The aim was to examine the role of cyclooxygenase (COX)‐2‐mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high‐fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co‐treated with vehicle (HFa), or a selective COX‐2 inhibitor celecoxib (HFa‐Cel) or mesulid (HFa‐Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12‐week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa‐Cel, and HFa‐Mes. Time‐dependent increases in plasma insulin, glucose, 8‐isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA‐IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. The enhanced COX‐2 and tumor necrosis factor‐α (TNF‐α) but attenuated PPAR‐γ and C/EBP‐α mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa‐Cel and HFa‐Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa‐Cel and HFa‐Mes. Our findings suggest that COX‐2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.

. Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs. Am J Physiol Endocrinol Metab 282: E286-E296, 2002; 10.1152/ajpendo.00201. 2001.-We tested the hypothesis that the loss of hepatic nerves decreases peripheral insulin sensitivity. Surgical hepatic denervation (DN) was performed in 22 dogs ϳ16 days before study; 7 dogs (Sham-Sal) had a sham procedure. A euglycemic hyperinsulinemic (1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ; arterial insulin 35 Ϯ 1 U/ml in all dogs) clamp was performed in conscious dogs. From 0 to 90 min of the clamp, all dogs received the same treatment; then the DN dogs were divided into three groups. From 90 to 180 min, DN-PeA (n ϭ 7) and DN-PoA (n ϭ 7) groups received acetylcholine 2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 via peripheral or portal vein, respectively, and DN-Sal (n ϭ 8) received no acetylcholine. During 150-180 min, the Sham-Sal, DN-Sal, DN-PeA, and DN-PoA groups exhibited glucose infusion rates of 12.4 Ϯ 0.8, 9.3 Ϯ 0.8 (P Ͻ 0.05 vs. Sham-Sal), 9.1 Ϯ 0.1 (P Ͻ 0.05 vs. ShamSal), and 12.7 Ϯ 1.6 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; nonhepatic glucose uptakes of 11.5 Ϯ 0.9, 8.9 Ϯ 0.7 (P Ͻ 0.05 vs. Sham-Sal), 8.6 Ϯ 0.9 (P Ͻ 0.05 vs. Sham-Sal), and 11.9 Ϯ 1.7 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; net hindlimb glucose uptakes of 18.4 Ϯ 2.1, 13.7 Ϯ 1.1 (P Ͻ 0.05 vs. Sham-Sal), 17.5 Ϯ 1.9, and 16.7 Ϯ 3.2 mg/min; and glucose utilization rates of 14.4 Ϯ 1.4, 10.4 Ϯ 0.8 (P Ͻ 0.05 vs. Sham-Sal), 9.8 Ϯ 0.9 (P Ͻ 0.05 vs. Sham-Sal), and 13.6 Ϯ 1.8 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively. DN caused peripheral insulin resistance, and intraportal but not peripheral acetylcholine restored insulin sensitivity. hepatic nerves; acetylcholine HEPATIC DENERVATION has been reported to result in peripheral insulin resistance in both rats and cats (49-51). The insulin resistance, which can be localized primarily to skeletal muscle (50), is reversible by intraportal, but not peripheral, infusion of acetylcholine (49) or a nitric oxide donor (35). This has led Lautt (19) to propose that insulin stimulates a hepatic parasympathetic reflex. According to this hypothesis, the reflex involves the release of acetylcholine, which binds to muscarinic receptors and stimulates the production of nitric oxide within the liver. As a result, the liver releases a humoral factor termed the hepatic insulinsensitizing substance, or HISS, that sensitizes skeletal muscle to insulin or has a direct insulin-like action (19). Although this is a very intriguing suggestion, the studies upon which it is based were performed in acutely denervated anesthetized animals under nonsteady-state conditions with the use of bolus injections of insulin. Therefore, the relevance of these findings to stable, conscious animals receiving physiological amounts of insulin remains to be established.We designed the current studies to test the hypothesis that loss of the hepatic nerves would impair peripheral glucose disposal under carefully controlled hormonal conditions in a physiological model. Specifically, we examined the response of conscious dogs ϳ16 days after hepatic denervation, u...

BackgroundOsteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone.MethodsIn total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up.ResultsAt the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601–0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without.ConclusionsPatients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.

Obesity and insulin resistance are two major risk factors for the development of metabolic syndrome, type 2 diabetes and associated cardiovascular diseases (CVDs). Cyclooxygenase (COX), a rate-limiting enzyme responsible for the biosynthesis of prostaglandins (PGs), exists in two isoforms: COX-1, the constitutive form, and COX-2, mainly the inducible form. COX-2 is the key enzyme in eicosanoid metabolism that converts eicosanoids into a number of PGs, including PGD2, PGE2, PGF2α, and prostacyclin (PGI2), all of which exert diverse hormone-like effects via autocrine or paracrine mechanisms. The COX-2 gene and immunoreactive proteins have been documented to be highly expressed and elevated in adipose tissue (AT) under morbid obesity conditions. On the other hand, the environmental stress-induced expression and constitutive over-expression of COX-2 have been reported to play distinctive roles under different pathological and physiological conditions; i.e., over-expression of the COX-2 gene in white AT (WAT) has been shown to induce de novo brown AT (BAT) recruitment in WAT and then facilitate systemic energy expenditure to protect mice against high-fat diet-induced obesity. Hepatic COX-2 expression was found to protect against diet-induced steatosis, obesity, and insulin resistance. However, COX-2 activation in the epidydimal AT is strongly correlated with the development of AT inflammation, insulin resistance, and fatty liver in high-fat-diet-induced obese rats. This review will provide updated information regarding the role of COX-2-derived signals in the regulation of energy metabolism and the pathogenesis of obesity and MS.