s-15261 and Insulin-Resistance

S 15261 is a novel oral antihyperglycaemic drug with both insulin secretagogue and insulin-sensitizing effects. The study was designed to determine the biological activity of its two major metabolites, S 15511 and Y 415, and whether or not they have an additive effect.. Zucker Diabetic Fatty rats were treated for 28 days with S 15511 (10 mg/kg), Y 415 (10 mg/kg), or a combination at the same doses for a period of 4 weeks starting at 6-7 weeks of age. An additional group was pair-fed to the level of S 15511-treated animals to determine if possible effects were due to reduced food intake.. S 15511 alone and combined with Y 415 reduced energy intake and weight gain (-13% vs. controls; both p < 0.01). Baseline fasting plasma glucose levels were maintained by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) for the entire treatment period (p < 0.01). Baseline insulin was maintained by pair-feeding only, whereas all other treated groups became hyperinsulinaemic (+110-276%; p < 0.05). Deterioration in insulin sensitivity [homeostasis model assessment (HOMA)-IR: + 239%; p < 0.01] was attenuated by S 15511, S 15511 + Y 415 and pair-feeding (p < 0.01) and was compensated for by improved insulin secretion (HOMA-beta; p < 0.01). Oral glucose tolerance tests, performed on days 0, 14 and 28, showed that all groups had an impaired insulin response, but by day 28, S 15511, S 15511 + Y 415 and pair-feeding had improved glucose disposal compared to the progressive deterioration in untreated controls (-44% to -48% vs. controls; p < 0.01), associated with progression to frank diabetes in these animals.. Treatment with these agents in a genetic model of type 2 diabetes reveals that they all have a transient effect compared to the progressive worsening of vehicle-treated controls. The improvements in glucose metabolism observed with S 15511 are significant, however, suggesting it has more therapeutic activity than the Y 415 metabolite of S 15261. It is associated with less frequent progression to diabetes; i.e. Y 415 exerts a non-significant effect alone and no significant additive effect when combined with S 15511. The mechanism of action of S 15511 may be via increased insulin sensitivity and beta-cell response preservation up to day 21. Thus, previously reported insulin secretagogue effects are likely to be attributable to the parent compound.

Topics: Animals; Blood Glucose; Body Fat Distribution; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Eating; Fluorenes; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Rats; Rats, Zucker; Weight Gain

S-15261 is a new oral anti-hyperglycemic agent that increases insulin sensitivity in various insulin-resistant animal models. The aim of this study was to determine the short- and long-term effects of S-15261 and its metabolites (S-15511 and Y-415) on fatty acid and glucose metabolism in hepatocytes isolated from 24-h starved rats. During short-term exposure (1h) neither S-15261 nor its metabolites affected fatty acid oxidation whatever the concentration used. By contrast, S-15261 and its two metabolites reduced the rates of glucose production from lactate/pyruvate and dihydroxyacetone. Using crossover plot analysis, it was shown that Y-415 reduced hepatic gluconeogenesis upstream the formation of dihydroxyacetone phosphate. After 48 h in culture, S-15261 and its two metabolites reduced the rates of glucose production from lactate/pyruvate secondarily to a decrease in PEPCK and Glc-6-Pase mRNA levels. A part of these effects on gene expression could be due to a drug-induced reduction in PGC-1 gene expression. When hepatocytes were cultured in the presence of a submaximal concentration of insulin (10(-9)M), S-15261, through its metabolite S-15511, enhanced insulin sensitivity both on gene expression (PEPCK, Glc-6-Pase, PGC-1) and on gluconeogenesis. Furthermore, S-15261 and S-15511 induced the expression of GK and FAS genes as the result of an increased in SREBP-1c mRNA levels. Finally, S-15511 enhanced the stimulatory effect of insulin on GK mRNA level through an additional increase in SREBP-1c gene expression. In conclusion, this work reveals that S-15261 via its metabolites reduces hepatic glucose production through direct and insulin-sensitizing effects on genes encoding regulatory proteins of hepatic glucose metabolism.

Topics: Animals; Base Sequence; Cells, Cultured; DNA Primers; Fluorenes; Gluconeogenesis; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Oleic Acid; Oxidation-Reduction; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

Topics: Animals; Blood Glucose; Body Weight; Chromans; Eating; Fluorenes; Gene Expression; Glucose Tolerance Test; Glucose-6-Phosphatase; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin Resistance; Lactic Acid; Lipids; Liver; Male; Mesenteric Arteries; Metformin; Muscle Relaxation; Muscle, Smooth, Vascular; Phosphoenolpyruvate Carboxylase; Rats; RNA, Messenger; Thiazoles; Thiazolidinediones; Troglitazone; Vascular Resistance

The new compound S 15261 (CAS 159978-02-6) is the I-isomer of 3-[2-[2-[4-[2-(alpha-Fluorenylacetylamino)ethyl]benzoyloxy]ethylam ino]-1- methoxyethyl]trifluoromethylbenzene. The general synthetic pathway used for the preparation of S 15261 and related esters is given in this paper. This compound was selected for its promising therapeutical action on blood glucose, insulin resistance and associated risk factors present in patients with non-insulin-dependent Diabetes mellitus (NIDDM). The general pharmacological profile of S 15261 was investigated. The data given in this paper show that S 15261 has presented a very low acute toxicity (lethal dose in mice greater than 1600 mg/kg orally) and did not induce significant behavioural changes in rats. A poor anorectic effects was observed after acute administration in rats. In guinea pigs S 15261 acutely induced a significant and dose-dependent hypoglycaemic effect (ED25 = 40 mg/kg orally). Biogenic amines and their metabolites in different structures of the brain were only slightly affected after acute administration of S 15261. Chronic administration of this compound (2.5 mg/kg bid for 14 days p.o.) did not cause significant alterations in the brain amines content, with the exception of an increase of serotonin (19%) in the striatum, a result not confirmed by the dose-effect study (from 1 mg/kg to 12.5 mg/kg bid for 14 days p.o.). In vitro binding assays with 31 different receptors did not show significant affinity of S 15261 for any of them. The rat arterial blood pressure was decreased (12 mmHg) after acute (25 mg/kg i.v.) or repeated administration (2.5 mg/kg bid for 14 days p.o.) without any dose-dependent effect. We therefore conclude that S 15261 may not have significant adverse effect even at doses higher than the pharmacological effective range of doses. Although the mechanism of action of this new class of compounds was not fully understood, other pharmacological data suggest that S 15261 acts at both the liver (intraportal infusion) and skeletal muscle (microdialysis studies) at least in part to enhance insulin sensitivity. For all these activities S 15261 may be useful to treat patients with NIDDM or insulin resistance known to be the major risk for onset of NIDDM.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Biogenic Monoamines; Blood Glucose; Blood Pressure; Brain Chemistry; Feeding Behavior; Female; Fluorenes; Guinea Pigs; Insulin Resistance; Male; Mice; Pain Measurement; Radioligand Assay; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Cell Surface; Serotonin Receptor Agonists

A histological study has been conducted on pancreata from insulin resistant sand rats treated with S15261. As previously shown, standard laboratory chow induced dietary hyperinsulinaemia, insulin resistance and hyperlipaemia in sand rats (Psammomys obesus). Degranulation, vacuolization and even necrosis of beta-cells were observed in these animals. These changes were often accompanied by fibrosis and lymphocytic infiltration. Insulin and amylin immuno-reactivity of beta-cells was markedly decreased whilst glucagon secreting cells were localized now in the centre of the islets. Chronic treatment with S15261, a compound able to restore insulin sensitivity in insulin resistant animals, promoted the regranulation of the beta-cells and maintained the usual cytoarchitecture and integrity of the islets.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Fluorenes; Gerbillinae; Insulin Resistance; Islets of Langerhans

S15261 is a novel compound that has been proposed for the treatment of insulin resistance syndrome. We have studied the effects of this drug in insulin resistant sand rats (Psammomys obesus). When sand rats are transferred from their natural desert environment and placed on a laboratory chow diet, they become overweight, develop hypertriglyceridaemia, hypercholesterolaemia, become insulin resistant, and ultimately diabetic. In the present study glucose intolerant animals, with very mild if any hyperglycaemia were used. Chronic treatment for a month with S15261 normalised plasma levels of triglycerides and cholesterol. The effects on cholesterol were the result of a decrease in LDL- and VLDL-cholesterol without any modification of HDL-cholesterol. In this study only female sand rats showed elevated plasma glucose levels, which were normalised by S15261. The compound also decreased plasma insulin levels both in male and female sand rats. An oral glucose tolerance test showed a major improvement in glucose tolerance in both male and female animals treated with S15261. These data confirm in another animal model the therapeutic benefits of S15261 in insulin resistant states.

Topics: Animals; Body Weight; Female; Fluorenes; Gerbillinae; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Lipids; Male

Amylin has been postulated to antagonise or inhibit the action of insulin in peripheral rat tissues and thus contribute to, or be responsible for, the development of insulin resistance. We have recently reported that S15261 is a compound capable of increasing insulin sensitivity in ageing insulin resistant rats. In order to assess whether S15261 had any effects on amylin induced insulin resistance we used a model where amylin causes an impairement in glucose tolerance in an acute manner, by means of an intraportal infusion of the hormone in normal rats. We report here that S15261 can antagonise this amylin-induced impaired glucose tolerance.

Topics: Amyloid; Animals; Fluorenes; Insulin Resistance; Islet Amyloid Polypeptide; Male; Rats; Rats, Sprague-Dawley

A new oral agent, S15261 (the L-isomer of 3-[2-[2-[4-[2-[alpha-fluorenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] trifluoromethyl-benzene), has been developed for the treatment of the so-called "insulin resistance syndrome". In obese, insulin-resistant ageing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg.kg-1.day-1 twice per day, for 14 days) resulted in dose-dependent decreases in plasma insulin (43%), and triglyceride levels (36%), and in an increase of the glucose disposal rate during an intravenous glucose tolerance test (IVGTT) (48.5%). An increase in peripheral insulin sensitivity produced by S15261 was revealed by the glucose clamp technique. Thus, the glucose infusion rate was increased by 20% whilst steady-state insulin levels decreased by 15%. At the higher doses S15261 led to a decrease in body weight (3%), plasma glucose (13%) and blood pressure (8 mm Hg) in mildly hypertensive animals. At the doses used to achieve these results, the compound has no hypoglycaemic activity in normoglycaemic animals. Acute administration of S15261 directly into the portal vein provoked a marked increase in glucose disappearance rate during an intravenous glucose tolerance test (60%) and also in the pancreatic response to the glucose challenge. Thus, acute administration of the compound has a direct effect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome.

Topics: Animals; Blood Glucose; Blood Pressure; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Fluorenes; Fluorobenzenes; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; In Vitro Techniques; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver Glycogen; Male; Obesity; Portal Vein; Rats; Rats, Sprague-Dawley; Syndrome; Triglycerides