Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism

Abstract

New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARγ‐agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats. Both BM13.1258 and BM15.2054 revealed to be potent PPARγ‐activators in transient transfection assays in vitro. In insulin‐resistant obese rats, but not in lean rats, 10 days of oral treatment with either compound increased the stimulatory effect of insulin on muscle glycogen synthesis to a similar extent (insulin‐induced increment in μmol glucose incorporated into glycogen g−1 h−1: control, +1.19±0.28; BM13.1258, +2.50±0.20; BM15.2054, +2.55±0.46; P<0.05 vs control each). In parallel to insulin sensitization, mean glucose oxidation increased insulin‐independently in response to BM13.1258 (to 191 and 183% of control in the absence and presence of insulin, respectively; P<0.01 each), which was hardly seen in response to BM15.2054 (to 137 and 124% of control, respectively; ns). Comparable effects on PPARγ activation and on amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore opposed by different effects on glucose oxidation. In contrast to chronic oral treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucose metabolism in specimens from both lean and obese rats. The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action. Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARγ are involved in the antidiabetic actions of thiazolidinediones. British Journal of Pharmacology (1999) 128, 1141–1148; doi:

Rosiglitazone balances insulin-induced exo- and endocytosis in single 3T3-L1 adipocytes

“…Although it is generally thought that TZDs mediate their insulin-sensitizing effects via PPARγ, PPARγ-independent pathways have also been suggested (Blackmore et al, 1993;Furnsinn et al, 1999;Preininger et al, 1999;Chawla et al, 2001). …”

Thiazolidinediones: metabolic actions in vitro

“…In many studies, TZDs were found to stimulate glucose transport into skeletal muscle in vitro [16,70,111,112,113,114,115,116,117,118,119,120] but the accompanying changes in intracellular glucose fluxes were rather inconsistent, ranging from stimulation to inhibition of both glucose oxidation and glycogen synthesis [16,70,111,112,113,114,121]. The heterogeneity of effects on intracellular glucose routing is obviously related to the diversity in experimental settings.…”

“…The most important observation supporting a causal interdependence between TZD-induced PPARγ activation and the improvement of glucose homeostasis is the association of PPARγ agonistic activity in vitro with antidiabetic action in vivo, which characterizes numerous TZDs [16,37,69,70,71,72], and also non-TZD PPARγ agonists belonging to the classes of isoxazolidinediones [73,74], tyrosine derivatives [75,76,77], and phenylacetic or phenoxyacetic acid derivatives [37]. Although the maximal antihyperglycaemic potentials of many TZDs and other PPARγ agonists are similar, oral dose requirements for half-maximal glucose lowering in diabetic mice differ considerably and correlate strongly with PPARγ binding activities and transactivating potentials of the respective compound in vitro [37, 69,71].…”

“…The heterogeneity of effects on intracellular glucose routing is obviously related to the diversity in experimental settings. Studies varied with regard to the structure and concentration of the TZD used, the period of exposure, and the muscle preparations which included perfused rat hindlimb [120], freshly isolated rat soleus muscle [16,111,112,113,121], pre-cultured human muscle biopsies [114,115,116], and permanently cultured muscle cell lines [70,117,118,119]. Comparing different studies is further complicated by the lipophilic character of TZDs that strongly bind to protein [122], which implies a modulation of the bioavailable TZD concentration in vitro by the quantity and quality of protein and detergent added to the incubation or perfusion medium.…”

“…Euglycaemic-hyperinsulinaemic clamp tests on Type II diabetic patients and insulin resistant rodents showed that oral TZD treatment improves insulinstimulated glucose disappearance [7,8,9,10,11,12,13,14,15], which is reflected by increased glucose transport into insulin-stimulated skeletal muscle [16,17,18] and fat [5,6,8,19] ex vivo. In parallel to TZD-induced peripheral insulin sensitization, an improved ability of insulin to suppress glucose appearance, which is basically a function of the liver, was observed in most [7,8,9,10,11] but not all [12,13,15] clamp studies.…”