oxadiazoles and Hyperglycemia

Topics: Animals; Benzimidazoles; Blood-Brain Barrier; Capillary Permeability; Cytokines; Diabetes Mellitus, Experimental; Hyperglycemia; Kruppel-Like Transcription Factors; Male; Mice; Neuroprotective Agents; Oxadiazoles

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats.. ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol.. ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats.. Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Blood Glucose; Blood Pressure; Diabetic Nephropathies; Endothelium, Vascular; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Male; Oxadiazoles; Oxidative Stress; Rats; Rats, Zucker

Glucose moves into airway secretions after a glucose load. Therefore people with diabetes or hyperglycemia spend a significant proportion of each day with glucose in their airways secretions. This study investigated the effects of glucose on isolated human airways and on cultured airway smooth muscle (ASM) cells. Human isolated bronchi were stimulated with acetylcholine, histamine, and transmural stimulation and treated with the selective ROCK inhibitors Y27632 and SB772077B under high-glucose conditions. The effect of high glucose concentrations on intracellular calcium flux and the phosphorylation of MYPT1 in ASM cells was also investigated. High (44 mM for 6 h) glucose, but not mannitol, concentrations led to an enhanced responsiveness of ASM to contractile agents. Y27632 and SB772077B completely abolished (P < 0.05) the enhanced contractile effects with a high-concentration glucose solution, compared with control tissues. In cultured ASM cells, incubation with high glucose concentrations significantly (P < 0.05) enhanced bradykinin-induced intracellular calcium flux and the levels of pMYPT1, which were inhibited by Y27632 (P < 0.05). Our study has demonstrated that high glucose concentrations leads to hyperresponsiveness of human isolated bronchi and enhances intracellular calcium release in cultured ASM cells via a Rho/ROCK- and pMYPT1-dependent pathway, suggesting that this crucial pathway may contribute to the reduced lung function observed in patients with diabetes. These data propose novel targets for the treatment of patients with respiratory diseases that also suffer from diabetes mellitus.

Topics: Acetylcholine; Amides; Bradykinin; Bronchi; Calcium Signaling; Cells, Cultured; Enzyme Activation; Female; Glucose; Histamine; Humans; Hyperglycemia; Imidazoles; In Vitro Techniques; Male; Mannitol; Middle Aged; Muscle Contraction; Muscle, Smooth; Myosin-Light-Chain Phosphatase; Osmolar Concentration; Oxadiazoles; Phosphorylation; Protein Processing, Post-Translational; Pyridines; rho GTP-Binding Proteins; rho-Associated Kinases

The large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels modulate the retinal vascular tone, but question of whether the impairment of the channel function contributes to abnormalities of retinal circulation has not yet been completely elucidated. The purpose of this study was to examine effects of diabetes on the vasodilation induced by activation of BK(Ca) channels. Male Wistar rats were treated with streptozotocin and experiments were performed 2 weeks later. The streptozotocin-treated animals were given drinking water containing 5% d-glucose to shorten the term in the development of retinal vascular dysfunction. The retinal vascular responses were assessed by measuring diameter of retinal arterioles in the fundus images that were captured with an original fundus camera system. In non-diabetic rats, vasodilator effects of acetylcholine on retinal arterioles were significantly reduced by iberiotoxin, an inhibitor of BK(Ca) channels. However, the inhibitory effect of iberiotoxin was not observed in diabetic rats, and the responses to the BK(Ca) channel opener BMS-191011 were almost completely abolished. The retinal vasodilator response to acetylcholine, possibly an endothelium-derived hyperpolarizing factor-mediated response, observed after treatment with N(G)-nitro-l-arginine methyl ester and indomethacin was markedly reduced in diabetic rats. The responses to pinacidil, an opener of ATP-sensitive K(+) channels, were unchanged. These results suggest that the retinal vasodilator response mediated through mechanisms involving activation of BK(Ca) channels is diminished at the early stage of diabetes in rats. The impairment of BK(Ca) channel function may contribute to abnormal retinal hemodynamics in diabetes and consequently play an important role in the pathogenesis of diabetic retinopathy.

Topics: Acetylcholine; Animals; Blood Glucose; Blood Pressure; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Fluorescein Angiography; Glucose; Heart Rate; Hyperglycemia; Indomethacin; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Peptides; Pinacidil; Potassium Channels; Rats; Rats, Wistar; Retinal Artery; Vasodilation; Vasodilator Agents

Insulin-like growth factor-I receptor and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways are among the most active areas of drug discovery in cancer research. However, due to their integral roles in insulin signaling, inhibitors targeting these pathways often lead to hyperglycemia and hyperinsulinemia. We investigated the mechanism of hyperglycemia induced by GSK690693, a pan-AKT kinase inhibitor in clinical development, as well as methods to ameliorate these side effects.. The effect of GSK690693 on blood glucose, insulin, and glucagon levels was characterized in mice. We then evaluated the effects of commonly prescribed antidiabetic agents on GSK690693-induced hyperglycemia. The mechanism of blood glucose increase was evaluated using fasting and tracer uptake studies and by measuring liver glycogen levels. Finally, approaches to manage AKT inhibitor-induced hyperglycemia were designed using fasting and low carbohydrate diet.. We report that treatment with antidiabetic agents does not significantly affect GSK690693-induced hyperglycemia in rodents. However, administration of GSK690693 in mice significantly reduces liver glycogen (approximately 90%), suggesting that GSK690693 may inhibit glycogen synthesis and/or activate glycogenolysis. Consistent with this observation, fasting before drug administration reduces baseline liver glycogen levels and attenuates hyperglycemia. Further, GSK690693 also inhibits peripheral glucose uptake and introduction of a low-carbohydrate (7%) or 0% carbohydrate diet after GSK690693 administration effectively reduces diet-induced hyperglycemia in mice.. The mechanism of GSK690693-induced hyperglycemia is related to peripheral insulin resistance, increased gluconeogenesis, and/or hepatic glycogenolysis. A combination of fasting and low carbohydrate diet can reduce the magnitude of hyperglycemia induced by an AKT inhibitor.

Topics: Animals; Diet, Carbohydrate-Restricted; Fasting; Female; Hyperglycemia; Liver Glycogen; Male; Mice; Mice, SCID; Oxadiazoles; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

To determine the relationship between hypoglycemic activity and body weight gain induced by insulin sensitizers, we compared the effects of thiazolidinedione analogs (troglitazone and pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis4[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phen oxy¿but-2-ene (YM440) in diabetic db/db mice. Oral treatment with YM440(100 mg/kg) for 28 days decreased the blood glucose concentration (control v YM440, 418 +/- 12 v243 +/- 44 mg/dL). The hypoglycemic activity of this agent was comparable to that of troglitazone (300 mg/kg) and pioglitazone (100 mg/kg). There were no changes in food intake among the groups. Troglitazone and pioglitazone, but not YM440, significantly increased body weight gain during treatment (control, 7.2 +/- 0.5 g; YM440, 7.5 +/- 0.8 g; troglitazone, 10.9 +/- 0.8 g; and pioglitazone, 14.5 +/- 1.1 g). To further assess whether the increase in body weight by troglitazone or pioglitazone was due to adipogenesis, the weight of intraabdominal fat tissue (epididymal, retroperitoneal, and perirenal) was determined. There were no differences in the total weight of visceral fat between the control and YM440 treatment (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast, troglitazone and pioglitazone significantly increased the fat weight (4.31 +/- 0.13 and 4.66 +/- 0.19 g). Thiazolidinediones are known as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor responsible for adipogenesis. Troglitazone and pioglitazone activated PPARgamma and increased triglyceride accumulation and mRNA expression of fatty acid-binding protein (FABP) in 3T3-L1 cells. However, YM440 had no effect on these indices for adipocyte differentiation. These results suggest that the mechanism is different for the hypoglycemic action of YM440 versus the thiazolidinediones. YM440 ameliorates hyperglycemia without changing PPARgamma activity, adipocyte differentiation, or fat weight. Thus, YM440 could be a useful hypoglycemic agent for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) without affecting body weight.

Topics: 3T3 Cells; Adipose Tissue; Animals; Blood Glucose; Cell Differentiation; Chromans; Diabetes Mellitus, Type 2; Hyperglycemia; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Oxadiazoles; Pioglitazone; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone; Weight Gain