Post-meal endogenous insulin secretion was significantly lower in head than in body/tail cancer of the pancreas.

THE AIM: Pancreatic cancer, a rapidly progressive malignancy, is often diagnosed in patients with diabetes. The incidence of pancreatic cancer has risen dramatically over recent decades. Early diagnosis of this malignancy is generally difficult because the symptoms do not become apparent until the disease has progressed, generally leading to a poor outcome. To achieve earlier diagnosis, we analyzed the clinical characteristics of pancreatic cancer patients showing deterioration of plasma glucose levels while hospitalized. METHOD: Thirty-six cases were divided into 2 groups;those diagnosed with diabetes more than a year prior to identification of pancreatic cancer and diabetes secondary to pancreatic cancer. These 2 groups were further subdivided according to the tumor site (head or body/tail), allowing analysis of 4 subgroups. Anthropometric measurements, laboratory values were determined. RESULTS: Both groups with diabetes lost at least 4 kg and showed HbA1c deterioration of at least 1% within 5 months of the pancreatic cancer diagnosis. The post-meal elevation of serum C-peptide immunoreactivity (CPR) was significantly decreased in the group with cancer of the pancreatic head, and this was unrelated to tumor size. CONCLUSION: Characteristically, pancreatic head cancer was associated with decreased endogenous insulin secretion as compared to body/tail cancer. J. Med. Invest. 70 : 350-354, August, 2023.

Emergent transcatheter arterial embolization to control critical blood pressure fluctuation associated with hypercatecholaminemic crisis in a patient with an unruptured retroperitoneal paraganglioma.

Pheochromocytoma/paraganglioma (PPGL)-related hypercatecholaminemic crisis is a rare lethal condition caused by uncontrolled catecholamine secretion, occasionally leading to critical fluctuation in blood pressure (BP). Emergent transcatheter arterial embolization (TAE) has been employed for spontaneous PPGL rupture, but never, to our knowledge, for critical fluctuation in BP associated with PPGL-related hypercatecholaminemic crisis. We describe here our experience utilizing this method to control critical fluctuation in BP associated with this crisis in a 44-year-old man with an unruptured retroperitoneal paraganglioma. The patient experienced sudden severe left abdominal pain and came to our emergency department, where he exhibited severe fluctuation in BP and underwent laboratory testing that showed hypercatecholaminuria and computed tomography (CT) that revealed a left retroperitoneal tumor with no apparent intra- or retroperitoneal hematoma. We performed emergent TAE from the left inferior phrenic artery using gelatin sponge, which stabilized his BP and relieved his abdominal pain. Histologic examination following elective surgical resection of the tumor confirmed our diagnosis of unruptured retroperitoneal paraganglioma. We believe that TAE represents an important option for the emergent treatment of the critical BP fluctuation associated with PPGL-related hypercatecholaminemic crisis.

Serum lactate levels are associated with serum alanine aminotransferase and total bilirubin levels in patients with type 2 diabetes mellitus: A cross-sectional study.

AIMS: It was recently reported that lactate acts as a metabolic mediator and rises in the diabetic state, but the physiological effects are as yet poorly understood. The objective of the current study was to evaluate the significance of serum lactate elevation in type 2 diabetes mellitus (T2DM) patients. METHODS: Fasting serum lactate levels, hematological and inflammatory serum markers and anthropometric parameters, obtained employing bioelectric impedance analysis, were measured in 103 patients with T2DM. RESULTS: Statistically significant correlations of serum lactate levels with C-reactive peptide, insulin, aspartate aminotransferase, alanine aminotransferase (ALT), serum lipids, total bilirubin, adiponectin, homeostasis model assessment-insulin resistance, body weight, body mass index and body fat (weight or percentage of subcutaneous fat, visceral fat or total body fat), but neither fasting plasma glucose nor HbA1c, were detected. Stepwise regression analysis showed ALT to be independently positively associated with total bilirubin, while being negatively associated with serum lactate levels. Furthermore, serum lactate levels were significantly higher in patients with ALT-predominant liver dysfunction. CONCLUSION: We found fasting serum lactate elevation in T2DM patients to be associated with the serum levels of ALT and total bilirubin independently of blood glucose control. TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000029178).

Novel Mechanisms Modulating Palmitate-Induced Inflammatory Factors in Hypertrophied 3T3-L1 Adipocytes by AMPK.

OBJECTIVE: A growing body of evidence indicates that AMP-activated protein kinase (AMPK) contributes to not only energy metabolic homeostasis but also the inhibition of inflammatory responses. However, the underlying mechanisms remain unclear. To elucidate the role of AMPK, in this study, we observed the effects of AMPK activation on monocyte chemoattractant protein-1 (MCP-1) release in mature 3T3-L1 adipocytes. METHODS: We observed signal transduction pathways regulating MCP-1, which increased in obese adipocytes, in an in vitro model of hypertrophied 3T3-L1 adipocytes preloaded with palmitate. RESULTS: Palmitate-preloaded cells exhibited significant increase in MCP-1 release and triglyceride (TG) deposition. Increased MCP-1 release and TG deposition were significantly decreased by an AMPK activator. In addition, the AMPK activator not only markedly diminished MCP-1 secretion but also augmented phosphorylation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) 1/2. In contrast, MCP-1 release suppression was abolished by the AMPK inhibitor compound C and the MEK inhibitor U0126. CONCLUSIONS: MCP-1 release from hypertrophied adipocytes is suppressed by AMPK activation through the NF-κB and ERK pathways. These findings provide evidence that AMPK plays a crucial role in ameliorating obesity-induced inflammation.

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 ß-Cells.

Astaxanthin, an antioxidant agent, can protect pancreatic ß-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in ß-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and VEGF120 (vascular endothelial growth factor). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF120 secretion in mouse insulinoma (MIN6) pancreatic ß-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre-treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH2-terminal protein kinase (JNK) pathways, and suppressed VEGF120 through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF120 secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon.

Correction: Long-Term Low Carbohydrate Diet Leads to Deleterious Metabolic Manifestations in Diabetic Mice.

[This corrects the article DOI: 10.1371/journal.pone.0104948.].

Clinical effect of real time pulse rate monitoring with a portable pulsimeter on physical exercise therapy for male patients with type 2 diabetes.

In patients with type 2 diabetes, it is recommended that exercise therapy is performed using heart rate as an index of exercise intensity. This study was designed to clinically evaluate whether continuous exercise therapy with a portable pulsimeter for self-monitoring of the pulse rate influences glycemic control in patients with type 2 diabetes. We randomly assigned 23 male patients to a pulse displayed group (in which the portable pulsimeter displayed a pulse rate) or a pulse non-displayed group (in which the portable pulsimeter only recorded the data and did not display a pulse rate). The patients then received exercise therapy for 1 month. Patients in the pulse displayed group were instructed to regulate their walking speed by maintaining their portable pulsimeter in the target pulse rate zone, whereas patients in the pulse non-displayed group were instructed to regulate their walking speed while taking their pulse rate and using the Borg scale to maintain the target pulse rate zone using the conventional method. We found the mean walking time within the target pulse rate zone during exercise therapy was significantly increased in the pulse displayed group (p < 0.01). Similarly, glycoalbumin and 1,5-anhydro-D-glucitol improved significantly in the pulse displayed group after 1 month of exercise therapy (p < 0.01, respectively). Our results suggest that this therapeutic device might be useful for improving glycemic control in patients with type 2 diabetes.

The association between impaired proinsulin processing and type 2 diabetes mellitus in non-obese Japanese individuals.

We aimed to examine the association between impaired proinsulin processing in pancreatic beta cells and type 2 diabetes mellitus in non-obese Japanese patients. Participants were divided into groups for normal glucose tolerance, prediabetes, and type 2 diabetes based on the oral glucose tolerance test (OGTT). Activities of prohormone convertase (PC) 1/3 and PC2 in fasting states were estimated. Multiple regression analysis was undertaken to ascertain if alteration of the activities of these enzymes contributes to the development of impaired glucose tolerance by comparison with HOMA-ß and the oral disposition index (DI(O)). Overall, 452 subjects were included. PC1/3 activity tended to decrease in type 2 diabetes compared with normal glucose tolerance. PC2 activity showed no difference among the three groups. Decreased estimated PC1/3 activity was significantly associated with type 2 diabetes after adjustment for sex, age, creatinine, triglycerides, HOMA-ß and DI(O). Odds ratios (95% CI) of PC1/3, HOMA-ß, and DI(O) were 2.16 (1.12-4.19), 3.44 (1.82-6.52) and 14.60 (7.87-27.11), respectively. Furthermore, decreased PC1/3(≤1.7) combined with decreased HOMA-ß (≤30) had a sensitivity of 73% and specificity of 62%. Decreased PC1/3 activity may be a useful measurement of beta-cell function alongside decreased HOMA-ß or DI(O). A combined decrease in estimated fasting PC1/3 activity and HOMA-ß measurement led to suspicion of type 2 diabetes in the non-obese Japanese population studied.

Ghrelin augments the expressions and secretions of proinflammatory adipokines, VEGF120 and MCP-1, in differentiated 3T3-L1 adipocytes.

Ghrelin is a physiological-active peptide with growth hormone-releasing activity, orexigenic activity, etc. In addition, the recent study has also suggested that ghrelin possesses the pathophysiological abilities related with type 2 diabetes. However, the ghrelin-direct-effects implicated in type 2 diabetes on peripheral tissues have been still unclear, whereas its actions on the central nervous system (CNS) appear to induce the development of diabetes. Thus, to assess its peripheral effects correlated with diabetes, we investigated the regulatory mechanisms about adipokines, which play a central role in inducing peripheral insulin resistance, secreted from mature 3T3-L1 adipocytes stimulated with ghrelin in vitro . The stimulation with 50 nmol/L ghrelin for 24 h resulted in the significant 1.9-fold increase on vascular endothelial growth factor-120 (VEGF(120)) releases (p < 0.01) and the 1.7-fold on monocyte chemoattractant protein-1 (MCP-1) (p < 0.01) from 3T3-L1 adipocytes, respectively, while ghrelin failed to enhance tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-10 and adiponectin secretions. In addition, Akt phosphorylation on Ser473 and c-Jun NH2 -terminal protein kinase (JNK) phosphorylation on Thr183/Tyr185 were markedly enhanced 1.4-fold (p < 0.01) and 1.6-fold (p < 0.01) in the ghrelin-stimulated adipocytes, respectively. Furthermore, the treatment with LY294002 (50 µmol/L) and Wortmannin (10nmol/L), inhibitors of phosphatidylinositol 3-kinase (PI3K), significantly decreased the amplified VEGF(120) secretion by 29% (p < 0.01) and 28% (p < 0.01) relative to the cells stimulated by ghrelin alone, respectively, whereas these inhibitors had no effects on increased MCP-1 release. On the other hand, JNK inhibitor SP600125 (10 µmol/L) clearly reduced the increased MCP-1, but not VEGF(120), release by 35% relative to the only ghrelin-stimulated cells (p < 0.01). In conclusion, ghrelin can enhance the secretions of proinflammatory adipokines, VEGF(120) and MCP-1, but fails to affect IL-10 and adiponectin which are considered to be anti-inflammatory adipokines. Moreover, this augmented VEGF(120) release is invited through the activation of PI3K pathways and the MCP-1 is through JNK pathways. Consequently, our results strongly suggest that ghrelin can induce the development of diabetes via its direct-action in peripheral tissues as well as via in CNS.

The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells.

Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPARγ activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPARγ transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPARγ activity enhancing effect of exendin-4 was observed 12h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPARγ activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPARγ activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPARγ activation would have major impacts on treatments for patients at high risk for cardiovascular disease.

Long-term low carbohydrate diet leads to deleterious metabolic manifestations in diabetic mice.

We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.

Estimated proinsulin processing activity of prohormone convertase (PC) 1/3 rather than PC2 is decreased in pancreatic ß-cells of type 2 diabetic patients.

Type 2 diabetic (T2D) patients exhibit fasting relative hyperproinsulinemia owing to pancreatic ß-cell dysfunction. To clarify the mechanism underlying this hyperproinsulinemic state, we evaluated the activities of the endopeptidases prohormone convertase (PC) 1/3 and PC2 in T2D patients. Fasting blood levels of intact proinsulin (IPI), total proinsulin (t-PI) and C-peptide were measured simultaneously, and intravenous glucagon loading was performed to investigate the dynamics of circulating proinsulin-related molecules released from pancreatic ß-cells in 12 healthy volunteers and 18 T2D patients. Taking advantage of the 95% cross-reactivity between proinsulin and des-31,32-proinsulin (des-31,32-PI) with the human proinsulin radioimmunoassay kit used in this study, we estimated PC1/3 and PC2 activities using the following formulas: des-31,32-PI = (t-PI-IPI)/0.95; PC1/3 activity = des-31,32-PI/IPI; and PC2 activity = C-peptide/des-31,32-PI. C-peptide responses to glucagon were slightly lower among T2D patients. IPI and the IPI/C-peptide ratio were significantly higher in T2D patients (p<0.05 and p<0.01, respectively). There was no difference in des-31,32-PI levels or PC2 activity between the two groups. However, PC1/3 activity was significantly lower in T2D patients than in the control group (p<0.01). We propose that decreased activity of PC1/3 rather than PC2 in pancreatic ß-cells is involved in the impaired proinsulin processing, resulting in elevated IPI levels in T2D patients.

Possible involvement of PI3K-dependent pathways in the increased VEGF120 release from osteoblastic cells preloaded with palmitate in vitro.

It have been reported that abnormal bone metabolism often occurs in patients with type 2 diabetes, but the underlying mechanisms remain to be elucidated. In recent years dyslipidemia (hyperlipidemia) has been presumed to have an influence on bone metabolism. In addition, the involvements of VEGF and MCP-1 derived from osteoblasts in bone abnormal metabolism were also observed. Thus, we investigated the pathogenic mechanism of this abnormal bone metabolism, which is included in the regulation of VEGF and MCP-1 secretions from osteoblasts, by using UMR-106 osteosarcoma cells as an osteoblast cell model and treating them with palmitate in order to mimic a state of hyperlipidemia. Palmitate-preloaded cells showed the significant increase of VEGF120 release (1.8-fold vs. control cells, p<0.01). Moreover, the treatment with palmitate significantly increased VEGF-A mRNA with the maximal 2.5-fold upregulation at 12h after the treatment (p<0.01). However, MCP-1 release was not affected by palmitate. Moreover, the amplified VEGF120 secretion with palmitate was significantly decreased by the treatment with TLR4 antagonist or PI3K pathway inhibitors, LY294002 and wortmannin (p<0.01, respectively). On the other hand, the stimulation with TNF-α, which osteoclasts were able to release, significantly enhanced MCP-1 secretion (p<0.01), but had no effect on VEGF120. On the contrary IL-1ß amplified VEGF120 release (p<0.01), but not MCP-1. These results suggest that palmitate can increase VEGF120 release from UMR-106 osteosarcoma cells, which is accelerated at the transcriptional level, and this increase of VEGF120 release may be mediated though, at least partly, TLR4 and the PI3K pathways. In addition, we also verified that TNF-α and IL-1ß, which are considered to be derived from osteoclasts, amplified the secretions of MCP-1 and VEGF120 from UMR-106 cells, respectively.

Endogenous oxidative stress, but not ER stress, induces hypoxia-independent VEGF120 release through PI3K-dependent pathways in 3T3-L1 adipocytes.

OBJECTIVE: Expressions of vascular endothelial growth factor (VEGF) are increased in obese adipocytes and is secreted from obese adipose tissue through hypoxia-independent pathways. Therefore, we investigated the hypoxia-independent mechanism underlying increased expression and release of VEGF in obese adipocytes. DESIGN AND METHODS: We compared signal transduction pathways regulating VEGF with those regulating monocyte chemoattractant protein-1 (MCP-1), which is increased in obese adipocytes, in an in vitro model of artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate, without the influence of hypoxia. RESULTS: Palmitate-preloaded cells exhibited significantly enhanced oxidative stress (P < 0.01) and showed increased VEGF120 and MCP-1 release (P < 0.01, respectively), while endoplasmic reticulum (ER) stress was not induced. Increased VEGF120 release was significantly decreased with PI3K inhibitor LY294002 (P < 0.01). In addition, antioxidant N-acetyl-cysteine (NAC) markedly diminished not only VEGF120 secretion (P < 0.01) but also augmented Akt phosphorylation on Ser473 (P < 0.01). In contrast, increased MCP-1 release was suppressed with JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 (P < 0.01). CONCLUSIONS: VEGF120 release from hypertrophied adipocytes can be enhanced through PI3K pathways activated by oxidative stress but not by ER stress, suggesting that VEGF120 secretion is regulated through oxidative stress-dependent pathways distinct from those involved in MCP-1 release through either JNK or p38 MAPK activation.

Higher levels of ATGL are associated with exercise-induced enhancement of lipolysis in rat epididymal adipocytes.

BACKGROUND: In adipose cells, adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte triacylglyceride hydrolysis, thereby regulating both basal and hormone-stimulated lipolysis. However, little is known about the molecular mechanism(s) underlying habitual exercise-induced adaptive modulation of ATGL in white adipocytes via alteration in transcription regulator and lipolytic cofactors. METHODOLOGY/PRINCIPAL RESULTS: Male Wistar rats were randomly divided into 2 groups a sedentary control group (CG) and a habitual exercise group (EG). The EG was subjected to running on a treadmill set at 5 days per week for 9 weeks. The CG was not subjected to running on a treadmill. In the EG, levels of ATGL mRNA and protein were elevated with a significant increase in lipolysis compared with the CG, accompanied by a significant increase in associations of CGI-58 with ATGL protein. Under these conditions, an upregulation of peroxisome proliferation-activated receptorg-2 (PPARg-2) was observed. In the EG, the addition of rosiglitazone further significantly increased the levels of ATGL protein compared with the CG. However, attenuated levels of the ATGL protein in adipocytes were obtained by the addition of insulin, which is known to inhibit the expression of ATGL, in both types of groups. Actually, levels of plasma insulin were significantly reduced in the EG compared with the CG. CONCLUSIONS: These data suggest that elevated levels of ATGL are involved in the exercise-induced enhancement of lipolysis in primary adipocytes. The exact mechanism(s) underlying this phenomenon is associated, at least in part, with upregulated transcriptional activation of PPARg-2. In addition, exercise-induced lower circulation levels of insulin also correlate with habitual exercise-induced higher levels of ATGL in primary adipocytes.

Preventive and improvement effects of exercise training and supplement intake in white adipose tissues on obesity and lifestyle-related diseases.

Recent increases in the number of obese individuals and individuals suffering from lifestyle-related diseases, such as type 2 diabetes, that accompany obesity have become a serious social problem. White adipose tissue (WAT) is more than a mere organ for storage of energy; it is also a highly active metabolic and endocrine organ that secretes physiologically active substances collectively known as adipokines, including tumor necrosis factor-α and adiponectin. Dysregulated expression of adipokines in WAT that is hypertrophied by obesity has been closely associated with the phenomenon of insulin resistance. Therefore, WAT is currently considered to be one of the tissues that promote lifestyle-related diseases. Reduction of excess WAT that results from obesity is seen as an important strategy in preventing and improving lifestyle-related diseases. This review shows that exercise training as well as intake of supplements, such as polyphenols, is one strategy for this, because this regimen can result in reduction of WAT mass, which affects the expression and secretory response of adipokines.

Induction of mitochondrial uncoupling enhances VEGF120 but reduces MCP-1 release in mature 3T3-L1 adipocytes: possible regulatory mechanism through endogenous ER stress and AMPK-related pathways.

Although white adipocytes contain a larger number of mitochondria per cytoplasmic volume, adipocyte mitochondrial uncoupling to reduce the efficiency of ATP production on cellular function including secretory regulation of bioactive molecules such as VEGF and MCP-1 remains to be elucidated. Here we induce mitochondrial uncoupling under hypoxia-independent conditions in mature 3T3-L1 adipocytes using a metabolic uncoupler, dinitrophenol (DNP). MCP-1 release was significantly decreased by 26% (p<0.01) in 24h DNP (30 µmol/L)-treated adipocytes compared to control cells. In contrast, secreted VEGF(120) lacking a heparin-binding domain was markedly increased 2.0-fold (p<0.01). CHOP content in these cells also were augmented (p<0.01), but no significant increase of endogenous oxidative stress was observed. Treatment with thapsigargin, which can induce exogenous endoplasmic reticulum (ER) stress, clearly attenuated MCP-1 release (p<0.01), but exhibited no effects on VEGF(120) secretion. On the other hand, exogenous H(2)O(2) amplified both MCP-1 and VEGF(120) secretion (p<0.05). In addition, under chronic activation of AMPK by AICAR, MCP-1 release was significantly diminished (p<0.05) but VEGF(120) secretion was increased (p<0.01). JNK phosphorylation in mature adipocytes was decreased by treatment with either DNP or AICAR (p<0.01). Enhanced VEGF(120) secretion with either DNP or AICAR was markedly suppressed by PI3K inhibitor LY294002 (p<0.01). Thus, induced mitochondrial uncoupling in adipocytes can reduce MCP-1 release through induction of endogenous ER stress and by reduced JNK activities via chronic activation of AMPK. Under this condition, VEGF(120) secretion was increased through PI3K-dependent pathways, which were chronically activated by AMPK, and not through ER stress. Because the decrease of MCP-1 secretion under mitochondrial uncoupling might attenuate chronic low-grade inflammation by suppressing macrophages recruitment to adipose tissue, clarification of the mechanism might reveal novel therapeutic targets for ameliorating obesity-associated insulin resistance in metabolic syndrome and type 2 diabetes.