Effects of Ipragliflozin on Postprandial Glucose Metabolism and Gut Peptides in Type 2 Diabetes: A Pilot Study.

INTRODUCTION: Ipragliflozin is a novel antidiabetic drug that inhibits renal tubular sodium-glucose cotransporter-2 (SGLT2). The aim of this study was to evaluate the effects of ipragliflozin on glucose, insulin, glucagon, and gastrointestinal peptide responses to a meal tolerance test, as well as to investigate the glucose-lowering mechanisms of ipragliflozin. METHODS: Nine Japanese patients with obesity and type 2 diabetes mellitus were treated with ipragliflozin (50 mg/day) for 12 weeks. The postprandial profiles of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured before and 12 weeks after ipragliflozin treatment. RESULTS: Body weight, body fat mass, systolic blood pressure, and HbA1c and serum uric acid levels were significantly decreased after the treatment. Postprandial glucose and insulin levels were also significantly decreased. Postprandial glucagon increased both before and after ipragliflozin treatment; however, the increment tended to be smaller after treatment. Active GLP-1, active GIP, ghrelin, and des-acyl ghrelin did not change after treatment. CONCLUSION: Ipragliflozin improved glycemic control by reducing body weight, postprandial inappropriate glucagon secretion, and the postprandial insulin requirement. Although this was a short-term study with a small sample size, ipragliflozin may offer benefits for patients with obesity and type 2 diabetes mellitus. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN No. 000017195).

Exploratory trial of intranasal administration of glucagon-like peptide-1 in Japanese patients with type 2 diabetes.

OBJECTIVE: This study aimed to assess the efficacy and safety of our newly developed nasal glucagon-like peptide-1 (GLP-1) compound and injector. RESEARCH DESIGN AND METHODS: Twenty-six patients with type 2 diabetes were enrolled in this double-blind placebo-controlled study. The nasal compound containing 1.2 mg of human GLP-1 (7-36) amide or placebo was administered immediately before every meal for 2 weeks. RESULTS: The plasma peak concentration of active GLP-1 was 47.2 pmol/L, and its Tmax was 8.1 min. The early phase of insulin and glucagon secretion were recovered and suppressed, respectively, in the GLP-1 group. Glycoalbumin levels became significantly lower and 1,5-anhydroglucitol levels significantly higher after GLP-1 administration. No marked adverse events were observed after using nasal GLP-1. CONCLUSIONS: The newly developed nasal GLP-1 compound may be a potential treatment for type 2 diabetes. The long-term application of the drug should be evaluated in future trials.

Therapeutic potential of ghrelin treatment for unloading-induced muscle atrophy in mice.

Ghrelin is a growth hormone (GH) secretagogue secreted mainly from the stomach that functions in controlling muscle volume and energy homeostasis. We here studied the effects of ghrelin on unloading-induced muscle atrophy using a mouse model of hindlimb suspension (HS). Ghrelin administration during 2-week HS alleviated reductions of muscle mass in the fast-twitch fiber-rich plantaris muscle and the slow-twitch fiber-rich soleus muscle of the hindlimb. Ghrelin administration during a 5-day recovery period following 2-week HS enhanced food intake and facilitated recovery from atrophy in both muscles. Ghrelin administration normalized hypercorticosteronemia in these studies. Ghrelin's anti-muscle atrophy effect was found even under pair-feeding condition, but not in mice given des-acyl ghrelin. Insulin-like growth factor (IGF)-1 mRNA expression was significantly reduced in the atrophied plantaris muscle compared with control muscles. A single ghrelin administration to HS mice acutely increased plasma GH and also amplified phosphorylation of signal transducer and activator of transcription (STAT) 5 and increased IGF-1 mRNA expression in the plantaris muscle, but not in the soleus muscle. This study demonstrated that ghrelin stimulated the GH-STAT5-IGF-1 axis in the locally atrophied plantaris muscle, and its administration alleviated muscle atrophy and facilitated recovery from muscle atrophy. Ghrelin's effects represent a novel therapeutic paradigm for the treatment of unloading-induced muscle atrophy induced by factors such as bed rest, injury, and joint immobilization.

Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic ß-cells.

Glucagon-like peptide-1 (GLP-1) and angiotensin II type 1 receptor blocker reduce ß-cell apoptosis in diabetes, but the underlying mechanisms are not fully understood. We examined the combination effects of GLP-1 and candesartan, an angiotensin II type 1 receptor blocker, on glucolipotoxicity-induced ß-cell apoptosis; and we explored the possible mechanisms of the antiapoptotic effects. The effects of GLP-1 and/or candesartan on glucolipotoxicity-induced apoptosis and the phosphorylation of insulin receptor substrate-2 (IRS-2), protein kinase B (PKB), and forkhead box O1 (FoxO1) were evaluated by using MIN6 cells and isolated mouse pancreatic islets. Although palmitate significantly enhanced the high-glucose-induced apoptosis in both islets and MIN6 cells, GLP-1 and candesartan significantly inhibited apoptosis; and combination treatment additively prevented apoptosis. Whereas palmitate significantly decreased the phosphorylation of IRS-2, PKB, and FoxO1 in MIN6 cells, these changes were significantly inhibited by treatment with GLP-1 and/or candesartan. In addition, wortmannin, an inhibitor of phosphoinositide 3-kinase, markedly inhibited GLP-1- and/or candesartan-mediated PKB and FoxO1 phosphorylation. The present results suggest that GLP-1 and candesartan additively prevent glucolipotoxicity-induced apoptosis in pancreatic ß-cells through the IRS-2/phosphoinositide 3-kinase/PKB/FoxO1 signaling pathway.

Telmisartan suppresses food intake in mice via the melanocortin pathway.

SUMMARY: Telmisartan, an angiotensin type 1 receptor blocker, is widely used for the treatment of hypertension and related cardiovascular and organ damage. We here describe the effects of telmisartan on food intake and body weight using C57BL/6N mice, KKAy mice that overexpress agouti protein (a mouse model of type 2 diabetes with obesity), and mice deficient for angiotensin II-1a receptor. Telmisartan combined with a high-fat diet significantly reduced food intake and body weight gain in the three groups of mice compared with respective control animals that were fed the high-fat diet without telmisartan. Telmisartan did not induce taste aversion or affect energy expenditure. Intracerebroventricular administration of agouti-related protein, a potent antagonist of the melanocortin 3 receptor (MC3-R) and melanocortin 4 receptor (MC4-R), did not stimulate feeding in telmisartan-treated mice. Telmisartan administration enhanced the alpha-melanocyte stimulating hormone-induced suppression of food intake. This study highlights a potential role for telmisartan in hypothalamic feeding regulation, including melanocortin receptors-mediated suppression of food intake and body weight gain.:

Fenofibrate ameliorates insulin resistance, hypertension and novel oxidative stress markers in patients with metabolic syndrome.

OBJECTIVE: The benefits of fenofibrate, a peroxisome proliferator-activated receptor α agonist, against cardiovascular risk factors have been established. To clarify the underlying mechanisms of these benefits, we examined the effects of fenofibrate on insulin resistance, hypertension, inflammation, oxidative stress and coagulation markers in patients with metabolic syndrome. METHODS: Eleven Japanese patients with metabolic syndrome underwent physical examinations and blood tests before and after treatment with fenofibrate 200 mg daily for 8 weeks. RESULTS: Fenofibrate significantly decreased systolic blood pressure, pulse wave velocity, serum insulin, insulin resistance (calculated from the homeostasis model assessment), total cholesterol, triglyceride, remnant-like particles cholesterol, uric acid, D-dimer, fibrinogen, serum amyloid A/low-density lipoprotein (LDL) and apoA1/LDL levels. It also significantly increased levels of high molecular weight adiponectin, thrombomodulin and high-density lipoprotein cholesterol in these patients. Plasminogen activator inhibitor-1, C-reactive protein, fasting plasma glucose and thrombin-antithrombin complex levels did not change. LIMITATION: Small sample size. CONCLUSION: Short-term fenofibrate administration not only improved lipid profiles, but also ameliorated insulin resistance, hypertension and oxidative stress markers in patients with metabolic syndrome, suggesting that fenofibrate can decrease the risk of arteriosclerosis through various pathways.

Atrial septal pacing to resynchronize atrial contraction and improve atrial transport function.

OBJECTIVES: Atrial septal pacing via a trans-septal breakthrough site within the right atrial septum can shorten global atrial activation time, resulting in significant reduction of recurrence of atrial fibrillation events. This study examined whether this pacing method will lead to resynchronization of atrial contraction and its benefit on hemodynamic function can be maintained for 24 months. METHODS: Thirty patients with atrial fibrillation and delayed atrial conduction were enrolled (17 males, 13 females, mean age 73 +/- 7 years). Trans-septal breakthrough site within the right atrial septum was identified through pacing from the dorsal left atrium. Continuous atrial septal pacing at the trans-septal breakthrough site was performed for 24 months. Time difference (TD) between right and left atrial contractions was measured during atrial septal pacing and sinus rhythm by pulse Doppler echocardiography of the trans-tricuspid (P-At) and mitral (P-Am) blood flows (TD = P-Am - P-At). RESULTS: The atrial lead was screwed near the fossa ovalis in 29 of 30 patients. Atrial septal pacing yielded significantly shorter P wave duration (101.9 +/- 10.4 vs 139.6 +/- 14.7 msec, p < 0.001), leading to significant reduction of TD in atrial contraction (-8.8 +/- 10.0 vs 29.8 +/- 13.6 msec, p < 0.001)as compared to sinus rhythm. Both shorter P wave duration and reduced TD during atrial septal pacing remained statistically significant during the follow-up period as compared to sinus rhythm. Both left atrial diameter and A to E ratio of filling waves at mitral valve were significantly decreased at 12 months and remained decreased at 24 months. CONCLUSIONS: Atrial septal pacing at the trans-septal breakthrough site can resynchronize atrial contraction and results in improved hemodynamic effects during 24 months of follow-up.

Effects of bezafibrate on lipoprotein subclasses and inflammatory markers in patients with hypertriglyceridemia--a nuclear magnetic resonance study.

BACKGROUND: Hypertriglyceridemia is often associated with elevated remnants, small dense LDL and decreased HDL-cholesterol (C). The objective of this study was to investigate the efficacy of bezafibrate on lipoprotein subfractions profile and inflammation markers in patients with hypertriglyceridemia. METHODS: Twenty-four hypertriglyceridemic subjects took bezafibrate, 400 mg daily, for 4 weeks. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy. Inflammation markers including C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) were also determined. RESULTS: Bezafibrate lowered triglyceride (TG) by 59% and increased HDL-C by 20%. NMR analysis revealed that bezafibrate lowered large TG-rich lipoproteins and IDL by 81% and 46%, respectively. Small LDL was selectively decreased by 53% with increase in large to intermediate LDL, thus altering the LDL distribution towards the larger particles (mean diameter 19.9 to 20.7 nm, p = 0.0001). Small (HDL1) and intermediate (HDL3) HDL significantly increased by 168% and 70%, whereby resulting in a significant reduction of the mean HDL particle size from 9.0 to 8.7 nm (p = 0.026). None of inflammation makers showed significant change by bezafibrate. CONCLUSIONS: Bezafibrate effectively ameliorates atherogenic dyslipidemia by reducing remnants and small LDL as well as by increasing HDL particles in hypertriglyceridemic subjects.

Infective endocarditis at the tricuspid valve following central venous catheterization.

We report a case of infective endocarditis at the tricuspid valve attributed to central venous catheterization. The patient was a 35-year-old woman who had multiple septic emboli in her lung due to tricuspid valve endocarditis after successful treatment of bronchiolitis obliterans organizing pneumonia. She also had right ileosacral arthritis. The case was closely related to catheter-associated Staphylococcus aureus bacteremia. She was treated with intravenous administration of vancomycin and surgical removal of vegetation and tricuspid valvuloplasty. Since infective endocarditis can be a complication of central venous catheterization with high morbidity and mortality, maximal precautions to minimize the risk, early detection, and appropriate treatment of these complications are mandatory to improve patients' outcome.

Various routes of septal propagation in common atrial flutter.

INTRODUCTION: Although in the treatment of common atrial flutter, the isthmus between the tricuspid valve annulus and the eustachian ridge is often chosen as the site for conduction block by radiofrequency ablation, the precise path of the flutter circuit remains unknown. We therefore investigated the propagation of the atrial flutter wave front around the coronary sinus ostium and how its path is altered by application of radiofrequency current. METHODS AND RESULTS: To assess activation pattern, activation in the region surrounding the coronary sinus ostium was mapped using a deflectable decapolar catheter under basal conditions and while applying radiofrequency current to the septal isthmus, between the tricuspid valve annulus and the eustachian ridge. In five of eleven patients studied, the eustachian ridge side, below the coronary sinus ostium, was activated earlier, and the flutter wave exited from either the tricuspid valve annulus side or the eustachian ridge side, above the coronary sinus ostium. In four patients, a partial line of block created by applying radiofrequency current between the tricuspid valve annulus and the coronary sinus ostium or between the coronary sinus ostium and the eustachian ridge led to a shift in the direction of propagation of the flutter wave front from anterior to posterior or from posterior to anterior of the coronary sinus ostium, and prolongation of the cycle length. CONCLUSION: Application of radiofrequency current to the septal isthmus, between the tricuspid valve annulus and the eustachian ridge, can shift both the anterior and posterior propagation of flutter around the coronary sinus ostium.

Effect of low-dose isoproterenol infusion on left atrial appendage function soon after cardioversion of chronic atrial tachyarrhythmias.

BACKGROUND: Cardioversion of chronic atrial fibrillation or atrial flutter to sinus rhythm is often associated with transient atrial mechanical dysfunction, i.e. 'atrial stunning', which may increase the risk of subsequent thromboembolic events. We hypothesized that, because of its positive inotropic action, a low-dose isoproterenol infusion might improve postcardioversion atrial mechanical function. METHOD: Eighteen patients (15 male, three female; 12 atrial fibrillation, six atrial flutter; mean age 65+/-10 years) exhibiting atrial postcardioversion stunning were included in the study. Isoproterenol was infused for 10 min at a dose sufficient to increase the heart rate by about 10%. Using transesophageal echocardiography, both the left atrial appendage emptying/filling flow velocity and function (fractional area change) were examined at baseline, before isoproterenol (immediately after cardioversion) and after isoproterenol. RESULTS: With infusion of 0.005-0.008 microg/kg/min isoproterenol, heart rate increased by 11.1+/-2.9%, and left atrial appendage emptying velocity, which was diminished following cardioversion, increased significantly (P<0.001) (baseline, before and after isoproterenol: 41.1+/-18.0, 20.3+/-8.5 and 27.3+/-9.6 cm/s, respectively). No major complications were associated with isoproterenol infusion. CONCLUSIONS: Short-term infusion of low-dose isoproterenol improved atrial function after cardioversion of chronic atrial fibrillation and atrial flutter.