cl-316243 and Diabetes-Mellitus--Type-2

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effect

Topics: Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dioxoles; Drug Design; Humans; Hypoglycemic Agents; Obesity; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.

Topics: Adipocytes; Adipose Tissue; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Diet, High-Fat; Dioxoles; Female; Glucose; Glucose Intolerance; Homeostasis; Humans; Hyaluronic Acid; Hypoglycemic Agents; Lipolysis; Male; Mice; Mice, Transgenic; Obesity

Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM).. Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective β. In T1DM, [. The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients.

Topics: Adipose Tissue; Adrenergic Agents; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dioxoles; Disease Models, Animal; Glucose; Male; Mice, Inbred ICR; Uncoupling Protein 1

Brown adipose tissue (BAT) has been regarded as a potential target organ to combat obesity and related metabolic disorders. However, the effect of BAT activation on the development of diabetic kidney disease (DKD) remains unclear.. Compared with untreated STZ-diabetic mice, CL316,243 treatment reduced blood glucose, albeit not significantly (20.58 ± 3.55 vs 23.60 ± 3.90 mM), and significantly decreased triglycerides and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol. Simultaneously, BAT activation significantly decreased 24-hour urinary albumin (34.21 ± 6.28 vs 70.46 ± 15.81 μg/24 h; P < 0.05) and 8-OHdG, improved renal fibrosis, inflammation, and oxidative stress, and ameliorated renal morphological abnormalities. In addition to enhancing BAT activity, CL316,243 significantly increased serum adiponectin concentrations and renal Fgf21 sensitivity, and reactivated the renal AMPK/Sirt1/Pgc1α signaling pathway. Furthermore, CL316,243 treatment increased levels of some circulating miRNAs and downregulated expression of their target genes in the kidney.. Activating BAT could improve kidney injury in diabetic mice via metabolic improvements and renal AMPK activation by beneficial adipokines and miRNAs.. 背景: 棕色脂肪组织(brown adipose tissue, BAT)是潜在的防治肥胖及相关代谢紊乱的器官, 目前BAT激活对糖尿病肾脏病(diabetic kidney disease, DKD)的影响尚不清楚。 方法: 对链脲佐菌素(STZ)联合高脂饮食诱导的糖尿病小鼠, 连续4周每天给予1 mg/kg的β3-肾上腺素能受体激动剂CL316,243以激活BAT, 观察其对小鼠血糖、血脂、脂肪因子、24 h尿白蛋白、8-羟基脱氧鸟苷(8-OHdG)、循环microRNA分子(miRNA)水平、肾脏组织病理、肾脏纤维化、炎症及氧化应激的影响, 并对肾脏成纤维细胞生长因子Fgf 21/β-klotho/FGFR1c和AMPK/Sirt1/Pgc1α信号通路进行分析。 结果: CL316,243干预组的糖尿病小鼠的血糖水平呈降低趋势(20.58±3.55 vs. 23.60±3.90 mmol/L), 且甘油三酯和低密度脂蛋白胆固醇明显降低, 而高密度脂蛋白胆固醇明显升高。同时, BAT激活显著降低糖尿病小鼠的24 h尿白蛋白水平(34.21±6.28 vs. 70.46±15.81 μg/24 h；P<0.05)和8-OHdG水平, 明显改善肾脏纤维化、炎症和氧化应激, 并改善肾脏形态学异常。CL316,243干预不仅增强了糖尿病小鼠的BAT活性, 还显著提高了血清脂联素水平和肾脏Fgf 21敏感性, 激活了肾脏AMPK/Sirt1/Pgc1α信号通路。此外, CL316,243干预可显著增加某些循环miRNAs水平, 并下调相应的肾脏靶基因表达。 结论: BAT激活可显著改善糖尿病小鼠的代谢紊乱, 增加血中脂肪因子水平、上调循环中某些miRNAs表达、激活肾脏AMPK信号通路, 从而发挥对糖尿病小鼠的肾脏保护作用。.

Topics: Adipokines; Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Blood Glucose; Circulating MicroRNA; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Dioxoles; Hypoglycemic Agents; Kidney; Lipids; Male; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Sirtuin 1; Streptozocin

Type 2 diabetes (T2D) is a complex metabolic disease leading to complications in multiple organs. Diabetic myopathy and liver disease are common complications of T2D, but are incompletely understood. To gain insight into the pathogenesis of these conditions we performed metabolomic analysis of skeletal muscle and liver in a mouse model of T2D.. Tissue metabolomics were performed by GC/MS and LC/MS of the skeletal muscle and liver in the MKR mouse model of T2D, compared with control mice. MKR mice were treated with the β-3 adrenergic receptor agonist, CL-316,243 to determine metabolite changes after correcting hyperglycemia.. Blood glucose was higher in MKR vs WT mice, and normalized with CL-316,243 treatment. Compared with WT mice, MKR mice had 2.5 fold higher concentrations of sorbitol and 1.7 fold lower concentrations of reduced glutathione in skeletal muscle. In liver, MKR mice had 2 fold higher concentrations of the pentitol ribitol. CL-316,243 treatment normalized sorbitol and ribitol concentrations in MKR skeletal muscle and liver, respectively to the levels of the WT mice.. These results demonstrate tissue-specific accumulation of polyols in a mouse model of T2D and provide novel insights into the pathogenesis of myopathy and liver disease in T2D.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Liver; Male; Metabolome; Mice; Muscle, Skeletal; Polymers

One of the common complications of type 2 diabetes mellitus (DM2) are cardiovascular diseases and dysfunctions of the reproductive system, indicating the urgency of developing new approaches to their correction. Last years for the treatment of DM2 began to use bromocryptine (BC), the agonist of type 2 dopamine receptors, which not only restores the energy metabolism, but also prevents the development of cardiovascular diseases. However, the mechanisms and targets of BC action are poorly understood. The purpose of this study was to investigate the effect of BC treatment on functional activity of adenylyl cyclase signaling system (ACSS) in the myocardium and testes of male rats with DM2, which is caused by high-fat diet and treatment with streptozotocin (25 mg/kg). The treatment with BC (60 days, orally at a dose of 0.6 mg/kg once every two days) was started 90 days after the beginning of high-fat diet. Diabetic rats had an increased body weight, elevated triglycerides level, impaired glucose tolerance, and insulin resistance. The treatment with BC resulted in the restoration of glycometabolic indicators and in the improvement of insulin sensitivity. Adenylyl cyclase (AC) stimulating effects of guanylylimidodiphosphate (GppNHp), relaxin, and agonists of β-adrenergic receptors (β3-AR)--isoproterenol and norepinephrine were decreased in the miocardium of the diabetic rats. The corresponding effects of the β-agonists BRL-37344 and CL-316243 was preserved. The inhibitory effect of somatostatin on forskolin-stimulated AC activity was attenuated, while the inhibitory effect of noradrenaline mediated through α2-AR increased. The treatment with BC resulted in the normalization of the adrenergic signaling in the myocardium and partially restoration of AC effects of relaxin and somatostatin. In the testes of diabetic rats, the basal and stimulated by GppNHp, forskolin, human chorionic gonadotropin and pituitary AC-activating polypeptide AC activity were decreased, and the inhibitory effect of somatostatin was attenuated. The changes in testicular ACSS in the case of BC treatment were weakly expressed. Thus, long-term BC treatment restores the functional activity of ACSS in the myocardium and testes of diabetic rats that underlies the therapeutic effect of BC on functions of the cardiovascular and reproductive systems disturbed in DM2 and should be considered when developing strategies for treatment type 2 diabetes and its complications.

Topics: Adenylyl Cyclases; Administration, Oral; Animals; Blood Glucose; Bromocriptine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dioxoles; Dopamine Agonists; Drug Administration Schedule; Ethanolamines; Guanylyl Imidodiphosphate; Humans; Insulin Resistance; Isoproterenol; Male; Myocardium; Norepinephrine; Rats; Rats, Wistar; Relaxin; Signal Transduction; Streptozocin; Testis; Triglycerides

Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.. Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases.. We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels.. Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.

Topics: Animals; Blood Glucose; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus, Type 2; Dioxoles; Female; Hyperinsulinism; Hypoglycemic Agents; Insulin; Lung Neoplasms; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neoplasm Transplantation; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Receptor, IGF Type 1; Receptor, Insulin; Tumor Burden; Vascular Endothelial Growth Factor A

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes-mediated mammary tumor progression.. We studied mammary tumor development in MKR(+/+) mice, a nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR(+/+) mice were either crossed with mice expressing the polyoma virus middle T oncogene specifically in the mammary gland or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR(+/+) or control mice harboring tumors were treated with CL-316243, a specific beta3-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells.. CL-316243 treatment significantly reduced the elevated insulin levels in MKR(+/+) mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of insulin and IGF-I receptors in transformed mammary tissue.. Insulin-sensitizing treatment is sufficient to abrogate type 2 diabetes-mediated mammary tumor progression. Therefore, early administration of insulin-sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.

Topics: Animals; Body Composition; Cell Line, Tumor; Comorbidity; Diabetes Mellitus, Type 2; Dioxoles; Disease Models, Animal; Disease Progression; Eating; Epithelial Cells; Female; Hyperinsulinism; Hypoglycemic Agents; Insulin; Lipids; Male; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mice; Mice, Inbred Strains; Mice, Transgenic; Polyomavirus; Risk Factors

The antiobesity and antidiabetic effects of the beta3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a beta3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that beta3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for beta3-adrenergic agonists in nonobese diabetic subjects.

Topics: Adipocytes; Adipose Tissue; Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Composition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Glucose; Insulin; Lipid Metabolism; Liver; Mice; Mice, Inbred NOD; Oxidation-Reduction; Receptors, Adrenergic, beta-3

Our aim was to determine the effect of a beta3-adrenoceptor agonist on plasma adiponectin levels and on the level of expression of mRNA for adiponectin, adiponectin receptor 1, and adiponectin receptor 2 in db/db mice. Two weeks' oral administration of CL-316,243 led to decreased plasma levels of hemoglobin A1c, glucose, insulin, triglyceride and free fatty acid, and to an increased plasma adiponectin levels. It also improved insulin resistance in the oral glucose tolerance test. Adiponectin mRNA expression was significantly higher in the CL-316,243-treatment group than in the control group in epididymal white adipose tissue but not in brown adipose tissue, soleus muscle or liver. Adiponectin receptor 2 mRNA expression was significantly lower only in the liver of the CL-316,243-treatment group (versus the control group). These results suggest that the increased plasma adiponectin levels seen in db/db mice treated with this beta3-adrenoceptor agonist induce a down-regulation of adiponectin receptor 2 mRNA expression specifically in the liver.

Topics: Adiponectin; Adipose Tissue; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dioxoles; Eating; Fatty Acids; Gene Expression; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Receptors, Adiponectin; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a beta(3)-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5 degrees C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary beta(3)-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Eating; Energy Metabolism; Insulin; Ion Channels; Islets of Langerhans; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Receptors, Cytoplasmic and Nuclear; Thermogenesis; Transcription Factors; Uncoupling Protein 1

Methylsulfonamide substituted 2,4-thiazolidinedione 22c is a potent (EC50=0.01 microM, IA=1.19) and selective (more than 110-fold over beta1 and beta2 agonist activity) beta3 agonist. This compound has also been proven to be active and selective in an in vivo mode.

Topics: Adrenergic beta-3 Receptor Agonists; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Mice; Mice, Knockout; Mice, Transgenic; Obesity; Structure-Activity Relationship; Thiazoles; Thiazolidinediones

CL316243 is a highly selective and potent beta3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.

Topics: Adrenergic beta-Agonists; Animals; Biological Availability; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Esters; Fatty Acids; Half-Life; Haplorhini; Humans; Hydrolysis; Hypoglycemic Agents; Mice; Obesity; Prodrugs; Rats

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Lipolysis; Male; Mice; Mice, Obese; Obesity; Substrate Specificity