DHA alleviated hepatic and adipose inflammation with increased adipocyte browning in high-fat diet-induced obese mice.

Obesity is associated with accumulation of inflammatory immune cells in white adipose tissue, whereas thermogenic browning adipose tissue is inhibited. Dietary fatty acids are important nutritional components and several clinical and experimental studies have reported beneficial effects of docosahexaenoic acid (DHA) on obesity-related metabolic changes. In this study, we investigated effects of DHA on hepatic and adipose inflammation and adipocyte browning in high-fat diet-induced obese C57BL/6J mice, and in vitro 3T3-L1 preadipocyte differentiation. Since visceral white adipose tissue has a close link with metabolic abnormality, epididymal adipose tissue represents current target for evaluation. A course of 8-week DHA supplementation improved common phenotypes of obesity, including improvement of insulin resistance, inhibition of macrophage M1 polarization, and preservation of macrophage M2 polarization in hepatic and adipose tissues. Moreover, dysregulated adipokines and impaired thermogenic and browning molecules, considered obesogenic mechanisms, were improved by DHA, along with parallel alleviation of endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and mitochondrial DNA stress-directed innate immunity. During 3T3-L1 preadipocytes differentiation, DHA treatment decreased lipid droplet accumulation and increased the levels of thermogenic, browning, and mitochondrial biogenesis molecules. Our study provides experimental evidence that DHA mitigates obesity-associated inflammation and induces browning of adipose tissue in visceral epididymal adipose tissue. Since obesity is associated with metabolic abnormalities across tissues, our findings indicate that DHA may have potential as part of a dietary intervention to combat obesity.

Tetramethylpyrazine alleviates mitochondrial abnormality in models of cerebral ischemia and oxygen/glucose deprivation Reoxygenation.

Traditional herbal medicine Ligusticum wallichii Franchat (Chuan Xiong) is frequently prescribed and highly recommended to patients with stroke. Rodent studies have demonstrated the neuroprotective effects of its active component tetramethylpyrazine against post-stroke brain injury and highlighted its role in antioxidant, anti-inflammation, and anti-apoptosis activity. Using permanent cerebral ischemia in rats and oxygen/glucose deprivation and reoxygenation (OGDR) in rat primary neuron/glia cultures, this study sheds light on the role of mitochondria as crucial targets for tetramethylpyrazine neuroprotection. Tetramethylpyrazine protected against injury and alleviated oxidative stress, interleukin-1ß release, and caspase 3 activation both in vivo and in vitro. Reduction of mitochondrial biogenesis- and integrity-related proliferator-activated receptor-gamma coactivator-1 alpha, mitochondrial transcription factor A (TFAM), translocase of outer mitochondrial membrane 20, mitochondrial DNA, and citrate synthase activity, as well as activation of mitochondrial dynamics disruption-related Lon protease, dynamin-related protein 1 (Drp1) phosphorylation, stimulator of interferon genes, TANK-binding kinase 1 phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase phosphorylation, eukaryotic initiation factor 2α phosphorylation, and activating transcription factor 4 were revealed in permanent cerebral ischemia in rats and OGDR in neuron/glia cultures. TMP alleviated those biochemical changes. Our findings suggest that preservation or restoration of mitochondrial dynamics and functional integrity and alleviation of mitochondria-oriented pro-oxidant, pro-inflammatory, and pro-apoptotic cascades are alternative neuroprotective mechanisms of tetramethylpyrazine. Additionally, mitochondrial TFAM and Drp1 as well as endoplasmic reticulum stress could be targeted by TMP to induce neuroprotection. Data of this study provide experimental base to support clinical utility and value of Chuan Xiong towards stroke treatment and highlight an alternative neuroprotective target of tetramethylpyrazine.

Associations of traditional Chinese medicine body constitution and all-cause mortality in patients with type 2 diabetes mellitus: a prospective cohort study of a Taiwanese medical center.

Introduction: The objective of this study was to investigate associations between baseline body constitutions (BCs) in traditional Chinese Medicine (TCM) and all-cause mortality in Chinese individuals with type 2 diabetes. Methods: A total of 887 individuals with type 2 diabetes who were enrolled in managed care in 2010 were included. These individuals were followed up until 2015, and their mortality status was determined through the use of Taiwan National Death Datasets. At baseline, BC status of participants, including Yin deficiency, Yang deficiency, and phlegm stasis, was assessed using a well-developed Body Constitutions Questionnaire. Hazard ratios (HR) were calculated using a multivariate Cox proportional hazards model. Results: During 6807.2 person-years of follow-up of 887 participants, with an average follow-up period of 7.7 years, a total of 190 individuals died, resulting in an incidence density of 0.0279 person-years. Yin deficiency was associated with all-cause mortality (HR, 95% CI: 1.39, 1.02-1.90). This study indicates that individuals diagnosed with Yin deficiency in TCM, characterized by symptoms such as thirst, reduced urine volume, hard stool, and hot flushes, had a 39% higher risk of all-cause mortality. Discussion: The findings may provide information for TCM practitioners on tailoring treatment plans for persons with type 2 diabetes. No conclusive statements can be made on the basis of the preliminary data presented here. Controlled prospective studies are warranted.

Traditional Chinese medicine body constitution predicts new-onset diabetic albuminuria in patients with type 2 diabetes: Taichung diabetic body constitution prospective cohort study.

This prospective cohort study explored whether body constitution (BC) independently predicts new-onset albuminuria in persons with type 2 diabetes mellitus (T2DM) enrolled in the diabetes care management program (DCMP) of a medical center, providing evidence of integrating traditional Chinese medicine into DCMP for improving care quality. Persons with T2DM (n = 426) originally without albuminuria enrolled in DCMP were recruited in 2010 and were then followed up to 2015 for detecting new-onset albuminuria. The participants received urinalysis and blood test annually. Albuminuria was determined by an elevated urinary albumin/creatinine ratio (≥ 30 µg/mg), and poor glucose control was defined as Glycosylated hemoglobin above or equal to 7%. BC type (Yin deficiency, Yang deficiency, and phlegm stasis) was assessed using a well-validated body constitution questionnaire at baseline. Risk factors for albuminuria (sociodemographic factors, diabetes history, lifestyle behaviors, lipid profile, blood pressure, and kidney function) were also recorded. Hazard ratios (HR) of albuminuria for BC were estimated using multivariate Cox proportional hazards model. During the 4-year follow-up period, albuminuria occurred in 30.5% of participants (n = 130). The HR indicated that Yin deficiency was significantly associated with an increased risk of new-onset albuminuria in persons with T2DM and good glucose control after adjustment for other risk factors (HR = 2.09; 95% confidence interval = 1.05-4.17, P = .04), but not in those with poor glucose control. In persons with T2DM and poor glucose control, phlegm stasis was also significantly associated with a higher risk of albuminuria (2.26; 1.03-4.94, P = .04) after multivariate adjustment, but not in those with good glucose control. In addition to already-known risk factors, BC is an independent and significant factor associated with new-onset albuminuria in persons with T2DM. Our results imply Yin deficiency and phlegm stasis interacting with glucose control status may affect new-onset albuminuria in persons with T2DM.

Trends in antidiabetic medical treatment from 2005 to 2014 in Taiwan.

BACKGROUND/PURPOSE: Several new antidiabetic drugs have been introduced in Taiwan. However, the trends in antidiabetic treatment remain unexamined. METHODS: We studied data from the Taiwan National Health Insurance Database to identify outpatient prescriptions for antidiabetic drugs from 2005 to 2014. The patterns in antidiabetic treatment and the number of different classes of antidiabetic drugs were analyzed. The proportions of prescriptions of antidiabetic monotherapy, combination therapy, or insulin therapy were further analyzed. RESULTS: The total and mean prescriptions gradually increased during the study period. Prescription of oral antidiabetic drugs (OADs) only or insulin-only therapy decreased slightly. Prescriptions of monotherapy and dual therapy decreased, whereas those of triple or higher order combinations increased. Prescriptions of sulfonylureas (SUs) decreased, whereas those of metformin and dipeptidyl peptidease-4 (DPP4) inhibitors increased. Insulin prescriptions increased but accounted for only 13.07% of prescriptions in 2014. Among monotherapy prescriptions, SU prescriptions decreased, but metformin and DPP4 inhibitor prescriptions increased. Among dual OAD prescriptions, those including SUs decreased, and those of metformin and DPP4 inhibitors increased. Although prescriptions of the metformin-SU combination decreased, they remained the most common among all dual OAD prescriptions, followed by the metformin-DPP4 inhibitor combination. Prescriptions of human insulin decreased and those of insulin analogs increased considerably; those of basal insulin increased, and those of mixed insulin decreased. However, mixed insulin was prescribed more than basal-bolus insulin. CONCLUSION: Antidiabetic treatment has become complex in Taiwan. Although combination therapy would become the major treatment strategy gradually, the underuse of insulin therapy must improve.

Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats.

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Evidence for an Association between Macular Degeneration and Thyroid Cancer in the Aged Population.

Direct evidence of whether thyroid cancer patients have a higher risk of age-related macular degeneration (AMD) has yet to be investigated. Patients older than 50 years-old and newly diagnosed with thyroid cancer between 2000 and 2008 were identified from the national health insurance research database (NHIRD). We applied time-varying Cox proportional hazard models to assess the association between thyroid cancer and AMD. The multivariable models included conventional cardiovascular risk factors, myopia, vitreous floaters, hypothyroidism, hyperthyroidism, and treatment modality of thyroid cancer. The analysis process was stratified by age, gender, and comorbidity. In this study, 5253 patients were included in a thyroid cancer cohort (men 24.5%; median age 59.1 years (53.7⁻67.4 years), and 21,012 matched controls were included in a non-thyroid cancer cohort. The AMD incidence was 40.7 per 10,000 person/year in the thyroid cancer cohort. The thyroid cancer cohort had a higher risk (adjusted hazard ratio (aHR) = 1.38, 95% confidence interval, CI = 1.09⁻1.75) of AMD than the non-thyroid cohort. Thyroid cancer patients had a higher risk of AMD, especially the male patients (aHR = 1.92, 95% CI = 1.38⁻3.14) and the patients with comorbidities (aHR = 1.38, 95% CI = 1.09⁻1.74). In conclusion, thyroid cancer patients older than 50 years-old have increased risk of AMD.

Hepatoprotective activities of rosmarinic acid against extrahepatic cholestasis in rats.

Though rosmarinic acid possesses nutritional, pharmaceutical, and toxic properties and shows therapeutic potential on liver diseases, its therapeutic effects against cholestatic liver diseases have not been proven. Using an extrahepatic cholestasis rat model by bile-duct ligation (BDL), daily oral administration of rosmarinic acid showed improvement effects on liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Rosmarinic acid alleviated BDL-induced transforming growth factor beta-1 (TGF-ß1) production and hepatic collagen deposition, and the anti-fibrotic effects were accompanied by reductions in matrix-producing cells and Smad2/3. BDL rats showed increased hepatic NF-κB/AP-1 activities, inflammatory cell infiltration/accumulation, and cytokine production, and these signs of hepatic inflammation were ameliorated by rosmarinic acid. Mechanistic study revealed an inhibitory effect of rosmarinic acid on the axis of the high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) in BDL rats. Results of cultured hepatic stellate cells further showed the impacts of rosmarinic acid which attenuated TGF-ß1-induced stellate cell mitogenic and fibrogenic activation. Our findings support the concept that rosmarinic acid could serve as a hepatoprotective agent, and dietary rosmarinic acid supplementation may be beneficial in terms of improving cholestasis-related liver injury via mechanisms involving resolution of oxidative burden and down-regulation of HMGB1/TLR4, NF-κB, AP-1, and TGF-ß1/Smad signaling.

Glechoma hederacea extracts attenuate cholestatic liver injury in a bile duct-ligated rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, Glechoma hederacea is frequently prescribed to patients with cholelithiasis, dropsy, abscess, diabetes, inflammation, and jaundice. Polyphenolic compounds are main bioactive components of Glechoma hederacea. AIM OF THE STUDY: This study was aimed to investigate the hepatoprotective potential of hot water extract of Glechoma hederacea against cholestatic liver injury in rats. MATERIALS AND METHODS: Cholestatic liver injury was produced by ligating common bile ducts in Sprague-Dawley rats. Saline and hot water extract of Glechoma hederacea were orally administrated using gastric gavages. Liver tissues and bloods were collected and subjected to evaluation using histological, molecular, and biochemical approaches. RESULTS: Using a rat model of cholestasis caused by bile duct ligation (BDL), daily oral administration of Glechoma hederacea hot water extracts showed protective effects against cholestatic liver injury, as evidenced by the improvement of serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Glechoma hederacea extracts alleviated BDL-induced transforming growth factor beta-1 (TGF-ß1), connective tissue growth factor, and collagen expression, and the anti-fibrotic effects were accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity. Glechoma hederacea extracts attenuated BDL-induced inflammatory cell infiltration/accumulation, NF-κB and AP-1 activation, and inflammatory cytokine production. Further studies demonstrated an inhibitory effect of Glechoma hederacea extracts on the axis of high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) intracellular signaling pathways. CONCLUSIONS: The hepatoprotective, anti-oxidative, anti-inflammatory, and anti-fibrotic effects of Glechoma hederacea extracts seem to be multifactorial. The beneficial effects of daily Glechoma hederacea extracts supplementation were associated with anti-oxidative, anti-inflammatory, and anti-fibrotic potential, as well as down-regulation of NF-κB, AP-1, and TGF-ß/Smad signaling, probably via interference with the HMGB1/TLR4 axis.

Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance.

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1-/- mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1-/- only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.

Glycemic excursions are positively associated with HbA1c reduction from baseline after treatment with acarbose in patients with type 2 diabetes on metformin monotherapy.

BACKGROUND: The aim of the present study was to examine the association between glycemic excursions before treatment and HbA1c reduction after treatment intensification with acarbose or glibenclamide in patients with type 2 diabetes (T2D). METHODS: Patients receiving single or dual oral antidiabetic drug treatment with an HbA1c of 7.0-11.0 % (53-97 mmol/mol) were switched to metformin monotherapy (500 mg, t.i.d.) for 8 weeks, followed by randomization to either acarbose (100 mg, t.i.d.) or glibenclamide (5 mg, t.i.d.) as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring. Treatment efficacy was evaluated as relative HbA1c reduction (%), calculated as (baseline HbA1c - post-treatment HbA1c)/baseline HbA1c × 100. RESULTS: Fifty patients (mean [±SD] age 53.5 ± 8.2 years, 48 % men, mean baseline HbA1c 8.4 ± 1.2 %) were analyzed. Baseline MAGE was positively correlated with relative HbA1c reduction from baseline in patients treated with acarbose (r = 0.421, P = 0.029) but not glibenclamide (r = 0.052, P = 0.813). Linear regression analysis revealed that the association between baseline MAGE and relative HbA1c reduction from baseline (ß = 0.125, P = 0.029) in patients treated with acarbose remained significant after adjustment for several confounders (P < 0.05 for all models). CONCLUSIONS: In patients with T2D on metformin monotherapy, baseline MAGE was positively correlated with relative HbA1c reduction from baseline after treatment with acarbose, but not glibenclamide. These findings highlight the importance of glycemic excursions in individualized treatment for patients with T2D.

Glycemic excursions are positively associated with changes in duration of asymptomatic hypoglycemia after treatment intensification in patients with type 2 diabetes.

AIM: The aim of this study was to examine the association between glycemic excursions and duration of hypoglycemia after treatment intensification in patients with type 2 diabetes (T2D). METHODS: Patients with T2D on oral anti-diabetes drug (OAD) with glycated hemoglobin (HbA1c) of 7.0-11.0% were switched to metformin monotherapy (500 mg thrice daily) for 8 weeks, followed by randomization to either glibenclamide or acarbose as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring (CGM) before randomization and at the end of study. Hypoglycemia was defined as sensor glucose level of less than 60 mg/dl in two or more consecutive readings from CGM. RESULTS: A total of 50 patients (mean age 53.5 ± 8.2 years, male 48%, mean baseline HbA1c 8.4 ± 1.2%) were analyzed. Duration of hypoglycemia significantly increased after treatment with glibenclamide (from 5.5 ± 13.8 to 18.8 ± 35.8 min/day, p=0.041), but not with acarbose (from 2.9 ± 10.9 to 14.7 ± 41.9 min/day, p=0.114). Post treatment MAGE was positively associated with change from baseline in duration of hypoglycemia after treatment with either glibenclamide (ß coefficient 0.345, p=0.036) or acarbose (ß coefficient 0.674, p=0.046). The association remained significant after multivariate adjustment (p<0.05 for all models). CONCLUSIONS: Post treatment glycemic excursions are associated with changes in duration of hypoglycemia after treatment intensification with OAD in patients with T2D. Glycemic excursions should be an important treatment target for T2D to reduce the risk of hypoglycemia.

Association between Albuminuria and Different Body Constitution in Type 2 Diabetes Patients: Taichung Diabetic Body Constitution Study.

Objective. Albuminuria in type 2 diabetes mellitus (T2DM) patients increases the risk of diabetic nephropathy, the leading cause of end-stage renal disease worldwide. Because albuminuria is modifiable, identifying relevant risk factors could facilitate prevention and/or management. This cross-sectional study investigated whether body constitution (BC) independently predicts albuminuria. Method. Patients with T2DM (n = 846) received urinalysis, a blood test, and diabetic retinopathy examination. Albuminuria was defined by an elevated urinary albumin/creatinine ratio (≥30 µg/mg). BC type (Yang deficiency, Yin deficiency, and Phlegm stasis) was assessed using a body constitution questionnaire (BCQ). Traditional risk factors for albuminuria were also recorded. Odds ratios (ORs) of albuminuria for BC were estimated using multivariate logistic regression. Results. Albuminuria was more prevalent in patients with Yang deficiency or Phlegm stasis (both P < 0.01). After adjustment, patients with both Yang deficiency and Phlegm stasis exhibited a significantly higher risk of albuminuria (OR = 3.037; 95% confidence interval = 1.572-5.867, and P < 0.001). Conclusion. BC is strongly associated with albuminuria in T2DM patients. Using a BCQ to assess BC is noninvasive, convenient, and inexpensive and can provide information for health care professionals to identify T2DM patients who are at a high risk of albuminuria.

Yang Deficiency Body Constitution Acts as a Predictor of Diabetic Retinopathy in Patients with Type 2 Diabetes: Taichung Diabetic Body Constitution Study.

Objective. Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus (DM), can cause severe visual impairment and blindness. To prevent the development of DR, identifying the associated risk factors for patient classification is critical. We conducted a cross-sectional study to determine whether body constitution (BC) is an independent predictor of DR. Method. 673 type 2 DM (T2DM) patients were recruited from a medical center, all received DR examination and body constitution questionnaire to assess BC. Other risk factors for DR were also recorded, including life style, history of diabetes, and blood pressure, etc. Multiple logistic regression analysis was conducted to calculate the odds ratios (ORs) for DR. Results. The prevalence of DR was significantly lower in Yang deficiency patients compared with non-Yang deficiency patients (24.69% versus 38.18% P = 0.02). After adjusting for other risk factors, we observed that patients exhibiting Yang deficiency BC were less likely to present with DR (OR = 0.531; 95% confidence interval = 0.312-0.903, P = 0.018). Conclusion. In addition to traditional risk factors, Yang deficiency BC might be an independent predictor of DR among T2DM patients and the results can be used as evidence for traditional Chinese medicine patient classification.

Reduced health-related quality of life in body constitutions of yin-xu, and yang-xu, stasis in patients with type 2 diabetes: taichung diabetic body constitution study.

Aim. To evaluate how health-related quality of life (HRQOL) and traditional Chinese medicine (TCM) constitutions of Yin-Xu, Yang-Xu, and Stasis are related in type 2 diabetes patients. Method. Seven hundred and five subjects were recruited in 2010 for this study from a Diabetes Shared Care Network in Taiwan. Generic and disease-specific HRQOL were assessed by the short form 36 (SF-36) and the diabetes impact measurement scale (DIMS). Constitutions of Yin-Xu, Yang-Xu, and Stasis were then assessed by the body constitution questionnaire (BCQ), a questionnaire consisting of 44 items that evaluate the physiological state based on subjective symptoms and signs. Results. Estimated effects of the Ying-Xu and Stasis on all scales of the SF-36 were significantly negative, while estimated effects of the Yang-Xu on all scales (except for SF, RE, MH, and MCS) were significantly negative. For DIMS, the estimated effects of the Ying-Xu and Stasis on all scales were significantly negative except for Stasis on well-being, while Yang-Xu has a significantly negative effect only on symptoms. Conclusions. This study demonstrates that TCM constitutions of Yin-Xu, Yang-Xu, and Stasis are closely related to a reduction in HRQOL. These findings support the need for further research into the impact of intervention for TCM constitutions on HRQOL in patients with type 2 diabetes.

Chinese Medicinal Formula (MHGWT) for Relieving Diabetic Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective. To investigate the effects of modified Hungqi Guizhi Wuwu Tang (MHGWT), a formula that comprises Chinese medicinal herbs, in relieving neuropathic pain in diabetics. Method. Between March 2008 and April 2009, 112 participants were randomly assigned to either the MHGWT group, whose members received MHGWT (n = 56), or the control group, whose members received a placebo (n = 56). Diabetic neuropathic pain (DNP) was rated using the 15-item Short-Form Brief Pain Inventory (SF-BPI), the 17-item Short-Form McGill Pain Questionnaire (SF-MPQ), the 13-item Modified Michigan Neuropathy Screening Instrument (MMNSI), and the 36-item "SF-36." Nerve conduction studies (NCSs) were performed before and after treatment. Results. After 12 weeks of treatment, the SF-MPQ and SF-BPI scores of the MHGWT group were significantly (P < 0.05) reduced and a significant difference between the groups was observed (P < 0.05). The levels of NCS in the MHGWT group were nonsignificantly (P > 0.05) reduced, and no significant difference in NCS level was observed between the groups (P > 0.05). Conclusions. MHGWT shows promise in relieving DNP and deserves further investigation.

Beneficial effect of docosahexaenoic acid on cholestatic liver injury in rats.

Bile duct obstruction and subsequent cholestasis are associated with hepatocellular injury, cholangiocyte proliferation, stellate cell activation, Kupffer cell activation, oxidative stress, inflammation and fibrosis. Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid that has been shown to possess health beneficial effects, including hepatoprotection. However, the molecular mechanism of DHA-mediated hepatoprotection is not fully understood. In the present study, we report the protective effect of DHA on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily administration of DHA was started 2 weeks before injury and lasted for 5 weeks. In comparison with the control group, the BDL group showed hepatic damage as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation and oxidative stress. These pathophysiological changes were attenuated by chronic DHA supplementation. DHA alleviated BDL-induced transforming growth factor beta-1 (TGF-ß1), intereukin-1beta, connective tissue growth factor and collagen expression. The anti-fibrotic effect of DHA was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of TGF-ß1. DHA also attenuated BDL-induced leukocyte accumulation and nuclear factor-κB (NF-κB) activation. Further studies demonstrated an inhibitory effect of DHA on redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Taken together, the hepatoprotective, anti-inflammatory and anti-fibrotic effects of DHA seem to be multifactorial. The beneficial effects of chronic DHA supplementation are associated with anti-oxidative and anti-inflammatory potential as well as down-regulation of NF-κB and transforming growth factor beta/Smad signaling probably via interference with ERK activation.

Effects of acarbose versus glibenclamide on glycemic excursion and oxidative stress in type 2 diabetic patients inadequately controlled by metformin: a 24-week, randomized, open-label, parallel-group comparison.

BACKGROUND: Glycemic excursion is significantly associated with oxidative stress, which plays a role in the development of chronic complications in type 2 diabetes mellitus (T2DM). Acarbose has been reported to reduce cardiovascular risk in patients with impaired glucose tolerance and T2DM. We hypothesize that treatment with acarbose could attenuate glycemic excursions and reduce oxidative stress in patients with T2DM. OBJECTIVE: This study aimed to evaluate the effects of acarbose versus glibenclamide on mean amplitude of glycemic excursions (MAGE) and oxidative stress in patients with T2DM who are insufficiently controlled by metformin. METHODS: T2DM outpatients aged 30 to 70 years who were taking single or dual oral antidiabetic drugs for ≥3 months and had a glycosylated hemoglobin (HbA(1c)) value between 7.0% and 11.0% were eligible. Patients were treated with metformin monotherapy (1500 mg daily) for 8 weeks, followed by randomization to either acarbose or glibenclamide add-on for 16 weeks. The dosage of acarbose and glibenclamide was 50 mg TID and 2.5 mg TID, respectively, for the first 4 weeks. In the following 12 weeks, the dosage was doubled in both groups. Continuous glucose monitoring (CGM) for 72 hours and a meal tolerance test (MTT) after a 10-hour overnight fast were conducted before randomization and at the end of study. MAGE was calculated from CGM data. ß-cell response to postprandial glucose increments was assessed by the ratio between incremental AUC of insulin and glucose during MTT. Oxidative stress was estimated by plasma oxidized LDL (ox-LDL) and urinary excretion rates of 8-iso prostaglandin F(2α) (8-iso PGF(2α)). The primary outcomes included changes in MAGE, plasma ox-LDL, and urinary excretion of 8-iso PGF(2α). Adverse events, including hypoglycemia, were recorded. RESULTS: A total of 55 patients were randomized (mean age, 54 years; males, 47%; mean body mass index, 25.9 kg/m(2); mean duration of diabetes, 6.9 years; mean HbA(1c), 8.3%) and 51 patients completed this study (acarbose, n = 28; glibenclamide, n = 23). HbA(1c) decreased significantly in both treatment groups (acarbose: 8.2 [0.8]% to 7.5 [0.8]% [P < 0.001]; glibenclamide: 8.6 [1.6]% to 7.4 [1.2]% [P < 0.001]). MAGE did not change significantly in glibenclamide-treated patients (6.2 [2.8] mmol/L to 6.3 [2.3] mmol/L; P = 0.82), whereas ox-LDL (242.4 [180.9] ng/mL to 470.7 [247.3] ng/mL; P = 0.004) and urinary excretion of 8-iso PGF(2α) (121.6 [39.6] pmol/mmol creatinine to 152.5 [41.8] pmol/mmol creatinine; P = 0.03) increased significantly. Acarbose decreased MAGE (5.6 [1.5] mmol/L to 4.0 [1.4] mmol/L; P < 0.001) without significant change in ox-LDL levels (254.4 [269.1] ng/mL to 298.5 [249.8) ng/mL; P = 0.62) or 8-iso PGF(2α) excretion rates (117.9 [58.1] pmol/mmol creatinine to 137.8 [64.4] pmol/mmol creatinine; P = 0.12). Body weight and serum triglycerides (fasting and 2-hour postprandial) decreased (all, P < 0.01) and serum adiponectin increased (P < 0.05) after treatment with acarbose, whereas HDL-C decreased (P < 0.01) after treatment with glibenclamide. ß-cell response to postprandial glucose increments was negatively correlated with MAGE (r = 0.570, P < 0.001) and improved significantly with acarbose (35.6 [32.2] pmol/mmol to 56.4 [43.7] pmol/mmol; P = 0.001) but not with glibenclamide (27.9 [17.6] pmol/mmol to 36.5 [24.2] pmol/mmol; P = 0.12). CONCLUSIONS: In this select population of adult Taiwanese patients with T2DM who were inadequately controlled by metformin, add-on acarbose or glibenclamide significantly reduced HbA(1c). However, treatment with acarbose decreased MAGE, body weight, and serum triglyceride and increased serum adiponectin without significant effect on oxidative stress. Treatment with glibenclamide had no statistically significant effect on MAGE but increased oxidative stress and decreased HDL-C. ClinicalTrials.gov identifier: NCT00417729.

The beneficial effect of α-glucosidase inhibitor on glucose variability compared with sulfonylurea in Taiwanese type 2 diabetic patients inadequately controlled with metformin: preliminary data.

AIMS: Although sulfonylurea added to metformin is the first oral drug combination regimen for patients with type 2 diabetes recommended by the American Diabetes Association/European Association for the Study of Diabetes consensus statement, it does not allow for individualizing and optimizing therapy with respect to sustaining glycemic control and the reduction of glucose variability. We therefore sought to investigate acarbose as an alternative to glibenclamide in combination with metformin and compare the effects on metabolic control and glucose variability. METHODS: Type 2 diabetic patients 30-70 years of age with glycosylated hemoglobin 7.0%-11.0% while treated with one or two oral antidiabetic drugs were successively enrolled. After 8 weeks of run-in with metformin 500 mg thrice daily, either acarbose 50 mg or glibenclamide 2.5 mg three times daily was randomly added on and force titrated to acarbose 100 mg or glibenclamide 5.0 mg three times daily for the subsequent 16 weeks. Demographic data, biochemical data and continuous glucose monitoring system data were recorded upon randomization and at the end of the study. Various parameters that measure glucose variability were derived from the continuous glucose monitoring system data. RESULTS: Of the 51 type 2 diabetes patients enrolled, data from 40 subjects, 20 in each group, were analyzed after excluding those unqualified information. Both drug combinations improved glycemic control. Glucose variability, expressed as mean amplitude of glycemic excursion or continuous overall net glycemic action and mean of daily differences, decreased significantly (all P<.05) after the addition of acarbose but not glibenclamide. The acarbose-metformin combination has the additional benefits of weight reduction and shorter durations of hyperglycemia compared with metformin monotherapy. CONCLUSIONS: This study suggests that both intraday and interday glucose variability are more effectively reduced by the acarbose-metformin combination than by the glibenclamide-metformin combination, while both combinations reduce the overall glucose level equally.