Effects of troglitazone on substrate storage and utilization in insulin-resistant rats

Abstract

Elevated serum and tissue lipid stores are associated with skeletal muscle insulin resistance and diminished glucose-stimulated insulin secretion, the hallmarks of type 2 diabetes. We studied the effects of 6-wk treatment with the insulin sensitizer troglitazone on substrate storage and utilization in lean control and Zucker diabetic fatty (ZDF) rats. Troglitazone prevented development of diabetes and lowered serum triglycerides (TG) in ZDF rats. Soleus muscle glycogen and TG content were elevated twofold in untreated ZDF rats, and both were normalized by troglitazone to lean control levels ( P < 0.05). Troglitazone also normalized insulin-stimulated glucose uptake as well as basal and insulin-stimulated glycogen synthesis, implying increased skeletal muscle glycogen turnover. The proportion of active pyruvate dehydrogenase (PDH) in soleus muscle was reduced in ZDF relative to lean control rat muscle (16 ± 2 vs. 21 ± 2%) but was restored by troglitazone treatment (30 ± 3%). Increased PDH activation was associated with a 70% increase in glucose oxidation. Muscle lipoprotein lipase activity was decreased by 35% in ZDF compared with lean control rats and was increased twofold by troglitazone. Palmitate oxidation and incorporation into TG were higher in ZDF relative to lean control rats but were unaffected by troglitazone treatment. Troglitazone decreased the incorporation of glucose into the acyl group of TG by 60% in ZDF rats. In summary, ZDF rats demonstrate increased skeletal muscle glycogen and TG stores, both of which were reduced by troglitazone treatment. Troglitazone appears to increase both glycogen and TG turnover in skeletal muscle. Normalization of PDH activity and decreased glucose incorporation into acyl TG may underlie the improvements in intracellular substrate utilization and energy stores, which lead to decreased serum TG and glucose.

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

“…[6][7][8][9][10][11] In the current studies, we concentrated on the role of resistin in lipid metabolism. We tested the hypothesis that resistin might promote release of FFA from adipocytes by suppressing the re-esterfication of FFA into triglycerides.…”

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

“…The lipid content of muscle, liver, and pancreas significantly correlates with insulin sensitivity (6,7), and a strong negative correlation has been demonstrated in skeletal muscle between insulin-stimulated glucose uptake and local accumulation of TG (5,8 -10). In support of this, reduction of skeletal muscle, liver, and islet TG, with either troglitazone or leptin, results in an increase in insulin-stimulated glucose uptake and a decrease in insulin resistance (11,12).…”

Thiazolidinediones: metabolic actions in vitro

“…4C) [121]. Under the latter conditions, an insulin-dependent increase in glycogen synthesis is accompanied by an insulin-independent increase in glucose oxidation [121], which is a pattern of changes as in soleus muscle specimens prepared from orally TZD-treated obese rodents [16,18,91]. Although parallel responses to prolonged TZD treatment in vitro and in vivo support the idea that direct action on muscle could be important for therapeutic TZD action, any conclusion from long-term incubation of isolated muscle is hampered by the fact that the regulation of glucose metabolism could change considerably in muscle cells devoid of their physiologic environment.…”

“…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.…”