pyrimidinones and Insulin-Resistance

MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes.. Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC. The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%).. MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; PPAR gamma; Pyrimidinones; src-Family Kinases; Treatment Outcome; Young Adult

Based on in vitro and animal data, PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear.. To strengthen the PI3Kβ target validation using the novel, short-acting inhibitor AZD6482.. AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC(50) 0.01 μm). A maximal anti-platelet effect was achieved at 1 μm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC(50) of 4.4 μm). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 μm but reduced by about 60% at a plasma exposure of 27 μm. In man, the homeostasis model analysis (HOMA) index increased by about 10-20% at the highest plasma concentration of 5.3 μm.. This is the first human target validation for PI3Kβ inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at 'supratherapeutic' plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition.

Topics: Adipocytes; Adolescent; Adult; Animals; Bleeding Time; Blood Platelets; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Fibrinolytic Agents; Glucose; Hemostasis; Hemostatics; Humans; Insulin Resistance; Male; ortho-Aminobenzoates; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidinones; Rats; Signal Transduction; Thrombosis; Time Factors; Young Adult

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.. HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.. A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.. In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

Topics: Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Carbamates; Confidence Intervals; Drug Administration Schedule; Drug Combinations; Dyslipidemias; Furans; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Organophosphates; Organophosphonates; Pyrimidinones; Ritonavir; Sulfonamides; Tenofovir

Dyslipidemia alone does not fully explain the increase in cardiovascular events among patients receiving protease inhibitor (PI)-based treatment for human immunodeficiency virus infection. Some PIs, such as indinavir, directly induce endothelial dysfunction, an effect that may mediate that portion of the increase in cardiovascular events that is not attributable to dyslipidemia.. Endothelium-dependent vasodilation, insulin-mediated vasodilation, and whole-body and leg glucose uptake during use of a 1-h euglycemic hyperinsulinemic clamp (insulin infusion, 40 mU/m(2)/min) were measured in healthy men before and after 4 weeks of treatment with placebo (12 men), with 400 mg atazanavir per day (9 men), or with 400 mg lopinavir and 100 mg ritonavir twice per day (9 men).. Median age (36 years) and mean body mass index SD (23.4+/-2.6; calculated as weight in kilograms divided by the square of height in meters) did not differ between groups. Endothelium-dependent vasodilation, expressed as the percentage change in the leg blood flow response to intrafemoral artery infusion of 15 microg/min of the endothelium-dependent vasodilator methacholine, did not change after 4 weeks of treatment in any group:mean percentage change +/- SD, 154+/-102 from baseline and 242+/-254 at week 4 with atazanavir (P=.36), 76+/-62 and 86+/-79, respectively, with lopinavir-ritonavir (P=.68), and 111+/-86 and 127+/-153, respectively,with placebo (P=.63; for between-group differences, P=.55). The response to the endothelium-independent vasodilator nitroprusside was not different at week 4 for any group, nor was insulin-mediated vasodilation or leg or whole-body insulin-mediated glucose uptake (all within-group P values were 1.1).. Unlike the dramatic impairment seen with indinavir, the newer PIs atazanavir and lopinavir-ritonavir do not induce endothelial dysfunction in healthy subjects. Thus, endothelial dysfunction does not appear to be a PI drug class effect. The cause of the non-lipid-mediated increase in cardiovascular events that are reported with PIs remains unclear.

Topics: Adult; Atazanavir Sulfate; Drug Therapy, Combination; Endothelium, Vascular; Glucose; Glucose Clamp Technique; HIV Protease Inhibitors; HIV Seronegativity; Humans; Insulin Resistance; Lopinavir; Male; Muscle, Skeletal; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Treatment Outcome; Vasodilation

Topics: Adult; Blood Glucose; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Lipids; Lopinavir; Male; Pyrimidinones; Risk Factors; Ritonavir

Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels.. 48-week substudy of a randomized, open-label, three-arm trial.. Hospital and community HIV clinics.. 140 HIV-infected adults naive to antiretroviral therapy.. Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine.. Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r.. Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml).. Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Topics: Adiponectin; Adult; Body Composition; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Lopinavir; Male; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

Patients with antiretroviral therapy (ART)-associated lipodystrophy frequently have disturbances in glucose metabolism associated with insulin resistance. It is not known whether changes in body composition are necessary for the development of these disturbances in ART-naive patients starting treatment with different combination ART regimens.. Glucose metabolism and body composition were assessed before and after 3 months of ART in a prospective randomized clinical trial of HIV-1-positive ART-naive men taking lopinavir/ritonavir within either a nucleoside reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine/lamivudine; n = 11) or a NRTI-sparing regimen (nevirapine; n = 9). Glucose disposal, glucose production and lipolysis were measured after an overnight fast and during a hyperinsulinaemic-euglycaemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry.. In the NRTI-containing group, body composition did not change significantly in 3 months; insulin-mediated glucose disposal decreased significantly (25%; P < 0.001); and fasting glycerol turnover increased (22%; P < 0.005). Hyperinsulinaemia suppressed glycerol turnover equally before and after treatment. The disturbances in glucose metabolism were not accompanied by changes in adiponectin or other glucoregulatory hormones. In contrast, glucose metabolism did not change in the NRTI-sparing arm. Glucose disposal significantly differed over time between the arms (P < 0.01).. Treatment for 3 months with a NRTI-containing, but not a NRTI-sparing, regimen resulted in a 25% decrease in insulin-mediated glucose disposal and a 22% increase in fasting lipolysis. In the absence of discernable changes in body composition, NRTI may directly affect glucose metabolism, the mechanism by which remains to be elucidated.

Topics: Adiponectin; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Glucose; Glycerol; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperinsulinism; Insulin Resistance; Lamivudine; Lipid Metabolism; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Time Factors; Treatment Outcome; Zidovudine

Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood.. In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers.. Ritonavir decreased insulin sensitivity (-15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (-30%; P = 0.0004), whereas neither were affected by amprenavir administration.. Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.

Topics: Adult; Aged; Blood Glucose; Carbamates; Double-Blind Method; Energy Metabolism; Furans; Glucose Clamp Technique; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Insulin Resistance; Lactic Acid; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Sulfonamides

Previously, we found that 4 weeks of treatment with lopinavir-ritonavir did not decrease insulin sensitivity but did increase adiponectin levels. In the present study, a single dose of lopinavir-ritonavir decreases insulin sensitivity but does not alter adiponectin levels. Insulin resistance from protease inhibitors may decrease with prolonged use; an increase in adiponectin levels may mediate this effect.

Topics: Adiponectin; Adult; Aged; Anti-HIV Agents; Blood Glucose; Double-Blind Method; Humans; Insulin; Insulin Resistance; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations.. To test the hypothesis that atazanavir combined with a lower dose of ritonavir would have significantly less effect on glucose metabolism than lopinavir/ritonavir in vitro and clinically.. Glucose uptake was measured following insulin stimulation in differentiated human adipocytes in the presence of ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l). These data were examined clinically using the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing (OGTT) in 26 healthy HIV-negative men treated with atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) for 10 days in a randomized cross-over study.. Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations. Ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l) did not further inhibit glucose uptake. During euglycemic clamp, there was no significant change from baseline insulin sensitivity with atazanavir/ritonavir (P = 0.132), while insulin sensitivity significantly decreased with lopinavir/ritonavir from the baseline (-25%; P < 0.001) and from that seen with atazanavir/ritonavir (-18%; P = 0.023). During OGTT, the HOMA insulin resistance index significantly increased from baseline at 120 min with atazanavir/ritonavir and at 150 min with lopinavir/ritonavir. The area under the curve of glucose increased significantly with lopinavir/ritonavir but not with atazanavir/ritonavir.. Both glucose uptake in vitro and clinical insulin sensitivity in healthy volunteers demonstrate differential effects on glucose metabolism by the combination PI atazanavir/ritonavir and lopinavir/ritonavir.

Topics: Adipocytes; Adult; Atazanavir Sulfate; Cell Differentiation; Cross-Over Studies; Drug Combinations; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; HIV Protease Inhibitors; HIV Seronegativity; Humans; Insulin Resistance; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance and type 2 diabetes mellitus, by inhibition of insulin-sensitive glucose transporters. Atazanavir (ATV) is a new PI with substantially less in vitro effect on glucose transport than observed with other PI, including lopinavir (LPV) or ritonavir (RTV).. Randomized, double-blind, crossover study of the effect of 5 days of administering ATV, lopinavir/ritonavir (LPV/r) or placebo on insulin-stimulated glucose disposal in 30 healthy HIV-negative subjects. Each subject was studied on two of three possible treatments with a wash-out period between treatments.. The mean insulin-stimulated glucose disposal (mg/min per kg body weight) per unit insulin (microU/ml) (M/I) was 9.88, 9.80 and 7.52 for placebo, ATV and LPV/r, respectively (SEM, 0.84 for all). There was no significant difference between ATV and placebo. The M/I for LPV/r was 23% lower than that for ATV (P = 0.010) and 24% lower than that for placebo (P = 0.008). The mean glycogen storage rates were 3.85, 4.00 and 2.54 mg/min per kg for placebo, ATV and LPV/r, respectively (SEM, 0.39 for all). There was no significant difference between ATV and placebo. The glycogen storage rate for LPV/r was 36% lower than ATV (P = 0.003) and 34% lower than placebo (P = 0.006).. ATV given to healthy subjects for 5 days did not affect insulin sensitivity, while LPV/r induced insulin resistance. This observation is consistent with differential in vitro effects of these PI on glucose transport. Further data are needed to assess clinical implications for body composition.

Topics: Adult; Analysis of Variance; Atazanavir Sulfate; Cross-Over Studies; Double-Blind Method; Energy Metabolism; Fatty Acids, Nonesterified; Glycogen; HIV Protease Inhibitors; HIV Seronegativity; Humans; Insulin Resistance; Lipids; Lipodystrophy; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones

Enlarged, hypertrophic adipocytes are less responsive to insulin and are a hallmark feature of obesity, contributing to many of the negative metabolic consequences of excess adipose tissue. Although the mechanisms remain unclear, the adipocyte size appears to be inversely correlated with insulin sensitivity and glucose tolerance, wherein smaller adipocytes are insulin-sensitive and larger adipocytes develop insulin resistance and exhibit an impaired glucose uptake. Thus, pharmacological strategies aimed at regulating adipocyte hypertrophy (increase in adipocyte size) in favor of promoting hyperplasia (increase in adipocyte number) have the potential to improve adipocyte insulin sensitivity and provide therapeutic benefits in the context of metabolic disorders. As white adipose tissue can metabolize large amounts of glucose to lactate, using transcriptomics and in vitro characterization we explore the functional consequences of inhibiting monocarboxylate transporter 1 (MCT1) activity in fully differentiated adipocytes. Our studies show that the pharmacological inhibition of MCT1, a key regulator of the cellular metabolism and proliferation, promotes the re-entry of mature adipocytes into the cell cycle. Furthermore, we demonstrate that inhibitor-treated adipocytes exhibit an enhanced insulin-stimulated glucose uptake as compared with untreated adipocytes, and that this outcome is dependent on the cyclin-dependent kinase 1 (CDK1) activity. In summary, we identify a mechanism though which MCT1 inhibition improves the insulin sensitivity of mature adipocytes by inducing cell cycle re-entry. These results provide the foundation for future studies investigating the role MCT1 plays in adipocyte hyperplasia, and its therapeutic potential as a drug target for obesity and metabolic disease.

Topics: 3T3-L1 Cells; Adipocytes; Animals; CDC2 Protein Kinase; Cell Cycle; Cell Proliferation; Down-Regulation; Glucose; Insulin Resistance; Mice; Models, Biological; Monocarboxylic Acid Transporters; Pyrimidinones; Symporters; Thiophenes

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Cold Temperature; Diabetes Mellitus, Type 2; Diet; Dimethylphenylpiperazinium Iodide; Energy Metabolism; Fatty Liver; Glucose Intolerance; Insulin Resistance; Male; Melanocortins; Mice, Inbred C57BL; Mice, Obese; Obesity; Pyrimidinones; Receptor, Melanocortin, Type 4; Receptors, Nicotinic; Thermogenesis; TRPM Cation Channels

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

Topics: Acetyl-CoA Carboxylase; Animals; Dyslipidemias; Enzyme Inhibitors; Fatty Liver; Female; Hep G2 Cells; Humans; Insulin Resistance; Male; Molecular Docking Simulation; Obesity; Protein Multimerization; Pyrimidinones; Rats, Sprague-Dawley; Rats, Zucker; Structure-Activity Relationship; Thiophenes

Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.

Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Diet, High-Fat; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Desaturases; Gene Expression; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice, Inbred C57BL; Obesity; Pyrimidinones; Pyrrolidinones; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss

Topics: Animals; Blood Platelets; Fibrinolytic Agents; Hemostatics; Humans; Insulin Resistance; Male; ortho-Aminobenzoates; Phosphoinositide-3 Kinase Inhibitors; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrimidinones

Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Bleeding Time; Blood Platelets; Class I Phosphatidylinositol 3-Kinases; Dogs; Drug Discovery; Fibrinolytic Agents; Inhibitory Concentration 50; Insulin Resistance; Molecular Structure; Morpholines; Protein Isoforms; Pyrimidinones; Rats

HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects.

Topics: Adipocytes; Cell Line; Cinnamates; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; HIV Protease Inhibitors; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Lopinavir; Phosphorylation; Pyrimidinones; Thiourea

The clinical use of HIV protease inhibitors is associated with insulin resistance and other metabolic changes that increase long-term cardiovascular risk. Since the failing heart has increased reliance on glucose, the influence of drug exposure on glucose homeostasis, myocardial glucose uptake, cardiac function, and survival was determined in TG9 mice, an established transgenic model of dilated cardiomyopathy generated by cardiac-specific overexpression of Cre-recombinase, as these animals progressed to overt heart failure. Beginning on day of life 75, TG9 mice and nontransgenic littermate controls were given a daily 10 mg/kg intraperitoneal injection of HIV protease inhibitors (ritonavir, lopinavir/ritonavir 4:1, atazanavir, atazanavir/ritonavir 4:1) or vehicle. Glucose tolerance testing, measurement of in vivo myocardial 2-deoxyglucose uptake, and echocardiography were performed before and 30 min following drug administration. The progression of dilated cardiomyopathy in TG9 animals was accompanied by impaired glucose tolerance, which was acutely exacerbated by exposure to ritonavir. Ritonavir and lopinavir precipitated acute, decompensated heart failure and death from pulmonary edema in TG9 mice. However, atazanavir, which does not inhibit glucose transport, had no effect. These studies demonstrate that, in the presence of dilated cardiomyopathy, HIV protease inhibitors that impair glucose transport induce acute, decompensated heart failure. The potential for HIV protease inhibitors to contribute to or exacerbate cardiomyopathy in human patients warrants further investigation.

Topics: Animals; Atazanavir Sulfate; Blood Glucose; Cardiomyopathy, Dilated; Deoxyglucose; Disease Models, Animal; Echocardiography; Glucose Tolerance Test; Glucose Transporter Type 4; Heart Failure; HIV Protease Inhibitors; Humans; Insulin Resistance; Lopinavir; Mice; Myocardium; Oligopeptides; Pulmonary Edema; Pyridines; Pyrimidinones

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Combinations; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

The clinical use of HIV protease inhibitors (PIs) is associated with the development of peripheral insulin resistance. The incidence and degree of impaired glucose tolerance observed in treated patients vary considerably between drugs, however. To compare the ability of HIV PIs to alter peripheral glucose disposal acutely in a genetically identical model system at therapeutically relevant drug levels, healthy lean male rats previously naive to PI exposure were given ritonavir, amprenavir, lopinavir/ritonavir (4:1), or atazanavir by continuous intravenous infusion to achieve steady state drug levels of 10 or 25 muM rapidly. Under euglycemic hyperinsulinemic clamp conditions, a dose-dependent reduction in the peripheral glucose disposal rate (Rd) was observed with all the PIs except atazanavir. The rank order of sensitivity was ritonavir, lopinavir, and then amprenavir. Changes in skeletal muscle and heart 2-deoxyglucose (2-DOG) uptake correlated with reductions in Rd. All 3 of these PIs also produced significant reductions in 2-DOG uptake into primary rat adipocytes in vitro. Atazanavir had no effect on glucose uptake in vitro or in vivo. The in vivo potency of PIs to impair peripheral glucose disposal acutely correlates with the degree of insulin resistance observed in HIV-infected patients receiving these drugs. Preclinical testing of novel candidate PIs in a rodent model system may be useful in identifying the future risk of altering glucose homeostasis.

Topics: Adipocytes; Animals; Atazanavir Sulfate; Carbamates; Deoxyglucose; Dose-Response Relationship, Drug; Furans; Glucose; Glucose Clamp Technique; HIV Protease Inhibitors; Infusions, Intravenous; Insulin Resistance; Lopinavir; Male; Models, Animal; Muscle, Skeletal; Myocardium; Oligopeptides; Pyridines; Pyrimidinones; Rats; Ritonavir; Sulfonamides

To evaluate the antidiabetic and hypolipidaemic potential of a novel thiazolidinedione, PMT13, in different animal models of insulin resistance.. PPAR transactivation study was performed in HEK293T cells using ligand binding domains of PPARalpha, gamma and delta. Insulin-resistant db/db and ob/ob mice were treated orally with different doses of PMT13 at 0.3-10 mg/kg/day for 15 and 14 days respectively. Zucker fa/fa rats were treated with 3 mg/kg (p.o.) dose of the compound. Plasma glucose, triglyceride, free fatty acid and insulin levels were measured. Liver glucose 6-phosphatase (G6-Ptase) and adipose lipoprotein lipase activity was measured in treated mice. Isolated rat aortic preparations preconstricted with phenylephrine were used to study the vascular relaxation potential of PMT13 in presence of insulin. A 28-day oral toxicity study was performed in Wistar rats.. PMT13 showed similar PPARgamma activation as rosiglitazone, but failed to show any activity against PPARalpha or PPARdelta. In obese and diabetic db/db and ob/ob mice, PMT13 showed better reduction in plasma glucose, triglyceride and insulin levels than rosiglitazone and an improvement in glucose tolerance. In insulin-resistant Zucker fa/fa rat model, PMT13 treatment showed better reduction in plasma triglyceride, free fatty acid and insulin levels than that of rosiglitazone. Treated mice showed decreased G6-Ptase activity in liver. The LPL activity was increased in post-heparin plasma and epididymal fat of treated db/db mice. In an isolated, precontracted rat aortic preparation, PMT13 treatment significantly increased insulin-induced relaxation. A 28-day oral toxicity study in rats showed no treatment-related adverse effects.. Our studies indicate that PMT13 is a potent activator of PPARgamma with antidiabetic, hypolipidaemic and insulin-sensitizing properties. Additionally, PMT13 inhibited liver G6-Ptase activity and increased lipoprotein lipase activity. It showed improvement in insulin-induced vasorelaxation. The compound also showed a good safety margin. Therefore, PMT13 can be a potential drug candidate for future development.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypoglycemic Agents; Insulin Resistance; Liver; Mice; Mice, Obese; Pyrimidines; Pyrimidinones; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors