Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load.

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.

Identification of physical and psychosocial problems associated with diabetic nephropathy using the International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus.

BACKGROUND: We previously demonstrated validation of the Comprehensive International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus (ICF-CS for DM) in patients with diabetic nephropathy (DMN). The objective of the present study was to identify differences in experience of physical and psychosocial problems between DMN patients with and without hemodialysis (HD), and diabetes patients without nephropathy using the ICF-CS for DM. METHODS: A total of 302 diabetes outpatients (men, 68 %; mean age, 62 years) were interviewed using four components of the ICF-CS for DM including "Body functions", "Body structures", "Activities and participation", and "Environmental factors". RESULTS: The mean number of categories in which difficulty was experienced in the four components was significantly greater in DMN patients with HD followed by DMN patients without HD, and diabetes patients without nephropathy (23.9 vs. 18.0 vs. 13.1, respectively). Multivariate logistic regression models revealed that, compared with diabetes patients without nephropathy, diabetes patients with nephropathy were more likely to have difficulty with physical problems and social activities and participation. Among DMN patients, dialysis patients were found to have larger numbers of problems, and face difficulty with employment status after adjusting for sex, age, type, and duration of diabetes. CONCLUSION: The results of this study using the ICF-CS for DM identified the areas for improvement among physical and psychosocial problems in DMN patients with and without HD in contrast to diabetes patients without nephropathy.

Validation of the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Diabetes Mellitus in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DMN) is the most common cause of end-stage renal disease. Progression of DMN leads to impairment of physical activity, restriction of daily activities, and diminished social participation. Therefore, the precise assessment of the physical and psychosocial problems of DMN patients is important. The objective of this study was to validate the Comprehensive International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus (ICF-CS for DM) from the perspective of DMN patients. METHODS: A total of 176 DMN outpatients were interviewed using the ICF-CS for DM. Content and construct validity were evaluated. Patients were divided into 2 groups: DMN patients without hemodialysis (HD) (non-HD group) and DMN patients undergoing HD (HD group). Content validity was evaluated based on the frequency of patients who had a problem in each category. For construct validity, the patients were divided into two groups based on DM duration and hemoglobin A1C levels. RESULTS: Content validity evaluation revealed 58 categories reported as problem categories: 39 categories in the non-HD group and 50 categories in the HD group. Construct validity evaluation showed that longer DM duration and poor glycemic control contributes to increased problems. CONCLUSIONS: Content and construct validity of the ICF-CS for DM was supported from the DMN patients' perspective. Some categories of the "Environmental factors" component need further studies to be appropriate.

Black soybean extract reduces fatty acid contents in subcutaneous, but not in visceral adipose triglyceride in high-fat fed rats.

It is known that black soybean (BS) extract, rich in polyphenols, has beneficial effects against obesity, inflammation and insulin resistance. However, detailed effects of BS on lipid metabolism have not been documented well. In the present study, we compared fatty acid composition in visceral and subcutaneous adipose tissues of high-fat fed (HFF) rats and BS administered HFF rats. Black soybean administration for 6 weeks influenced neither body nor adipose tissue weights, blood glucose, plasma insulin levels, or insulin sensitivity. However, BS reduced several saturated (C14:0 and C16:0), monounsaturated (C14:1n-5 and C18:1n-9) and n-6 polyunsaturated (C18:2n-6, C20:3n-6, C20:4n-6 and C22:4n-6) fatty acid contents in subcutaneous fat without any change in n-3 polyunsaturated fatty acid contents. No such effect was observed in fatty acid composition in visceral fat. Long-chain fatty acids are involved in regulation of inflammation. Therefore, those reduced fatty acids may be linked to the effects on suppressing inflammation.

Effects of SGLT2 Inhibitors and DPP-4 Inhibitors on Advanced Glycation End Products.

Clinical trials have revealed that sodium glucose cotransporter 2 (SGLT2) inhibitors suppress the onset of heart failure and cardiovascular death in diabetic patients. On the other hand, few reports have been published concerning such effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. We undertook the present study to evaluate the effects of SGLT2 inhibitors and DPP-4 inhibitors on the advanced glycation end products (AGEs), well known as a risk factor for the development of cardiovascular disorders.Type 2 diabetes mellitus were divided into two groups and treated with either SGLT2 inhibitors or DPP-4 inhibitors for 3 months. Before and after the 3-month treatment period with each drug, the AGEs and diabetes-related parameters were measured. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured as one of the AGEs.In the SGLT2 inhibitor group, both the blood HbA1c and MG-H1 levels decreased significantly after the 3-month treatment period. In the DPP-4 inhibitor group, only the blood HbA1c level decreased significantly, with no significant change of the blood MG-H1 level.SGLT2 inhibitor reduced both the blood levels of HbA1c and AGEs (MG-H1). Considering that the blood levels of AGEs are associated with the risk of heart failure and cardiovascular disorders, the results of the present study suggest that the effect of SGLT2 inhibitors in suppressing cardiovascular death might be mediated by the reduction in the blood levels of AGEs induced by this class of drugs. DPP-4 inhibitors showed no significant effects on the blood levels of AGEs.

Effects of electrical microstimulation of peripheral sympathetic nervous fascicle on glucose uptake in rats.

Artificial pancreas systems control insulin-mediated glucose uptake. Although these systems are widely used in the clinical setting, they are still fraught with structural and biological problems. The non-insulin mediated glucose uptake (NIMGU) mechanism could be an alternative candidate as a target system for the artificial control of peripheral glucose uptake. Although the sympathetic nervous system is known to be one of the regulators of NIMGU, the effects of peripheral sympathetic activation on glucose uptake have not been well documented. We electrically stimulated a sympathetic nerve fascicle to clarify the possibility of controlling peripheral glucose uptake. A sympathetic signal was microneurographically obtained in the unilateral sciatic nerve in normal (NRML), insulin-resistant high-fat-fed (HFF), and streptozotocin-induced insulin-depleted (STZ) rats, and electrical stimulation was applied via the microelectrode (microstimulation). The microstimulation was also applied to sites other than the sympathetic fascicles in an additional group of normal rats (NSYMP group). The stimulation applied to the sympathetic fibers resulted in an immediate and transient decrease of blood glucose (BG) in the NRML, HFF, and STZ groups, with little change in the plasma insulin. The change in BG level seemed to depend on the basal BG level (NRML < HFF < STZ). In contrast, no reduction in BG was observed in the NSYMP group. These results suggest that microstimulation in the peripheral sympathetic fascicle could enhance glucose uptake in peripheral tissues-independently of insulin function-and show an alternative possibility for controlling glucose uptake.

Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus.

Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.

Effects of Dapagliflozin on Adipose and Liver Fatty Acid Composition and mRNA Expression Involved in Lipid Metabolism in High-Fat-Fed Rats.

BACKGROUND: SGLT2 inhibitor enhances not only glucose excretion but also fatty acid utilization. Those facts suggest that SGLT2 inhibitor affects fat accumulation and lipid storage. OBJECTIVE: In the present study, we evaluated the effects of dapagliflozin on fatty acid composition and gene expression involved in fatty acid metabolism in rat adipose and liver tissues. METHODS: We administered 1 mg/kg/day dapagliflozin for 7 weeks to male high-fat-fed rats (DAPA group), and then weights and 22 fatty acid contents in the epididymal (EPI), mesenteric (MES), retroperitoneal (RET), and subcutaneous (SUB) adipose tissues, and the liver were compared with the vehicle-administered control group. RESULTS: In the EPI, RET, and SUB in the DAPA group, contents of several fatty acids were lower (P<0.05) than those in the control group, while no significant difference was detected in tissue weight. In the MES, tissue weight and a wide variety of fatty acid contents, including saturated, monounsaturated, and polyunsaturated fatty acids, were lower (P<0.05). As for the liver tissue, no significant difference was observed in fatty acid contents between the groups. mRNA expression of Srebp1c in EPI was significantly higher (P<0.05) in the DAPA group than in the control group, while Scd1 expression in the liver was lower (P<0.01). CONCLUSION: These results suggest that dapagliflozin might suppress lipid accumulation especially in the MES, and could reduce contents of fatty acids not in the liver but in adipose tissues in high-fat-fed rats. In addition, dapagliflozin could influence mRNA expression involved in lipogenesis in the EPI and liver.

Influence of Luseogliflozin on Vaginal Bacterial and Fungal Populations in Japanese Patients With Type 2 Diabetes.

BACKGROUND: Selective sodium-glucose cotransporter 2 inhibitors, known to lower the blood glucose levels by promoting the urinary glucose excretion, can predispose to genitourinary infections. This prospective study investigated the influence of selective sodium-glucose cotransporter 2 inhibitors luseogliflozin on the vaginal flora of the pre- and postmenopausal women with type 2 diabetes mellitus. METHODS: Twelve premenopausal and 24 postmenopausal female Japanese patients with type 2 diabetes mellitus took luseogliflozin 2.5 mg once daily for 6 months. The intravaginal fungal and bacterial populations, together with the body weight and serum parameters of diabetes mellitus and lipid metabolism were measured before and after the treatment. RESULTS: After luseogliflozin treatment, the body weight, body mass index and hemoglobin A1c decreased, and the serum levels of high-density lipoprotein cholesterol increased significantly. Luseogliflozin treatment revealed to increase vaginal colony concentrations of Enterococcus faecalis (P = 0.0077) and E. coli (P = 0.0201) in premenopausal patients, and Enterococcus faecalis (P = 0.0051) and Candida albicans (P = 0.0355) in postmenopausal patients. In both pre- and postmenopausal patients, colony concentrations of Staphylococcus spp. had decreased (P = 0.0261 and P = 0.0161). CONCLUSIONS: Treatment with selective sodium-glucose cotransporter 2 inhibitors luseogliflozin was associated with changes of the vaginal flora. These findings provide basic data on the increased susceptibility to genital infections during luseogliflozin treatment.

The Effects of Pemafibrate in Japanese Patients with Type 2 Diabetes Receiving HMG-CoA Reductase Inhibitors.

OBJECTIVE: The combination therapy of HMG-CoA reductase inhibitors (statins), which are anti-hyperlipidemic agents, and fibrates may increase the risk of hepatic dysfunction and myopathy, therefore, this combination required careful administration for patients. In the present study, the effects of combination therapy of pemafibrate, a novel fibrate, and statins, was evaluated. METHODS: Pemafibrate was administered for 6 months as an add-on to statin therapy in 27 type 2 diabetes patients with dyslipidemia already receiving statins for 6 months (combination group), and the efficacy and safety of the combination therapy in comparison with a pemafibrate monotherapy group was examined. RESULTS: In the combination group, a decrease in serum total cholesterol levels was observed after 6 months of pemafibrate treatment compared to baseline, along with an increase in HDL-cholesterol. While serum triglyceride level was reduced, HbA1c level was elevated in both the groups. Serum creatinine kinase level, which is an indicator of myopathy, was lowered in the combination group. In addition, a decrease in γ-glutamyl transpeptidase, a parameter of hepatic dysfunction, was observed in the combination group. CONCLUSION: The statin-pemafibrate combination therapy in type 2 diabetes patients with dyslipidemia improved lipid metabolism safely without increasing the risk of hepatic dysfunction and myopathy.

Effect of Treatment With Sodium-Glucose Cotransporter 2 Inhibitor on the Initiation of Continuous Positive Airway Pressure Therapy in Type 2 Diabetic Patients With Obstructive Sleep Apnea Syndrome.

BACKGROUND: Obese patients with type 2 diabetes mellitus often develop obstructive sleep apnea syndrome (OSAS). In this study, continuous positive airway pressure (CPAP) was initiated in Japanese patients with type 2 diabetes mellitus who developed OSAS during treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the effect of the SGLT2 inhibitor therapy on the patients was investigated. METHODS: The study was conducted in outpatients with type 2 diabetes mellitus with serum hemoglobin A1c (HbA1c) values of ≥ 6.5% who developed OSAS. The patients were divided into two groups according to whether they were receiving treatment with an SGLT2 inhibitor or with other oral hypoglycemic agents: the SGLT2 inhibitor group (n = 9) and non-SGLT2 inhibitor group (n = 7). The patients in the former group were under treatment with one of the following three SGLT2 inhibitors: luseogliflozin (2.5 mg/day), dapagliflozin (5 mg/day) and empagliflozin (10 mg/day). The patients took the drugs once daily, before or after breakfast. The patients were initiated on CPAP therapy for OSAS, and their weight, body mass index (BMI), serum HbA1c level, lipid profile, liver function parameters, serum uric acid, and apnea-hypopnea index (AHI) measured before the initiation of CPAP therapy (baseline) were compared with the values measured 3 months after the start of CPAP therapy. RESULTS: The AHI decreased significantly after 3 months of CPAP therapy, as compared to that at the baseline, in both the SGLT2 inhibitor and non-SGLT2 inhibitor groups. There was no significant change in the serum HbA1c value after 3 months of CPAP therapy as compared to that at the baseline in either group. The body weight and BMI increased significantly after 3 months of CPAP therapy in the SGLT2 inhibitor group, but not in the non-SGLT2 inhibitor group. CONCLUSION: The body weight and BMI increased significantly after 3 months of CPAP therapy initiated for OSAS in the type 2 diabetic patients who were receiving SGLT2 inhibitor therapy. Thus, when CPAP therapy is adopted for an obese diabetic patient with OSAS, it should be borne in mind that the body weight may increase if the patient is receiving SGLT2 inhibitor treatment.

Effects of Additional Administration of a Selective Inhibitor of Sodium Glucose co-transporter-2 Inhibitor on the Glycemic Control in Japanese Type 2 Diabetes Mellitus Patients Receiving Treatment with a Dipeptidyl Peptidase-4 Inhibitor.

We conducted this study to determine whether additional administration sodium-glucose co-transporter 2 (SGLT2) inhibitor might provide further improvement of glycemic control and also to explore any advantages in Japanese type 2 diabetes patients showing relatively good glycemic control under treatment dipeptidyl peptidase-4 (DPP-4) inhibitors. We divided the patients in two groups, MT group and CT group. The MT group were continued on the DPP-4 inhibitor treatment for 6-months, and CT group were additionally administered an SGLT2 inhibitor treatment for 6-months. The MT group showed a significant decrease of hemoglobin A1c (HbA1c), but a significant increase of body weight, body mass index and serum uric acid, compared to the baseline values, while the CT group showed a significant decrease of HbA1c, body weight, BMI, and serum uric acid, and also a significant increase of serum HDL-cholesterol and decrease of serum triglyceride levels. Furthermore, this group showed a significant decrease of serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (γ-GTP), which are markers of liver function. These results suggest that the combination therapy is useful, in particular, for the treatment of type 2 diabetes mellitus patients with hyperlipidemia and liver dysfunction. Among the SGLT2 inhibitors added to the DPP-4 inhibitor treatment, the decreases of serum levels of AST, ALT and γ-GTP were particularly significant in the group receiving luseogliflozin, suggesting that the combination of a DPP-4 inhibitor with luseogliflozin is particularly effective for the treatment of type 2 diabetes mellitus patients with liver dysfunction.

Effects of Concomitant Administration of a Dipeptidyl Peptidase-4 Inhibitor in Japanese Patients with Type 2 Diabetes Showing Relatively Good Glycemic Control Under Treatment with a Sodium Glucose Co-Transporter 2 Inhibitor.

We conducted this study to determine whether additional administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor might provide further improvement of the glycemic control in Japanese type 2 diabetes patients showing relatively good glycemic control under treatment with a sodium glucose co-transporter 2 (SGLT2) inhibitor. Five SGLT2 inhibitor (luseogliflozin, dapagliflozin, tofogliflozin, empagliflozin and canagliflozin) preparations and five DPP-4 inhibitor (sitagliptin, vildagliptin, alogliptin, anagliptin and linagliptin) preparations were used. The results showed that monotherapy with SGLT2 inhibitor produced significant decreases of the body weight and BMI, hemoglobin A1c (HbA1c) also decreased, but not to a significant extent. However, decreases of the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GTP) and uric acid were observed in this group. On the other hand, in type 2 diabetes patients treated concomitantly with a DPP-4 inhibitor and SGLT2 inhibitor, significant decrease of the HbA1c was observed, indicating the favorable effect of the concomitant therapy. The body weight and BMI decreased. As for the serum lipid profile, elevation of the serum HDL-cholesterol (HDL-C) was observed. Furthermore, AST, ALT, γ-GTP and uric acid decreased in the combined treatment group. Then, the therapeutic responses to concurrent administration with SGLT2 inhibitor of each of the 5 individual DPP-4 inhibitors used in this study were analyzed. The results showed that concomitant administration of sitagliptin, a DPP-4 inhibitor, with the SGLT2 inhibitor yielded the best results in terms of the lowering of the HbA1c and improvement of the serum lipid profile.

Effects of Concomitant Administration of Sodium Glucose Co-transporter 2 Inhibitor with Insulin on Hemoglobin A1c, Body Mass Index and Serum Lipid Profile in Japanese Type 2 Diabetic Patients.

In patients with type 2 diabetes mellitus who show suboptimal blood glucose control under insulin therapy alone, concomitant treatment with an additional hypoglycemic agent that differs in its mechanism of action from insulin may be considered. We conducted this clinical trial to explore whether further control of increased blood glucose level can be achieved with concomitant use of sodium glucose co-transporter 2 (SGLT2) inhibitor as concomitant with other hypoglycemic therapy, as compared to SGLT2 inhibitor monotherapy, in patients with type 2 diabetes mellitus showing decrease in blood glucose level but less than the effect of insulin monotherapy and there was no significant differences. In the SGLT2 inhibitor monotherapy group, decreases of the serum hemoglobin A1c (HbA1c) level, body weight, body mass index (BMI) and serum triglyceride, and elevation of the serum high density lipoprotein cholesterol concentration were observed as compared to the baseline values. In the type 2 diabetic patients under insulin therapy who received combined insulin plus SGLT2 inhibitor therapy, however decreases in the body weight and BMI, with only a tendency towards decrease of the serum HbA1c value, not reaching statistical significance, were observed. The combined therapy group also showed no appreciable changes of the serum triglyceride level, while the serum adiponectin level increased. The present study data indicate that combined insulin plus SGLT2 inhibitor treatment failed to afford any further improvement of the blood glucose control, as compared to SGLT2 monotherapy, in Japanese type 2 diabetic patients.

Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: Consumption of polyunsaturated fatty acids (PUFA) improves the lipid metabolism of diabetics, leading to prevents of arteriosclerosis. Exact relationship between saturated fatty acids (SFA) or PUFA and the insulin resistance of diabetics are unknown. SUBJECTS AND METHODS: We investigated the relationship between the serum concentrations of saturated and unsaturated fatty acids and the homeostasis model insulin resistance index (HOMA-R) in Japanese patients with type 2 diabetes mellitus. RESULTS: The SFA, i.e., lauric acid, myristic acid, palmitic acid, and stearic acid; the monounsaturated fatty acids (MUFA), i.e., palmitoleic acid, oleic acid, and erucic acid; and the PUFA, i.e., eicosadienoic acid, dihomo-gamma-linolenic acid, docosatetraenoic acid, and docosapentaenoic acid were positively correlated with HOMA-R. However, no correlations were found between HOMA-R and SFA, i.e., arachidic acid, behenic acid, and lignoceric acid; the MUFA, i.e., eicosenoic acid and nervonic acid; and the PUFA, i.e., linoleic acid, gamma-linolenic acid, linolenic acid, 5-8-11 eicosatrienoic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. CONCLUSIONS: Some PUFA as well as SFA were positively correlated with HOMA-R. These results indicate that the intake of diet fatty acid must be well balanced in diabetic patients and it is not always true to refrain from taking SFA and increase the unsaturated fatty acids in their diets.

Gender differences in the perception of difficulty of self-management in patients with diabetes mellitus: a mixed-methods approach.

AIM: The aim of this study was to examine the challenges of self-management of diabetes comparing gender. METHODS: Sixty-four women and 129 men (mean age 63 vs. 60 years) with diabetes mellitus (DM) were interviewed using 12 categories (classification codes b1300, d240, d570, d620, d845, d920, e410 + e414, e420, e425, e465, e560) related to self-care management selected from 99 categories of the International Classification of Functioning, Disability and Health (ICF) Core Set for DM. In a mixed-methods analysis, interviews were analyzed according to the Grounded Theory approach, and gender effects on ICF categories related to self-care management were investigated using logistic models. RESULTS: In quantitative data, compared with men, women tended to experience greater difficulty obtaining foods/ingredients for well-balanced meals to maintain appropriate glucose level (P = 0.004); handling stress and other psychological demands around diabetes treatment (P = 0.034); and social norms, practices, and ideologies that defined an experience of unpleasant treatment after disclosure of DM diagnosis to close family and friends (P = 0.023). Qualitative data shows that women perceived prejudice against people with DM from close family, friends, and neighbors. In contrast, men reported excessive media information on diabetes treatment, which induced prejudice by family members and at the workplace. CONCLUSIONS: Women were more likely to be sensitive to attention from close family and friends, whereas men were more likely to be occupied by work and daily living concerns. Health professionals should pay attention to such gender differences in a patient-professional relationship.

PPARγ activation alters fatty acid composition in adipose triglyceride, in addition to proliferation of small adipocytes, in insulin resistant high-fat fed rats.

It was reported that adipocyte size is potentially correlated in part to amount of long chain polyunsaturated fatty acids (PUFAs) and insulin resistance because several long chain PUFAs can be ligands of peroxisome proliferator-activated receptors (PPARs). In our previous study, marked reduction of PUFAs was observed in insulin-resistant high-fat fed rats, which may indicate that PUFAs are consumed to improve insulin resistance. Although PPARγ agonist, well known as an insulin sensitizer, proliferates small adipocytes, the effects of PPARγ agonist on FA composition in adipose tissue have not been clarified yet. In the present study, we administered pioglitazone, a PPARγ agonist, to high-fat fed rats, and measured their FA composition of triglyceride fraction in adipose tissue and adipocyte diameters in pioglitazone-treated (PIO) and non-treated (control) rats. Insulin sensitivity was obtained with hyperinsulinemic euglycemic clamp. Average adipocyte diameter in the PIO group were smaller than that in the control one without change in tissue weight. In monounsaturated FAs (MUFAs), 14:1n-5, 16:1n-7, and 18:1n-9 contents in the PIO group were lower than those, respectively, in the control group. In contrast, 22:6n-3, 20:3n-6, 20:4n-6, and 22:4n-6 contents in the PIO group were higher than those, respectively, in the control group. Insulin sensitivity was higher in the PIO group than in the control one. These findings suggest that PPARγ activation lowered MUFAs whereas suppressed most of C20 or C22 PUFAs reduction, and that the change of fatty acid composition may be relevant with increase in small adipocytes.

NO-1886 (ibrolipim), a lipoprotein lipase activator, increases the expression of uncoupling protein 3 in skeletal muscle and suppresses fat accumulation in high-fat diet-induced obesity in rats.

Although the lipoprotein lipase (LPL) activator NO-1886 shows antiobesity effects in high-fat-induced obese animals, the mechanism remains unclear. To clarify the mechanism, we studied the effects of NO-1886 on the expression of uncoupling protein (UCP) 1, UCP2, and UCP3 in rats. NO-1886 was mixed with a high-fat chow to supply a dose of 100 mg/kg to 8-month-old male Sprague-Dawley rats. The animals were fed the high-fat chow for 8 weeks. At the end of the administration period, brown adipose tissue (BAT), mesenteric fat, and soleus muscle were collected and levels of UCP1, UCP2, and UCP3 messenger RNA (mRNA) were determined. NO-1886 suppressed the body weight increase seen in the high-fat control group after the 8-week administration (585 +/- 39 vs 657 +/- 66 g, P < .05). NO-1886 also suppressed fat accumulation in visceral (46.9 +/- 10.4 vs 73.7 +/- 14.5 g, P < .01) and subcutaneous (43.1 +/- 18.1 vs 68.9 +/- 18.8 g, P < .05) tissues and increased the levels of plasma total cholesterol and high-density lipoprotein cholesterol in comparison to the high-fat control group. In contrast, NO-1886 decreased the levels of plasma triglycerides, nonesterified free fatty acid, glucose, and insulin. NO-1886 increased LPL activity in soleus muscle (0.082 +/- 0.013 vs 0.061 +/- 0.016 mumol of free fatty acid per minute per gram of tissue, P < .05). NO-1886 increased the expression of UCP3 mRNA in soleus muscle 3.14-fold (P < .01) compared with the high-fat control group without affecting the levels of UCP3 in mesenteric adipose tissue and BAT. In addition, NO-1886 did not affect the expression of UCP1 and UCP2 in BAT, mesenteric adipose tissue, and soleus muscle. In conclusion, NO-1886 increased the expression of UCP3 mRNA and LPL activity only in skeletal muscle. Therefore, a possible mechanism for NO-1886's antiobesity effects in rats may be the enhancement of LPL activity in skeletal muscle and the accompanying increase in UCP3 expression.

Effects of aldose reductase inhibitor on microneurographically assessed peripheral sympathetic nerve activity in rats.

Autonomic neuropathy, one of the serious complications of diabetes, decreases quality of life. Aldose reductase inhibitor (ARI) blocks sorbitol production, and results in prevention of damage of nerve fibers. Beneficial effects of ARI have usually been confirmed through nerve conduction velocity tests in motor and sensory nerves. On the other hand, few reports have dealt with the effects of ARI on the small fiber activity such as sympathetic nerve one. In the present study, we administered eparlestat, ARI orally for 3weeks, to streptozotocin-induced diabetic (STZ+ARI) rats, and then recorded peripheral sympathetic nervous signal detected with microneurographic technique. Action potentials (APs) and bursts of APs were detected from the recorded signal, and their rates and incidences (=rates/heart rate) were compared with those in non-diabetic control (normal) and ARI-untreated streptozotocin-induced diabetic (STZ) rats. While streptozotocin and/or epalrestat did not influence burst parameters in all the three groups, AP parameters in the STZ+ARI and normal groups were higher than those in the STZ group. However, response of AP parameters to the intravenous glucose administration (IVGA) was not large in the STZ+ARI group, similar to that of the STZ group and different from that of the normal group in which AP parameters increased after IVGA. The results suggest that epalrestat may prevent sympathetic nerve activity (SNA) from reduction under hyperglycemic and insulin-depleted conditions, that enhancement of SNA was not induced after IVGA under that condition, and that AP parameters might be useful to assess the degree of neuropathy.

Black soybean extract improves lipid profiles in fenofibrate-treated type 2 diabetics with postprandial hyperlipidemia.

Black soybeans (Glycine max (L.) Merr.) are known to be rich in polyphenols, including anthocyanins, and they have been consumed since ancient times for their beneficial effects on health. In addition, it has been reported that black soybean (BS) seed coat may ameliorate obesity and insulin resistance. In the present study, we administered BS extract to type 2 diabetics for 2 months to investigate the effects of BS on glycemic control and lipid metabolism parameters. In addition, we administered BS and antihyperlipidemic agent, fenofibrate, to patients with type 2 diabetes complicated by postprandial hyperlipidemia for 2 months and assessed the combined effects of fenofibrate and BS on serum lipid profile. The results showed that administration of the BS alone had no effect on the blood glucose or lipid levels, but that administration of fenofibrate alone and fenofibrate in combination with the BS significantly lowered their serum triglyceride (TG) level at fasting state, and the percent decrease in the serum TG level after combined administration was significantly higher than in the subjects who received fenofibrate alone. Furthermore, the serum LDL cholesterol concentration, which did not decrease when fenofibrate was administered alone, decreased significantly when the BS and fenofibrate were administered in combination. These results suggest that combined administration of the BS with fenofibrate enhanced the antihyperlipidemic action of fenofibrate, and the results of this study demonstrated the usefulness of the BS in clinical practice.