Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats.

OBJECTIVE: Severe insulin resistance and impaired pancreatic beta-cell function are pathophysiological contributors to type 2 diabetes, and ideally, antihyperglycaemic strategies should address both. RESEARCH DESIGN AND METHODS: Therapeutic benefits of combining the long-acting human glucagon-like peptide-1 (GLP-1) analog, liraglutide (0.4 mg/kg/day), with insulin sensitizer, pioglitazone (10 mg/kg/day), were assessed in severely diabetic Zucker diabetic fatty rats for 42 days. Impact on glycaemic control was assessed by glycated haemoglobin (HbA(1C)) at day 28 and by oral glucose tolerance test at day 42. RESULTS: Liraglutide and pioglitazone synergistically improved glycaemic control as reflected by a marked decrease in HbA(1C) (liraglutide + pioglitazone: 4.8 +/- 0.3%; liraglutide: 8.8 +/- 0.6%; pioglitazone: 7.9 +/- 0.4%; vehicle: 9.7 +/- 0.3%) and improved oral glucose tolerance at day 42 (area under the curve; liraglutide + pioglitazone: 4244 +/- 445 mmol/l x min; liraglutide: 7164 +/- 187 mmol/l x min; pioglitazone: 7430 +/- 446 mmol/l x min; vehicle: 8093 +/- 139 mmol/l x min). A 24-h plasma glucose profile at day 38 was significantly decreased only in the liraglutide + pioglitazone group. In addition, 24-h insulin profile was significantly elevated only in the liraglutide + pioglitazone group. Liraglutide significantly decreased food intake alone and in combination with pioglitazone, while pioglitazone alone increased cumulated food intake. As a result, rats on liraglutide alone gained significantly less weight than vehicle-treated rats, whereas rats on pioglitazone alone gained significantly more body weight than vehicle-treated rats. However, combination therapy with liraglutide and pioglitazone caused the largest weight gain, probably reflecting marked improvement of energy balance because of reduction of glucosuria. CONCLUSIONS: Combination therapy with insulinotropic GLP-1 agonist liraglutide and insulin sensitizer, pioglitazone, improves glycaemic control above and beyond what would be expected from additive effects of the two antidiabetic agents.

Morphine reduces spinal c-fos expression dose-dependently during experimental laparotomy in pigs: a combined pharmacokinetic and surgical study.

The pharmacokinetics of intravenous morphine 2.5mg/kg (n=4) and 10mg/kg (n=4) in plasma and cerebrospinal fluid (CSF) of pigs was studied. Plasma half-life was 1.0+/-0.1h and the main metabolite was morphine-3-glucuronide, whereas morphine-6-glucuronide was negligible. CSF morphine concentration peaked after 20-30min (2.5mg/kg) and 60-120min (10mg/kg), and elimination half-life was 3.5+/-0.3h. Subsequently, the effect of morphine on surgery-induced spinal nociception in pigs subjected to unilateral laparotomy was evaluated by stereological quantification of the total number of Fos-like-immunoreactive (Fos-LI) spinal neurons of the dorsal horn. Surgery (n=4) induced 91,680+/-14,974 Fos-LI neurons ipsilaterally and morphine reduced this number to 45,771+/-8755 following the 2.5mg/kg dose (p<0.01; n=6) and 14,981+/-2327 following the 10mg/kg dose (p<0.001; n=6). These results indicate that morphine dose-dependently reduces the number of surgery-induced Fos-LI neurons in the spinal cord. As even a high dose of morphine does not reduce spinal c-fos expression to basal level, it may be appropriate to use other analgesics simultaneously with morphine during surgery.

Local anaesthetics attenuates spinal nociception and HPA-axis activation during experimental laparotomy in pigs.

The effect of local anaesthetics on spinal nociception and activation of the hypothalamic-pituitary-adrenal axis (HPA-axis) was examined in a porcine model of abdominal surgery. A standardised laparotomy without visceral involvement was performed on 24 pigs. One group received a unilateral infiltration of mixed lidocaine and bupivacaine in skin, muscle and peritoneum of the surgical area prior to surgery (n=12), while local anaesthetics were replaced by isotonic saline in a second group (n=12). A sham group was subjected to anaesthesia (n=8), but did not undergo surgery. Two hours after surgery, half of the pigs from each group were perfused with formalin and the spinal cord was taken out for stereological quantification of the total number of Fos-like-immunoreactive (Fos-LI) neurones in the dorsal horn. Surgery with saline gave rise to a significant increase in the number of Fos-LI neurones ipsilaterally (107,001+/-16,548; p<0.001) as well as contralaterally (12,766+/-3,842; p<0.01) compared to the sham group. In animals undergoing surgery with LA, the number of Fos-LI neurones ipsilaterally was not significantly different from the sham group (p=0.78), and was reduced significantly both ipsilaterally (6960+/-1662; p<0.001) and contralaterally (3974+/-1131; p<0.05) compared to the saline group. In the other half of each group, blood samples, for determination of ACTH, cortisol, C-reactive protein and interleukin-6 concentrations, were drawn prior to and at predetermined time-points during and after surgery. Surgery with saline gave rise to dramatic increases in plasma ACTH and cortisol (p<0.01 and p<0.001, respectively) within 15 min of incision. In contrast, no changes from the initial concentrations of ACTH and cortisol were observed in pigs receiving local anaesthetics. No changes in plasma concentrations of C-reactive protein or interleukin-6 were observed in either of the groups. These results indicate that spinal nociception and HPA-axis activation caused by laparotomy in pigs can be attenuated by use of infiltration and incisional local anaesthetics prior to surgery. The present model provides a valuable tool in the evaluation of analgesic treatment during surgery, offering objective measures of both nociception and stress.

Duplex Doppler measurements of renal blood flow in a dog with Addison's disease.

Abnormal intrarenal flow in a seven-year old female Tibetan terrier with Addison's disease was demonstrated by duplex Doppler examination. Abnormal flow may reflect renal vasoconstriction due to increased activity of the renin-angiotensin system. Although not pathognomonic, an increased resistive index (> 0.70) in an otherwise ultrasonographically normal kidney can be due to Addison's disease and the technique may prove valuable as a quick non-invasive tool in the management of this disease.