oxadiazoles and Insulin-Resistance

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hypertension; Insulin Resistance; Obesity; Oxadiazoles

Topics: Animals; Blood Glucose; Drug Design; Humans; Hypoglycemic Agents; Insulin Resistance; Isoxazoles; Lipid Metabolism; Oxadiazoles; Receptor, Insulin; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors

Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting.. This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (≥20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure.. The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, -1.09-1.52) in the azilsartan group and -0.23 (95% CI, -0.72-0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group.. Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/day) exerted comparable antihypertensive effects.. ClinicalTrials.gov NCT02079805.

Topics: Adult; Aged; Aged, 80 and over; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Oxadiazoles; Telmisartan

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Topics: Adipose Tissue; Administration, Oral; Animals; Blood Glucose; Body Temperature; Body Weight; Diamines; Diet, Western; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose Clamp Technique; Humans; Insulin Resistance; Liver; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Obesity; Oxadiazoles; Oxidative Stress; Pyrazines

GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in

Topics: Adipokines; Animals; Apoptosis; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Gene Expression Profiling; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Knockout; Oxadiazoles; Pyrimidines; Receptors, G-Protein-Coupled

Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Cardiac Output; Creatine Kinase; Diet, High-Fat; Echocardiography; Heart Ventricles; Hypertrophy, Left Ventricular; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Oxadiazoles; Plasminogen Activator Inhibitor 1; Ventricular Pressure

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Insulin Resistance; Male; Obesity; Oxadiazoles

Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats.. Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR.. In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression.. These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Blood Glucose; Blood Pressure; Enzyme-Linked Immunosorbent Assay; Hypertension; Insulin; Insulin Resistance; Male; Obesity; Oxadiazoles; Polymerase Chain Reaction; PPAR gamma; Rats; Rats, Inbred SHR

The effects of a new AT(1) receptor blocker (ARB), TAK-536, on insulin resistance were explored using type 2 diabetic KK-A(y) mice and compared with those of candesartan cilexetil (candesartan).. Male KK-A(y) mice were treated with TAK-536 or candesartan at doses of 0.0005%, 0.001%, and 0.005% in laboratory chow for 2 weeks. Results of an oral glucose tolerance test (OGTT) and tissue glucose uptake were examined. Expression of markers for insulin resistance and adipocyte differentiation was measured by quantitative reverse transcriptase-polymerase chain reaction.. Both TAK-536 and candesartan suppressed the increase in plasma glucose level in the OGTT without significant change in insulin concentration and improved insulin sensitivity. Both ARBs also increased tissue glucose uptake, especially in skeletal muscle and adipose tissue. These effects of TAK-536 on glucose intolerance were stronger than those of candesartan. In skeletal muscle, TAK-536 but not candesartan decreased the expression of TNF-alpha at doses of 0.001%. In adipose tissue, TAK-536 and candesartan reduced TNF-alpha expression but increased the expression of adiponectin, PPARgamma, C/EBalpha, and aP2. The effects of TAK-536 on these parameters were also greater than those of candesartan. Adipose tissue weight and cell size were decreased by TAK-536 at 0.005%.. These results indicate the greater beneficial effects of TAK-536 in improving glucose intolerance, insulin sensitivity, and induction of adipocyte differentiation, and suggest that TAK-536 is advantageous as a new ARB for treatment of metabolic syndrome.

Topics: Adipocytes; Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Cell Differentiation; Cell Size; Eating; Glucose; Glucose Intolerance; Insulin Resistance; Male; Mice; Muscle, Skeletal; Oxadiazoles; Tetrazoles; Tumor Necrosis Factor-alpha

The novel hypoglycemic agent YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor (PPAR) gamma. YM440 has unique pharmacological profiles both in vitro and in vivo, but, it is not clear whether the compound has a significant effect on hepatic or peripheral insulin response throughout the body. The aim of this study is to examine the effects of YM440 on hepatic and peripheral insulin resistance in Zucker fatty (ZF) rats using the euglycemic-hyperinsulinaemic clamp technique. Treatment of ZF rats with YM440 (300 mg/kg per day) for 2 weeks significantly decreased plasma concentrations of glucose and insulin without inducing obesity. YM440 caused a 2-fold increase in the glucose infusion rate during euglycemic clamping compared with the vehicle control. YM440 also decreased the percent change in hepatic glucose production rate caused by intravenous insulin infusion in ZF rats. YM440 had no significant effect on the glucose disposal rate. These results indicate that YM440 ameliorates hepatic, but not peripheral insulin resistance in ZF rats. These findings strongly suggest that the main target organ of YM440 is the liver, unlike other PPARgamma agonist.

Topics: Algorithms; Animals; Blood Glucose; Body Weight; Drug Evaluation, Preclinical; Eating; Glucose; Glucose Clamp Technique; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Male; Molecular Structure; Obesity; Oxadiazoles; PPAR gamma; Rats; Rats, Zucker; Time Factors; Tritium

The hepatic parasympathetic nerves and hepatic nitric oxide synthase (NOS) are involved in the secretion of a hepatic insulin sensitizing substance (HISS), which mediates peripheral insulin sensitivity. We tested whether binding of ACh to hepatic muscarinic receptors is an upstream event to the synthesis of nitric oxide (NO), which, along with the activation of hepatic guanylate cyclase (GC), permits HISS release. Male Wistar rats (8-9 wk) were anesthetized with pentobarbital sodium (65 mg/kg). Insulin sensitivity was assessed using a euglycemic clamp [the rapid insulin sensitivity test (RIST)]. HISS inhibition was induced by antagonism of muscarinic receptors (atropine, 3 mg/kg i.v.) or by blockade of NOS [NG-nitro-L-arginine methyl ester (L-NAME), 1 mg/kg intraportally (i.p.v.)]. After the blockade, HISS action was tentatively restored using a NOdonor [3-morpholynosydnonimine (SIN-1), 5-10 mg/kg i.p.v.] or ACh (2.5-5 microg.kg(-1).min(-1) .i.p.v.). SIN-1 (10 mg/kg) reversed the inhibition caused by atropine (RIST postatropine 137.7 +/- 8.3 mg glucose/kg; reversed to 288.3 +/- 15.5 mg glucose/kg, n = 6) and by L-NAME (RIST post-L-NAME 152.2 +/- 21.3 mg glucose/kg; reversed to 321.7 +/- 44.7 mg glucose/kg, n = 5). ACh did not reverse HISS inhibition induced by L-NAME. The role of GC in HISS release was assessed using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 nmol/kg i.p.v.), a GC inhibitor that decreased HISS action (control RIST 237.6 +/- 18.6 mg glucose/kg; RIST post-ODQ 111.7 +/- 6.2 mg glucose/kg, n = 5). We propose that hepatic parasympathetic nerves release ACh, leading to hepatic NO synthesis, which activates GC, triggering HISS action.

Topics: Acetylcholine; Animals; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; In Vitro Techniques; Injections, Intravenous; Insulin Resistance; Liver; Male; Molsidomine; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxadiazoles; Portal Vein; Quinoxalines; Rats; Rats, Wistar; Signal Transduction