Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

Mediobasal hypothalamic PTEN modulates hepatic insulin resistance independently of food intake in rats.

Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.

Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD.

AIMS/INTRODUCTION: We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone. MATERIALS AND METHODS: In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. RESULTS: At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. CONCLUSIONS: Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.

Effects of Dapagliflozin Compared with Sitagliptin and Metformin in Drug-Naïve Japanese Patients with Type 2 Diabetes: A 12-Week, Open-Label, Randomized, Active-Controlled Trial.

INTRODUCTION: To compare the efficacy and tolerability of dapagliflozin with those of sitagliptin and metformin in patients with type 2 diabetes who have never received glucose-lowering agents. METHODS: In this randomized, 12-week, open-label, active-controlled trial, 32 patients were randomly assigned to receive dapagliflozin 5 mg, sitagliptin 50 mg, or metformin 1000 mg per day for 12 weeks. At baseline and at week 12, the patients underwent a meal tolerance test (MTT). RESULTS: After 12 weeks of treatment, the changes in fasting and postprandial plasma glucose and plasma glucose area under the curve (AUC)0-120 min levels during the MTT from baseline were significantly improved in the three study groups, and there were no significant differences among the three study groups (P < 0.05). The mean changes in glycated hemoglobin (HbA1c) from baseline to week 12 were - 0.96%, - 1.24%, and - 1.40% in the dapagliflozin, sitagliptin, and metformin groups, respectively. Although there was no significant difference among the three study groups, the lowering effect of HbA1c tended to be greater in the metformin group than in the dapagliflozin group. In contrast, the insulin AUC0-120 min levels at week 12 significantly decreased only in the dapagliflozin group (P = 0.049). Similarly, body weight was significantly reduced only in the dapagliflozin group (- 2.1 kg [- 2.7%], P = 0.047). Moreover, dapagliflozin significantly improved serum adiponectin levels (P = 0.003). However, there were no significant differences in the changes in these glycemic and metabolic parameters among the three study groups. No serious adverse events were documented in any group. CONCLUSIONS: Dapagliflozin exerted beneficial effects similar to sitagliptin and metformin on glycemic parameters. In addition, dapagliflozin significantly reduced body weight and insulin AUC levels and improved serum adiponectin levels. Therefore, we suggest that these three hypoglycemic agents could be viable first-line medications for drug-naïve Japanese patients with type 2 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000024427).

Long-Term Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: 104-Week Follow-up of an Open-Label Study.

BACKGROUND: In our previous study, we investigated the efficacy of ipragliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor on diabetic nephropathy in patients with type 2 diabetes and demonstrated that ipragliflozin significantly improved diabetic nephropathy in addition to reducing HbA1c and body weight. Herein, we conducted post-trial monitoring to determine whether these lowering effects on blood glucose and body weight or the beneficial effects on diabetic nephropathy were maintained long-term (104 weeks) after starting ipragliflozin treatment. METHODS: Initially, during a 24-week interventional trial period, a 50 mg dose of ipragliflozin was administered to 50 patients with type 2 diabetes without changing other treatments. During the post-trial monitoring period, these patients returned to hospital-based diabetes care according to their clinical needs. We continued monitoring their clinical data for 104 weeks in each hospital and analyzed the results on an intention-to-treat basis. RESULTS: The improvements in glycemic control and body weight reduction provided by 24-week ipragliflozin administration were maintained for 104 weeks. Despite a transient decrease during the intervention period, the estimated glomerular filtration rate (eGFR) was restored to near the baseline level at 104 weeks. Notably, in patients with diabetic nephropathy, the median urinary albumin-to-creatinine ratio (UACR) was significantly decreased from 119.2 (98.9 - 201.8) at baseline to 36.9 (19.7 - 204.7) mg/gCr at 104 weeks. In addition, eGFR was stable for 104 weeks, showing no decrease. In contrast, a significant positive correlation between UACR and blood pressure observed at 24 weeks disappeared after discontinuation of the intervention therapy. CONCLUSIONS: The well-controlled HbA1c and body weight reductions were maintained for 104 weeks of post-trial follow-up. Moreover, ipragliflozin significantly reduced urinary albumin excretion in patients with diabetic nephropathy without decreasing eGFR.

Effects of the Activation of Three Major Hepatic Akt Substrates on Glucose Metabolism in Male Mice.

Insulin suppresses glucose output from the liver via Akt activation; however, which substrate of Akt plays the major role in transducing this effect is unclear. We tested the postnatal expression of Akt-unresponsive, constitutively active mutants of three major Akt substrates widely considered to regulate glucose metabolism [i.e., FoxO1, PGC1α, and glycogen synthase kinase-3ß (GSK3ß)] using adenoviral gene delivery to the mouse liver. We performed physiological hyperinsulinemic-euglycemic clamp studies using these mice under awake and nonrestrained conditions with blood sampling via an arterial catheter. Hepatic expression of constitutively active FoxO1 induced significant hepatic and systemic insulin resistance. However, neither the expression of constitutively active PGC1α nor that of GSK3ß significantly changed insulin sensitivity. Simultaneous expression of all three mutants together induced no further insulin resistance compared with that of the FoxO1 mutant. The glycogen content in the liver was significantly reduced by constitutively active GSK3ß expression. In cultured hepatocytes, constitutively active PGC1α induced markedly stronger transcriptional enhancement of gluconeogenic key enzymes than did constitutively active FoxO1. From these results, we conclude that FoxO1 has the most prominent role in transducing insulin's effect downstream from Akt to suppress hepatic glucose output, involving mechanisms independent of the transcriptional regulation of key gluconeogenic enzymes.

Influence of Treatment with Extracts of Hypsyzigus marmoreus Mushroom on Body Composition during Obesity Development in KK-A(y) Mice.

Hypsyzigus marmoreus (HM), an edible mushroom, has several effects, including antitumor, antioxidant and anti-allergy properties. On the other hand, the possibly useful effect of HM in diabetic mice has not as yet been elucidated. In this study, we showed treatment with a water soluble extract from HM (EHM) to reduce fat deposits without affecting body weight loss in KK-A(y) mice. EHM treatment also abolished the expressions of pro-inflammatory adipokines, such as tumor necrosis factor α and monocyte chemoattractant protein 1, as compared with vehicle treatment. The expressions of uncoupling protein 3 and peroxisome proliferator-activated receptor gamma coactivator 1α in the soleus muscles of EHM treatment groups were significantly elevated as compared to those in vehicle-treated muscle tissues. These results raise the possibility that EHM can regulate both obesity and insulin resistance.

The efficacy of vildagliptin concomitant with insulin therapy in type 2 diabetic subjects.

BACKGROUND: In Japan, dipeptidyl peptidase 4 (DPP4) inhibitors have become standard therapeutic agents for type 2 diabetes, and numbers of patients receiving insulin therapy combined with DPP4 inhibitors, which is a highly effective regimen, are increasing. METHODS: In this study, we evaluated the efficacy of vildagliptin administered at the dose of 100 mg twice daily in 57 patients with type 2 diabetes already receiving insulin treatment. RESULTS: The 36 patients who simply received add-on vildagliptin showed a 0.6% decrease in HbA1c levels, despite a marked insulin dose reduction, mainly bolus insulin, of approximately 8.3 units. In addition, body mass index exhibited a significant negative correlation with the efficacy of vildagliptin, i.e., ΔHbA1c. On the other hand, the 21 patients switched from 50 mg of sitagliptin to vildagliptin showed HbA1c decreases approaching 0.7%. CONCLUSION: Taking into consideration that twice-daily oral vildagliptin has already been reported to be advantageous in reducing postprandial hyperglycemia, this drug was suggested to be more effective in reducing HbA1c than sitagliptin under conditions in which it is used as a supplement to basal insulin, as in this study.

Effects of telmisartan on insulin resistance in Japanese type 2 diabetic patients.

OBJECTIVE: PPARgamma agonists are widely used in type 2 diabetic patients to reduce insulin resistance. Recently, telmisartan, an AT1 receptor antagonist, was reported to function as a partial agonist of PPARgamma based on in vitro experiments. The aim of the present study was to investigate whether the PPARgamma enhancing activity of telmisartan is exerted clinically in diabetic patients. METHODS: We compared the effects of telmisartan with those of candesartan, on insulin sensitivity, the serum levels of various adipocytokines and oxidative stress. PATIENTS: In total, 85 Japanese type 2 diabetic patients with hypertension, maintained on 8 mg per day of candesartan, were randomly assigned to the TM group (candesartan switched to 40 mg of telmisartan, n=38) or the CD group (no treatment change, n=47). RESULTS: After 3 months, oxidized lipids were significantly decreased only in the TM group. Although the homeostasis assessment model of insulin resistance (HOMA-R) tended to be improved and serum concentrations of HDL-cholesterol and HMW adiponectin tended to be increased only in the TM group, these alterations were too small to be significant by unpaired t-test. Interestingly, in subgroup analysis, the alterations of HOMA-R, serum concentrations of oxidized lipids, and HMW adiponectin were more apparent in obese TM group subjects and the changes reached statistical significance. CONCLUSION: Switching from candesartan to telmisartan in obese subjects increases serum adiponectin and improves both insulin resistance and oxidative stress, while these effects were not statistically apparent in the total patient population. These results support the idea that telmisartan exerts its PPARgamma enhancing activity clinically in obese type 2 diabetic patients.