Endocrine Abstracts

Lipid sensing by pancreatic beta cells is co-ordinated through the expression and activity of peroxisome proliferator-activated receptors (PPARs). Through their action to lower triacylglycerol delivery to peripheral tissues, PPARalpha activators also oppose insulin resistance by relieving inhibition of insulin-stimulated glucose disposal. Mid to late pregnancy is an insulin-resistant state associated with hypertriglyceridaemia. We investigated regulatory interactions between PPARalpha activation and insulin sensitivity and glucose-stimulated insulin secretion (GSIS) at mid (15 day) pregnancy in the rat (term = 23 days). Pregnancy was associated with increased GSIS after intravenous glucose challenge (500 mg/kg) at 15 days of pregnancy. Both the acute insulin response (AIR, mean of suprabasal 2- and 5-min plasma insulin) and total suprabasal 30-min area under insulin curve (IAUC-insulin) were increased (by 2.5-fold and 2.7-fold respectively; both P<0.001)) compared with unmated female rats. Pregnancy-induced hyperinsulinaemia compensates for the development of insulin resistance. The insulin resistance (IR) index, the product of the areas under the glucose and insulin curves after glucose challenge, had increased significantly by 3.2-fold (P<0.001) at day 15 of pregnancy. GSIS at day 15 of pregnancy was greatly attenuated by 24 h treatment with PPARalpha activation by WY14,643, as reflected by 50% and 54% decreases in AIR (P<0.01) and IAUC-insulin (P<0.001). PPARalpha activation specifically targeted insulin hypersecretion since GSIS was unaffected by WY14,643 treatment in unmated rats. Acute (24 h) treatment of 15-day-pregnant rats with WY14,643 did not affect IAUC-glucose (suprabasal 30-min area under glucose curve) and only slightly decreased (9%) the k value for glucose disappearance, but the IR index (IAUC-insulin x IAUC-glucose) was significantly lowered (by 50%; P<0.01), indicating that acute (24 h) PPARalpha activation significantly improved insulin sensitivity in the pregnant group. Our data demonstrate, for the first time, an acute (24 h) effect of PPARalpha activation to enhance whole-body insulin sensitivity during pregnancy, in conjunction with attenuated differences in GSIS in vivo.