Relationship Between Acyl and Desacyl Ghrelin Levels with Insulin Resistance and Body Fat Mass in Type 2 Diabetes Mellitus.

Purpose: Although strong evidence suggests that ghrelin plays an important role in regulating energy balance, the effects of acylated ghrelin (AG) and deacylated ghrelin (DAG) on fat mass are largely undefined. This study aimed to investigate the differential associations of both forms of ghrelin with insulin resistance and body fat mass in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 162 patients with type 2 diabetes were recruited and classified based on BMI and visceral fat area (VFA) as VFA normal group (n = 78), normal-BMI VFA obesity group (n = 20) and high-BMI VFA obesity group (n = 64). VFA and subcutaneous fat area (SFA) were detected by bioelectrical impedance analysis. Blood samples were collected to measure fasting glucose, insulin, lipids, AG and DAG levels after clinical examination. Results: Compared with VFA normal group, DAG levels were significantly lower (421.7 ± 106.0 and 388.7 ± 96.5 pg/mL vs 524.4 ± 141.5 pg/mL, P < 0.01) in the two VFA obesity groups. No significant difference was found in AG levels within three groups. Among all subjects, BMI, VFA, SFA, fasting insulin and HOMA-IR were negatively correlated with DAG but positively with AG/DAG ratio (P < 0.01). In contrast, AG was positively correlated with HOMA-IR and fasting glucose (P < 0.01). Multiple stepwise regression analysis showed that fasting glucose was the independent factor of AG, VFA and HOMA-IR were the independent factors related to DAG. Conclusion: DAG levels have a strong negative association with excess body fat mass and insulin resistance, whereas AG levels are closely related to elevated blood glucose levels in T2DM patients.

Time in range, especially overnight time in range, is associated with sudomotor dysfunction in patients with type 1 diabetes.

BACKGROUND: Time in range (TIR) is advocated as key metric of glycemic control and is reported to be associated with microvascular complications of diabetes. Sudomotor dysfunction is among the earliest detectable diabetic peripheral neuropathy (DPN). We set about to research the relationship between TIR including overnight TIR and sudomotor function detected by SUDOSCAN with the intention of exploring the correlation of TIR including overnight TIR and early DPN in type 1 diabetes (T1D). METHODS: 95 patients with T1D were enrolled. TIR including nocturnal TIR of 3.9-10.0 mmol/L was evaluated with CGM. SUDOSCAN measured feet electrochemical skin conductance (FESC) and sudomotor dysfunction was defined as average FESC < 60µS. Logistic regressions were applied to examine the independent association of TIR and overnight TIR with sudomotor function. RESULTS: The overall prevalence of sudomotor dysfunction was 28.42%. Patients with sudomotor dysfunction had significantly lower TIR for the whole recorded phase and for nighttime. The sudomotor dysfunction prevalence progressively declined with the ascending tertiles of TIR and nocturnal TIR (P for trend < 0.05). Correlation analysis showed that the relationship between nocturnal TIR and FESC was stronger than that between TIR and FESC with correlation coefficients were respectively 0.362 and 0.356 (P < 0.001). Finally, logistic regression analysis indicated the independently negative relation between TIR and nocturnal TIR and sudomotor dysfunction (P < 0.05), and the correlation between nocturnal TIR and sudomotor dysfunction was more statistically significant. CONCLUSIONS: TIR is negatively correlated with sudomotor dysfunction in T1D independent of HbA1c. Furthermore, decreased nocturnal TIR is more closely related to the impaired function of sudomotor nerves in sweat glands.

Association between time in range, a novel measurement of glycemic control and islet secretory function in chinese patients with type 2 diabetes mellitus-An observational study.

AIMS: To explore the association between dynamic islet secretory function and TIR (time in range), a new valuable metric of glycemic control in type 2 diabetes (T2D). METHODS: In this observational study 256 patients with type 2 diabetes were included and continuous glucose monitoring system (CGMS) were applied to monitor blood glucose and also the calculation of TIR [the time spent in an individual's target glucose range (usually 3.9-10 mmol/L)]. The participants were divided into 3 groups according to the tertiles of TIR, 85 cases with TIR ≥ 65.05% (T1 group), 86 cases with 41.84 < TIR ≤ 65.05% (T2 group) and 85 cases with TIR < 41.84% (T3 group). Serum glucagon (GLA0h, GLA0.5h, GLA1h, GLA2h, GLA3h), C-peptide (Cp0h, Cp0.5h, Cp1h, Cp2h, Cp3h) concentration at different time points were measured after a 100 g standard steamed buns meal test to assess the pancreatic alpha cell and beta cell function. Spearman correlation analysis and multivariate linear stepwise regression analysis were adopted for statistical analysis. RESULTS: The average age and diabetes duration of all the participants were separately 56.09 ± 13.8 years and 8.0 (4.0,15.0) years. Compared with patients in T1 group, participants in group T2 and T3 tend to have a lower concentration of C-peptide at all time points, as well as GLA0h, GLA2h and GLA3h (p < 0.05). TIR was positively correlated with C-peptide at different time points, area under the curve of C-peptide in half an hour (AUCCp0.5h), GLA0h, GLA3h, area under the curve of glucagon in half an hour (AUCGLA0.5h)(rs = 0.263, 0.414, 0.510, 0.587, 0.528, 0.360, 0.259, 0.144 and 0.208, respectively, p < 0.05) and was negatively correlated with the increment of serum glucagon from baseline at 0.5 h, 1 h and 2 h after the standard energy loaded(△GLA0.5h, △GLA1h, △GLA2h)(rs = -0.152,-0.172 and -0.203, respectively, p < 0.05). Cp2h, Cp0h and GLA0h were independent factors for TIR (ß = 6.558,-6.930, 0.247, respectively, p < 0.01). CONCLUSION: Both islet alpha cell and beta cell secretory function have important influence on TIR, a novel vital index of glycemic fluctuation.

The Relationship Between ß-cell Function Indices and Sudomotor Function in Chinese Patients with Type 2 Diabetes.

PURPOSE: SUDOSCAN, a new non-invasive, quick, sensitive and quantitative technique, has been developed to detect diabetic peripheral neuropathy, and the latter is believed to be correlated with impaired ß-cell function. The purpose of the present study was to investigate the associations between ß-cell function indices and sudomotor function in Chinese type 2 diabetes. METHODS: A total of 266 Chinese patients with type 2 diabetes were enrolled. Sudomotor function was assessed using electrochemical skin conductance of hands and feet. Pancreatic ß-cell function was determined by homeostasis model assessment of ß-cell function index, early-phase ß-cell function indices and total ß-cell function indices. Pearson correlation analysis and multiple linear stepwise regression analysis were carried out to explore the associations between ß-cell function indices and sudomotor function. RESULTS: Patients with lower early-phase ß-cell function had lower electrochemical skin conductance levels of hands and feet and higher asymmetry ratio of hands and feet. Both Pearson correlation analysis and multiple linear stepwise regression analysis showed significantly positive relationships between early-phase ß-cell function and electrochemical skin conductance levels of hands and feet, after controlling for potential confounders (P<0.05). CONCLUSIONS: Impaired early-phase ß-cell function was positively associated with sudomotor dysfunction in Chinese patients with type 2 diabetes. We speculated that impaired early-phase ß-cell function may be associated with the incidence of sudomotor dysfunction in patients with T2DM.

Continuous glucose monitoring defined time-in-range is associated with sudomotor dysfunction in type 2 diabetes.

BACKGROUND: Time in range (TIR), as a novel metric for glycemic control, has robust relevance with diabetic complications. Diabetic peripheral neuropathy (DPN) is characterized by sudomotor dysfunction. AIM: To explore the relationship between TIR obtained from continuous glucose monitoring (CGM) and sudomotor function detected by SUDOSCAN in subjects with type 2 diabetes. METHODS: The research enrolled 466 inpatients with type 2 diabetes. All subjects underwent 3-d CGM and SUDOSCAN. SUDOSCAN was assessed with electrochemical skin conductance in hands (HESC) and feet (FESC). Average feet ESC < 60 µS was defined as sudomotor dysfunction (+), otherwise it was sudomotor dysfunction (-). TIR refers to the percentage of time when blood glucose is between 3.9-10 mmol/L during 1 d period. RESULTS: Among the enrolled subjects, 135 (28.97%) presented with sudomotor dysfunction. Patients with sudomotor dysfunction (+) showed a decreased level of TIR (P < 0.001). Compared to the lowest tertile of TIR, the middle and the highest tertiles of TIR was associated with an obviously lower prevalence of sudomotor dysfunction (20.51% and 21.94% vs 44.52%) (P < 0.001). In addition, with the increase of TIR, HESC and FESC increased (P < 0.001). Regression analysis demonstrated that TIR was inversely and independently linked with the prevalence of sudomotor dysfunction after adjusting for confounding values (odds ratio = 0.979, 95%CI: 0.971-0.987, P < 0.001). CONCLUSION: The tight glycemic control assessed by TIR is of vitally protective value for sudomotor dysfunction in type 2 diabetes mellitus.

Associations of serum glucagon levels with glycemic variability in type 1 diabetes with different disease durations.

PURPOSE: Glucagon has been recognized as a pivotal factor implicated in the pathophysiology ofdiabetes. The purpose of this study is to investigate the dynamic secretion levels of serum glucagon (GLA) in patients with type 1 diabetes mellitus (T1DM) with different courses of disease, and to analyze its correlation with blood glucose fluctuation. METHODS: This observational study included 55 T1DM patients and divided into 3 groups according to the courses of disease. Group 1(the disease duration <1 year), Group 2(1≤the disease durations≤5), 3(the disease durations >5 years). All patients underwent a 100g standard steamed buns meal test,measuring the levels of serum glucose, glucagon, insulin, C-peptide in different points of time, and 48 of the total patients used continuous glucose monitoring system (CGMS) to monitor blood glucose. RESULTS: The fasting glucagon level in Group 1 was significantly higher than it in Group 2. Furthermore, the GLA1h, the GLA3h and the AUCGLA0-3h in Group 1 were greatly larger than those in Group 3. Referring to glycemic variability, the LBGI, AUC of hypoglycemia, the percentage of hypoglycemia time andthe times of nocturnal hypoglycemia in Group 1 were significantly lower than those in Group 3. Moreover,the fasting glucagon level was the independent factors to SD and MAGE. The AUCGLA0-3h were negatively correlated with MODD, LBGI, GRADE-hypo and AUC of nocturnal hypoglycemia. CONCLUSIONS: It is concluded that glucagon secretory function impairs with duration of type 1 diabetes extended and correlates to glycemic fluctuation, especially hypoglycemia.

Effect of Schisandra chinensis on interleukins, glucose metabolism, and pituitary-adrenal and gonadal axis in rats under strenuous swimming exercise.

OBJECTIVE: To investigate the effect of Chinese medicine (CM) Schisandra chinensis on interleukin (IL), glucose metabolism, and pituitary-adrenal and gonadal axis of rats after strenuous navigation and exercise. METHODS: A total of 45 Sprague-Dawley rats were randomized into the quiet control group, the stress group, and the CM group (15 in each group). The CM group received 2.5 g/kg of Schisandra chinensis twice per day for one week before modeling. Except the quiet controls, rats were trained using the Bedford mode for 10 days. On the 11th day, they performed 3 h of stressful experimental navigation and 3 h of strenuous treadmill exercise. The levels of serum testosterone (T), cortisol (CORT), luteinizing hormone (LH), IL-1, IL-2, and IL-6 were tested by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. The adrenal cortex ultrastructure was observed using electron microscopy. RESULTS: Compared with the quiet control group, after navigation and strenuous exercise, blood glucose was increased, and T level was decreased in the stress group (both P<0.01). The blood glucose, CORT, IL-1 and IL-2 levels were significantly reduced in the CM group (P<0.05 or P<0.01) as compared with the stress group. Electron microscopy revealed that the rats in the CM group had a smaller decrease in adrenal intracellular lipid droplets and higher levels of apoptosis than those in the stress group. CONCLUSIONS: Schisandra chinensis can reduce serum CORT and blood glucose levels in stressed rats. It appears to protect the cell structure of the adrenal cortex, and offset the negative effects of psychological stress and strenuous exercise related to immune dysfunction. Schisandra chinensis plays a regulatory role in immune function, and can decrease the influence of stress in rats.

CETP gene polymorphisms and risk of coronary atherosclerosis in a Chinese population.

BACKGROUND: Coronary atherosclerosis, the most common form of coronary artery disease (CAD), is characterized by accumulation of lipid in the walls of coronary arteries. Recent data from clinical trials have showed that high-density lipoprotein cholesterol (HDL-C) has causal role in the pathogenesis and development of coronary atherosclerosis. Cholesteryl ester transfer protein (CETP) is an important regulator of plasma HDL-C. Several genetic mutations in the CETP gene were found to be associated with HDL-C levels. The aim of the present study is to evaluate the association of HDL-C-related CETP polymorphisms and risk of coronary atherosclerosis. METHODS: We investigated the association of seven single nucleotide polymorphisms (SNP) (rs1800775, rs708272, rs5882, rs1532624, rs1864163, rs7499892, and rs9989419) in the CETP gene with the risk of coronary atherosclerosis and levels of HDL-C in a case-control study in China. Included in the study were 420 patients with coronary atherosclerosis and 424 healthy controls. SNP genotyping was performed by TaqMan allelic discrimination assay and serum lipid levels were measured by standard laboratory methods. RESULTS: Carriers of the AA and GA + AA genotypes of rs708272 had significant lower risks of coronary atherosclerosis (OR = 0.55, 95% CI: 0.36-0.85, p = 0.003; OR = 0.67, 95% CI: 0.50-0.90, p = 0.007, respectively) compared to those with GG genotype. These relations remained significant after adjustment for confounding effects of age, smoking, diabetes and hypertension. The rs1800775 polymorphism was significantly associated with serum levels of HDL-C in healthy controls (p = 0.04). Besides, rs708272 was in close linkage disequilibrium (LD) with rs1800775 in this study. CONCLUSIONS: Our findings indicated that CETP rs708272 may be associated with the risk of coronary atherosclerosis and rs1800775 may influence serum HDL-C levels in healthy controls in Chinese.

[Effect of early intervention with rhein on islet function in db/db mice].

OBJECTIVE: To investigate the hypoglycemic action of rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), one of the anthraquinone derivatives isolated from rhubarb, and study its effects on pancreatic beta-cells in db/db mice. METHODS: Thirty 4-week-old db/db mice were randomized for an 8-week treatment with intragastric administration of rhein (120 mg/kg, n=15) or placebo (1% natrium cellulose solution, n=15). After the treatment, intraperitoneal glucose tolerance test (IPGTT) was performed and the area under curve (AUC) of insulin levels in IPGTT was calculated to evaluate insulin secretory function. The AUC(INS0-30) was calculated to evaluate the early-phase insulin secretion. Immunohistochemical staining for insulin was performed to estimate the beta-cell mass, and beta-cell apoptosis was detected using TUNEL assay. RESULTS: Compared with the control group, rhein-treated group showed significantly reduced blood glucose concentrations at 0, 30, 60 and 120 min after glucose load with significantly higher insulin levels at 30, 60 and 120 min. The early-phase insulin secretion was also obviously increased. The beta-cell mass was obviously rescued by the 8-week treatment with rhein, which also notably improved the staining intensity of insulin and suppressed beta-cell apoptosis compared with the control. CONCLUSIONS: Early rhein treatment significantly improves glucose tolerance by restoring the early-phase insulin secretion in db/db mice and inhibiting the apoptosis of the beta-cells, suggesting the potential of rhein as a novel therapeutic agent for type 2 diabetes.

[Islet perifusion: a new method to evaluate first-phase insulin secretory function of beta-cell in vitro].

OBJECTIVE: To set up islet perifusion system, a new method to evaluate first-phase insulin secretory function of beta-cell in vitro. METHODS: Islet perifusion system was set up, including perifusion framework, waterbath system, infusion pump system, afferent system, islet capsule, and efferent system. Kinetics of insulin release in vitro was studied using the perifusion system. Pancreatic islets were isolated as mentioned above and used freshly after isolation. Size-matched 50 islets were placed in each column. Then the columns were gently closed with the top adaptors, immersed in vertical position and controlled temperature in the water bath at 37 degrees C. The perifusion medium was maintained at 37 degrees C in a water bath. And all columns were perifused in parallel at a flow rate of 0.5 ml/min with KRBB (2.8 mmol/L glucose) at 37 degrees C. After 60 min static incubation with KRBB (2.8 mmol/L glucose), the islets were stimulated in the continuous presence of a high concentration of 16.7 mmol/L glucose. Samples were collected every 20-second until 2 min, every 1 min until 5 min, thereafter every 5 min until 30 min. Samples were immediately stocked at -80 degrees C until further analysis. Insulin concentration was measured with an insulin RIA kit. RESULTS: An Islet perifusion system was established successfully, and kinetic curves of insulin secretion of db/m and db/db mice were traced out. CONCLUSION: An established islet perifusion system, could be widely used to evaluate insulin secretory function of beta-cell in in vitro research of diabetes.

[Effects of atorfastatin on the cognitive function of patients with vascular cognitive impairment and different apolipoprotein E genotypes].

OBJECTIVE: To study the effect of atorfastatin on the cognitive function of patients with vascular cognitive impairment (VCI) and different apolipoprotein E genotypes. METHODS: The ApoE polymorphism was genotyped by PCR sequencing and the patients were divided into Eepsilon4 carrier (epsilon4+) group (n=24) and epsilon4- group (n=51). All the patients were given 20 mg oral atorfastatin every evening. The indices of TC, TG, HDL-C, LDL-C, as well as the scores of MMSE and clock-drawing test were compared between the two groups before and 24 weeks after the treatment. RESULTS: Compared with those without epsilon4 allele, epsilon4+ patients had obviously increased plasma LDL level and lowered scores of MMSE. Plasma TC, TG and LDL-C were decreased significantly in the two groups after the treatment, and the improvement of TC was greater in patients without epsilon4 allele. The scores of MMSE increased significantly in patients with epsilon4 allele. The improvement in the scores of MMSE and clock-drawing test was greater in epsilon4+ group than in epsilon4- group. CONCLUSION: Atorfastatin may improve the cognitive function in patients with VCI carrying epsilon4 allele, the effect of which may not be related to lowed blood lipids.

[Salidroside protects the hypothalamic-pituitary-gonad axis of male rats undergoing negative psychological stress in experimental navigation and intensive exercise].

OBJECTIVE: To study the effects of salidroside on the function and ultramicro-pathological change of the hypothalamic-pituitary-gonadal (HPG) axis of male rats in experimental navigation and intensive exercise. METHODS: Six-week SD rats were randomized into 3 groups: non-stress control (NC, n = 10), training control (TC, n = 12) and salidroside treatment (ST, n = 12) group. Blood samples were collected from the NC rats that did not receive any stimulus after a 7-day intragastric administration of saline. The TC rats underwent a 10-day running training with increasing load on the treadmill followed by a 7-day intragastric administration of saline. The ST rats were subjected to the same process of running training as the TC group and received intragastric administration of salidroside. Then blood samples were immediately obtained and the levels of testosterone (T), corticosterone (CORT), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) measured by radioimmunoassay. The testis histopathology was observed by HE staining, and the ultrastructural changes of the pituitaries and testes investigated by electron microscopy. RESULTS: The serum T level was significantly lower in the TC than in the NC group, but showed no significant difference between the ST and NC groups. HE staining revealed no significant difference in testis histopathology among the 3 groups. Ultramicro-pathology showed that the secretory granules of the pituitary cells were significantly reduced in the TC rats compared with the NC ones; the number of the granules significantly increased in the ST group compared with the TC rats; and mitochondrial swelling, increase of electron density and decrease/disappearance of mitochondrial cristae were observed in the Leydig cells of the TC rats. But no significant differences were found in the testicular cells between the ST and NC groups. CONCLUSION: Negative psychological stress and intensive exercise can significantly suppress the function of the HPG axis in rats. Salidroside therapy has protective effect on the HPG axis.

[Effects of schisandra on the function of the pituitary-adrenal cortex, gonadal axis and carbohydrate metabolism in rats undergoing experimental chronic psychological stress, navigation and strenuous exercise].

OBJECTIVE: To investigate the effects of schisandra on the function of the pituitary-adrenal cortex, gonadal axis and carbohydrate metabolism in male rats undergoing experimental chronic psychological stress, navigation and strenuous exercise. METHODS: Thirty-four SD rats were randomly allocated into a non-stress group (Group A), a stress control group (Group B) and a schisandra group (Group C). The latter two groups received 10 days of Benford's high-intensity training, followed by 3 hours of wearing floating with psychological stress and another 3 hours of running at the speed of 26.7 m/min. Then blood samples were immediately obtained for the measurement of the levels of testosterone (T), corticosterone (CORT), luteinizing hormone (LH) and blood glucose (Glu). Meanwhile the adrenal gland was excised and its cortex ultrastructure observed under the electron microscope. RESULTS: The Glu level was increased while the T level decreased significantly in Group B as compared with Group A. The CORT level remained unchanged in Group B. Both the Glu and CORT levels were significantly reduced in Group C in comparison with B. However, no significant differences were found in serum LH levels among the three groups. And electron microscopy revealed a reduction of lipid droplets and apoptosis of the adrenal cortex cells in Group B as compared with C. CONCLUSION: Schisandra can reduce the levels of CORT and Glu and protect the structure of the adrenal cortex.

[Experimental navigation and deuteroexhaustive exercise suppress the function of the hypothalamic-pituitary-testicle axis in rats].

OBJECTIVE: To study the effects of experimental navigation and deuteroexhaustive exercise on the serum levels of testosterone (T), corticosterone (CORT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). METHODS: Thirty-six male SD rats were randomly divided into an experimental navigation group (Group A), which underwent 180 min wearing floating with psychological stress, a deuteroexhaustive exercise group (Group B), which were subjected to 120 min intensive running on the treadmill after the accomplishment of the same procedure as Group A, and a control group (Group C). Blood samples were obtained at the end of the experiment to determine the T, CORT, LH and FSH of the rats. RESULTS: Compared with Group C, serum T was statistically decreased in Group A and B (P < 0.05), while CORT was increased slightly in Group A and significantly in Group B (P < 0.05). A statistically lower level of serum LH was observed in Group B (P < 0.05), but no significant differences were found in serum FSH among the three groups. CONCLUSION: Stresses of experimental navigation and intensive exercise suppress the function of the hypothalamic-pituitary-testicle axis in rats.

[Effects of angiotensin II type 1 receptor blocker on islet of diabetic db/db mice].

OBJECTIVE: Several epidemiological studies suggested that treatment with angiotensin II type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of hyperactive local intra-islet renin-angiotensin system in diabetes state and relieve hyperglycemia using diabetic (db/db) mice. METHODS: 8-week-old db/db mice were randomized to candesartan cilexetil 1 mg/kg, candesartan cilexetil 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were given with placebo and acted as non-diabetic controls. After 6 weeks of treatment, intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, and electron microscopy observation of the pancreatic islet cells were performed. RESULTS: Chronic candesartan treatment provided a slight improvement of glucose tolerance, but greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies. Furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal. CONCLUSIONS: After diabetes is initiated, candesartan treatment does not reverse the state of diabetes, but it slightly improves glucose tolerance, and protects beta-cell function by attenuating oxidative stress and ultrastructure disruption. These benefits are independent of blood pressure lowering. The characteristics of candesartan may make itself a novel therapeutic means for protecting from progressive beta-cell failure in diabetes.

Angiotensin II receptor blocker provides pancreatic beta-cell protection independent of blood pressure lowering in diabetic db/db mice.

AIM: Several epidemiological studies have suggested that treatment with angiotensin II type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of the hyperactive local intra-islet renin-angiotensin system in the diabetes state. METHODS: Eight-week-old db/db mice were randomized to candesartan 1 mg/kg, candesartan 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were treated with placebo and acted as nondiabetic controls. After 6 weeks' treatment, an intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, CD31, azan staining and an electron microscopy observation were performed. RESULTS: Chronic candesartan treatment provided an improvement of glucose tolerance, and greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as attenuating intra-islet fibrosis and improving blood supply in the islet. In the electron microscopy observation, candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies; furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal. Both the benefits of reducing oxidative stress and ultrastructure protection were in a dose-dependent and blood pressure-independent manner. CONCLUSION: After diabetes was initiated, candesartan treatment could not reverse the state of diabetes, but it effectively improved glucose tolerance and protected beta-cell function by attenuating oxidative stress, islet fibrosis, sparsity of blood supply and ultrastructure disruption in a dose-dependent and blood pressure-independent manner.

[Immunosuppressive therapies in patients with Graves' ophthalmopathy].

OBJECTIVE: To compare the efficacy and tolerability of 4 immunosuppressants in treating Graves' ophthalmopathy (GO). METHODS: Seventy-five untreated GO patients were enrolled in this study. The diagnosis of GO was based on the presence of the typical clinical features and exclusion of possible cranial/orbital diseases. In group A, 31 patients were randomly assigned to receive either prednisone (n = 16, treatment completed in 13 cases with doses of 40 mg, 20 mg and 10 mg per day for 4 weeks) or tripterygium wilfordii multiglycoside (TW, n = 15, 30 - 60 mg per day); in group B, 23 adults were randomized to receive cyclosporin A (CsA, n = 11, 5 - 6 mg per kilogram of body weight per day) or mycophenolate mofetil (MMF, n = 12, 16 - 18 mg per kilogram of body weight per day) therapy. The remaining 21 patients (control group) were given only anti-thyroid drugs and levo-thyroxine. The disease severity and therapeutic response were quantitatively assessed according to the Ophthalmopathy Index Scoring System from Given-Wilson (1989) with sensible modification. Improvement or progression of ophthalmopathy was defined if the difference, either increase or decrease, of the score, reached 3 or more in the ophthalmopathy index. If this did not occur, a lack of response was indicated. RESULTS: After 12 weeks, 7 of the 13 treated with prednisone improved and the remaining 6 lacked response. In the TW group, 10 of the 15 responded to the therapy; 5 had no change. There was no significant difference in clinical response between the above 2 groups (P > 0.05). Five CsA-treated and 11 MMF-treated patients responded to the therapy (45% vs 92%; P < 0.05). It seems that MMF is more effective than CsA in the treatment of GO, although a significant decrease (P < 0.01) in the mean score of the CsA group has also been shown at the end of the course. Four of the controls improved, 5 (24%) showed worsening of ophthalmopathy, and the remaining 12 (57%) had no significant change. In the prednisone group, 3 gained body weight by more than 5%, and 2 developed impaired glucose tolerance. These two and one of the three weight gaining patients ceased the therapy. CONCLUSIONS: New immunosuppressant MMF may be more effective than CsA in the treatment of Graves' ophthalmopathy. TW may be equally effective as and perhaps better tolerable than prednisone in the immunotherapy of Graves' ophthalmopathy.