Disease Models, Animal ; Hepatocytes ; cytology ; Insulin Resistance ; Lipids ; blood ; Liver ; metabolism ; pathology ; Non-alcoholic Fatty Liver Disease ; drug therapy ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo observe the influence of high blood glucose fluctuation on the endothelial function of type 2 diabetes mellitus (T2DM) rats and the effects of Panax Quinquefolius Saponin (PQS) of stem and leaf.

METHODSThe T2DM model was induced by intraperitoneal injection of a small dose of streptozotocin (STZ, 35 mg/kg) plus high fat and high caloric laboratory chow. Then, diabetic rats were divided into steady high blood glucose (SHG) group and fluctuant high blood glucose (FHG) group according to fasting blood glucose coefficient of variation (FBG-CV), and then, the FHG group rats were divided into 4 groups according to the level of FBG-CV and fasting blood glucose: PQS 30 mg/(kg·d) group, PQS 60 mg/(kg·d) group, metformin hydrochloride control (MHC) group, and FHG control group, 10 in each group. Meanwhile, 10 rats without any treatment were used as normal control (NOR) group. Eight weeks later, the aortic arteries histology, plasma hepatocyte growth factor (HGF), and serum nitric oxide (NO), endothelin-1 (ET-1), tumor necrosis factor α (TNF-α), and soluble intercellular adhesion molecule 1 (sICAM-1) were measured.

RESULTSIn comparison with the NOR group, the level of plasma HGF and serum NO, ET-1 and TNF-α, and sICAM-1 in SHG and FHG control groups were all significantly increased (P<0.01); in comparison with the SHG group, plasma HGF and serum NO, ET-1, TNF-α, and sICAM-1 in FHG group were all significantly increased further (P<0.01 or P<0.05); meanwhile, in comparison with the FHG control group, the level of plasma HGF and serum NO, ET-1, TNF-α, and sICAM-1 in PQS and MHC groups were all decreased significantly (P<0.01). However, comparison of the aortic arteries histology among groups showed no significant differences either before or after treatment.

CONCLUSIONBlood glucose fluctuation could facilitate the development of vascular endothelial dysfunction in T2DM rats, while PQS could improve the endothelial function of T2DM rats with high blood glucose fluctuation, which may be related to its effects of relieving vessel stress, decreasing vasoconstrictor ET-1 production, preventing compensated increase of NO, and reducing inflammatory reaction.

Animals ; Aorta ; drug effects ; pathology ; Blood Glucose ; metabolism ; Body Weight ; drug effects ; Diabetes Mellitus, Type 2 ; blood ; drug therapy ; Endothelin-1 ; blood ; Endothelium, Vascular ; drug effects ; physiopathology ; Hepatocyte Growth Factor ; blood ; Intercellular Adhesion Molecule-1 ; blood ; Male ; Nitric Oxide ; blood ; Panax ; chemistry ; Plant Leaves ; chemistry ; Plant Stems ; chemistry ; Rats ; Saponins ; pharmacology ; therapeutic use ; Solubility ; Tumor Necrosis Factor-alpha ; blood

The objective of this study is to fully investigate the therapeutic effect and mechanisms of action of Gegen Qinlian decoction (GD) on type 2 diabetes mellitus (type 2 DM). A rat model of type 2 DM was established with the combination of high-fat diet and multiple low doses of streptozotocin (STZ). Biochemical indicators related to glucose metabolism disorders, insulin resistance, oxidative stress were observed. The type 2 DM rats were administrated with GD for 80 days, the above-mentioned indexes were detected. The results indicated that the hepatic glycogen synthesis level was promoted, fasting blood glucose level and fasting blood insulin level were significantly reduced, insulin sensitivity index was significantly improved; the level of superoxide dismutase (SOD) was increased and the level of malondialdehyde (MDA) was reduced; pathologic morphology of pancreas and kidney was ameliorated in the GD group. It was indicated that the therapeutic mechanisms of action of GD on type 2 DM might be related to its effect of ameliorating glucose metabolism disorders, relieving insulin resistance, increasing the tissues' sensitivity to insulin, improving the antioxidative ability of living system, GD has therapeutic effect on type 2 DM and protective effects against damaged pancreatic function.
Animals ; Blood Glucose ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; therapeutic use ; Female ; Glycogen ; metabolism ; Hypoglycemic Agents ; isolation & purification ; pharmacology ; therapeutic use ; Insulin ; blood ; Insulin Resistance ; Kidney ; pathology ; Liver ; metabolism ; Male ; Malondialdehyde ; metabolism ; Pancreas ; pathology ; Phytotherapy ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism