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Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)[gamma] and PPAR[alpha] potentially provides beneficial effects over existing PPAR[gamma] and [alpha] preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPAR[alpha]/[gamma] agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPAR[gamma]/preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb [A.sub.1c] and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb [A.sub.1c] by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPAR[alpha]/[gamma] agonist ragaglitazar seemed to have beneficial impact over that of the PPAR[gamma]-preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats. euglycemic clamp; peroxisome proliferator-activated receptor; ragaglitazar; rosiglitazone; type 2 diabetes; Zucker diabetic fatty

Peroxisome proliferator-activated receptor (PPAR)[alpha], and PPAR[gamma] agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPAR[alpha]/[gamma] agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPAR[alpha] agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPAR[gamma] agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPAR[alpha]/[gamma] agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPAR[gamma] ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPAR, activation, but without hepatomegaly. peroxisome proliferator-activated receptor subtypes; adipokines; tissue lipids; insulin resistance

Research was conducted to examine altered muscle metabolism associated with vasoconstriction in spontaneously hypertensive rats. The effects of norepinephrine (NE), angiotensin II and vasopressin on perfusion pressure and related changes in vasoconstriction and oxygen consumption, glucose uptake and lactate production in the perfused hindlimbs of spontaneously hypertensive rats (SHR) were compared. Results indicate that SHR muscle thermogenesis and glucose uptake are impaired during vasoconstriction, particularly with regards to NE.

The role of alpha1-adrenoceptors on the regulation of oxygen uptake (VO2) by the sympathetic nervous system (SNS) was analyzed in perfused isolated rat hindlimbs. Administration of the alpha1-adrenoceptor, prazosin, in perfused rat hindlimbs attenuated low-frequency increases in VO2 and infusions with phenylephrine (PE) increased perfusion pressure in a dose-dependent manner. The effects of prazosin and PE indicated the regulatory role of alpha1-adrenoceptors on vasoconstriction and metabolic changes induced by SNS.

The regulation of thermogenesis in Tasmanian bettong, Bettongia gaimardi, was investigated in the presence or absence of alpha-adrenoceptors. Injection of norepinephrine, naphazoline, and phenylephrine stimulated oxygen consumption in a dose-dependent manner with a peak at 46.7%, 29.6%, and 34.8%. In contrast, injection of alpha2-adrenergic agonist clonidine had no effect in oxygen consumption, while the beta-adrenergic blocker propranolol blocked the effect of norepinephrine. These results suggest that norepinephrine-induced thermogenesis is mediated by alpha1-adrenoceptors.

A study was conducted to examine the effect of constant-pressure perfusion of the rat hindlimb on alpha- and beta-adrenergic stimulation of oxygen consumption (VO2). The addition of norepinephrine, phenylephrine, vasopressin, isoproterenol and propanolol increased VO2. In contrast, prazosin blocked the increase in VO2 and constricted oxygen flow. These results show that adrenergic agents cause alpha-adrenergic stimulation of VO2.