Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic ß-cells in db/db mice: The earlier and longer, the better.

AIMS: We compared the protective effects of sodium glucose co-transporter (SGLT) 2 inhibitor luseogliflozin on pancreatic ß-cells between early and advanced stages of diabetes and between short- and long-term use. MATERIALS AND METHODS: Diabetic db/db mice were treated with luseogliflozin for 2 weeks in an early stage of diabetes (7-9 weeks of age) and an advanced stage of diabetes (16-18 weeks) for a longer period of time (7-18 weeks). We performed various morphological analyses of pancreatic islets and examined gene expression profiles in islets after such treatment. RESULTS: In diabetic db/db mice, insulin biosynthesis and secretion were markedly increased by luseogliflozin in an early stage of diabetes but not in an advanced stage. In addition, ß-cell mass was preserved by luseogliflozin only in an early stage. Furthermore, when db/db mice were treated with luseogliflozin for a longer period of time, starting from an early stage, ß-cell function and mass were markedly preserved even after a longer period of time compared to untreated db/db mice. CONCLUSION: Luseogliflozin exerts more protective effects in an early stage of diabetes compared to an advanced stage, and longer-term use of luseogliflozin exerts more beneficial effects on pancreatic ß-cells compared to short-term use.

Seven-year Observational Study on the Association between Glycemic Control and the New Onset of Macroangiopathy in Japanese Subjects with Type 2 Diabetes.

Objective To examine the association between glycemic control and the new onset of macroangiopathy in Japanese subjects with type 2 diabetes. Methods We examined seven-year follow-up data for 572 patients. We divided the subjects by the average of seven-year glycemic control based on the guidelines. First, we excluded the subjects with a past history of macroangiopathy and then examined the incidence of the new onset of macroangiopathy. Results The incidence of ischemic heart disease (IHD) was 1.0% per year, and that of cerebral vascular disease (CVD) was 1.0% per year. However, IHD events were not observed at all for five years in the most intensive glycemic control group (HbA1c<6%). Similarly, CVD events were not observed at all for seven years in the most intensive glycemic control group (HbA1c<6%). In addition, the cumulative incidence rate of IHD tended to increase as the glycemic control became poorer (HbA1c<6%, 4.5%; 6%≤HbA1c<7%, 6.0%; 7%≤HbA1c<8%, 7.2%; HbA1c≥8%, 10.7%). Furthermore, a logistic regression analysis showed that the duration of diabetes and HbA1c level were independent risk factors contributing to the onset of IHD, but not to the onset of CVD. Conclusion This seven-year observational study showed the possible association between glycemic control and the onset of macroangiopathy in a total of 572 Japanese subjects with type 2 diabetes.

Influence of atherosclerosis-related risk factors on serum high-sensitivity C-reactive protein levels in patients with type 2 diabetes: Comparison of their influence in obese and non-obese patients.

AIMS/INTRODUCTION: Increased levels of high-sensitivity C-reactive protein (hs-CRP) likely leads to the development of atherosclerosis. Therefore, it is very important to know which factors largely influence hs-CRP levels. In the present study, we examined the influence of various atherosclerosis-related factors on hs-CRP levels in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 275 patients (176 men, 99 women) were enrolled in this study. We tested the relationship between the number of risk factors reaching a desired value and hs-CRP levels. The Mann-Whitney U-test was used to compare two groups. The Kruskal-Wallis test was used to carry out overall group comparisons, and the Steel-Dwass test was used to carry out between-group comparisons. Spearman's rank correlation was carried out to study the correlation between hs-CRP levels and clinical parameters. Multivariate regression method was used to analyze the factors independently contributing to hs-CRP levels. RESULTS: Hs-CRP levels were lower in patients with a larger number of risk factors reaching a desired value. In particular, triglyceride and body mass index (BMI) were independent risk factors determining hs-CRP levels in a multivariate regression analysis. Furthermore, we compared the influence of various factors on hs-CRP levels in both obese (BMI ≥25 kg/m(2)) and non-obese patients with type 2 diabetes (BMI <25 kg/m(2)). In obese groups, BMI and urinary albumin were independent risk factors determining hs-CRP levels, whereas triglyceride and statin were independent risk factors in non-obese patients. CONCLUSIONS: There is some difference in the factors responsible for hs-CRP levels in obese and non-obese patients with type 2 diabetes.

Anti-hypertensive azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes.

It is known that reactive oxygen species (ROS) are involved in the development of insulin resistance as well as pancreatic ß-cell dysfunction both of which are often observed in type 2 diabetes. In this study, we evaluated the effects of azelnidipine, a calcium channel blocker, on ROS-mediated insulin resistance in adipocytes. When 3T3-L1 adipocytes were exposed to ROS, insulin-mediated glucose uptake was suppressed, but such phenomena were not observed in the presence of azelnidipine. Phosphorylation of insulin receptor and phosphorylation of Akt were suppressed by ROS, which was mitigated by azelnidipine treatment. Activation of the JNK pathway induced by ROS was also reduced by azelnidipine. Various inflammatory cytokine levels were increased by ROS, which was also suppressed by azelnidipine treatment. In contrast, adiponectin mRNA and secreted adiponectin levels were reduced by ROS, which was refilled by azelnidipine treatment. In conclusion, azelnidipine preserves insulin signaling and glucose uptake against oxidative stress in 3T3-L1 adipocytes.

Concomitant use of miglitol and mitiglinide as initial combination therapy in type 2 diabetes mellitus.

AIM: To evaluate the efficacy of miglitol and mitiglinide alone or in combination on the metabolic profile and incretin secretion in Japanese type 2 diabetes patients. METHODS: Patients on diet and exercise with or without metformin, were randomized to receive either miglitol, mitiglinide, or a combination, three times daily for 12 weeks. RESULTS: At 12 weeks, HbA1c decreased significantly (p<0.001) and 1,5-AG increased significantly (p<0.001) in all three groups, with the greatest change seen with combination therapy. Effective improvement of postprandial hyperglycemia was demonstrated by a meal-loading test in all three interventions but serum insulin concentration was not increased by miglitol. In a subset of patients without prior metformin administration, faster and better glycemic control was achieved with the initial combination. After meal loading, serum total GLP-1 significantly increased only with miglitol monotherapy (p<0.05) and serum total GIP significantly decreased (p<0.01) in the arms employing miglitol after 12 weeks. CONCLUSION: Miglitol/mitiglinide combination is more potent than monotherapy in improving glycemic control through the reduction of postprandial glucose excursion and the simultaneous sparing of additional insulin secretion. A marked difference in the effects of miglitol and mitiglinide on incretin secretion was also demonstrated.