Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)␥ and -␣ influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR␥ agonist pioglitazone and PPAR␣/␥ dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR␣ agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR␥ compounds markedly increased feed efficiency, whereas PPAR␣ agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazoneand ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fatfed rats. In conclusion, PPAR␥ activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR␥ activation on feeding and feed efficiency appears to be partially independent because the PPAR␣ component of ragaglitazar completely counteracts the orexigenic actions of PPAR␥ activation without marked impact on feed efficiency. Diabetes 52:2249 -2259, 2003 T he nuclear receptors, peroxisome proliferatoractivated receptors (PPARs), constitute a family of three genes, PPAR␣, -␥, and -(␦), all of which are involved in control of energy homeostasis (1,2). Unequivocal evidence of endogenous ligands for PPAR␣ and -␥ is lacking, but a number of synthetic PPAR activating ligands exist, of which hypolipidemic fibric acids are typical examples of PPAR␣ activators while hypoglycemic thiazolidinediones are typical examples of PPAR␥ activators.The antidiabetic effects of PPAR␥ agonists are partly mediated via increased insulin sensitivity of adipose tissue and skeletal muscle. From clinical experience, PPAR␥ agonists are associated with weight gain, whereas PPAR␣ agonists appear body weight neutral (3). Part of the body weight increase may be caused by their oedema-inducing class effect, but activators of PPAR␥ also induce adipogenesis (4,5). They act preferentially on subcutaneous adipocytes, which in comparison to intrabdominal adipocytes express higher levels of PPAR␥ (6). The long-term metabolic consequences of the increased fat accumulation accompanying treatment with PPAR␥ agonists are not fully elucidated. Intrabdominal body fat accumulation is one of several hallmarks typifying the metabolic syndrome and, as such, an independent risk factor of type 2 diabetes (7-9). Many clinical trials of oral antidiabetic agents (including PPAR␥ agonists) are conspicuous by their absence of obese test subjec...
Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.
BackgroundIn humans and animal models, excessive intake of dietary fat, fructose and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD). However, the individual roles of the dietary components remain unclear. To investigate this further, we compared the effects of a high-fat diet, a high-fructose diet and a combination diet with added cholesterol on the development of NAFLD in rats.MethodsForty male Sprague–Dawley rats were randomized into four groups receiving either a control-diet (Control: 10% fat); a high-fat diet (HFD: 60% fat, 20% carbohydrate), a high-fructose diet [HFr: 10% fat, 70% carbohydrate (mainly fructose)] or a high-fat/high-fructose/high-cholesterol-diet (NASH: 40% fat, 40% carbohydrate (mainly fructose), 2% cholesterol) for 16 weeks.ResultsAfter 16 weeks, liver histology revealed extensive steatosis and inflammation in both NASH- and HFD-fed rats, while hepatic changes in HFr-rats were much more subtle. These findings were corroborated by significantly elevated hepatic triglyceride content in both NASH- (p < 0.01) and HFD-fed rats (p < 0.0001), elevated hepatic cholesterol levels in NASH-fed rats (p < 0.0001), but no changes in HFr-fed rats, compared to Control. On the contrary, only HFr-fed rats developed dyslipidemia as characterized by higher levels of plasma triglycerides compared to all other groups (p < 0.0001). Hepatic dysfunction and inflammation was confirmed in HFD-fed rats by elevated levels of hepatic MCP-1 (p < 0.0001), TNF-alpha (p < 0.001) and plasma β-hydroxybutyrate (p < 0.0001), and in NASH-fed rats by elevated levels of hepatic MCP-1 (p < 0.01), increased hepatic macrophage infiltration (p < 0.001), and higher plasma levels of alanine aminotransferase (p < 0.0001) aspartate aminotransferase (p < 0.05), haptoglobin (p < 0.001) and TIMP-1 (p < 0.01) compared to Control.ConclusionThese findings show that dietary fat and cholesterol are the primary drivers of NAFLD development and progression in rats, while fructose mostly exerts its effect on the circulating lipid pool.
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