Acylation stimulating protein stimulates insulin secretion

Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal.     

Assessment of residual tissue viability by exercise testing in recent myocardial infarction: comparison of the electrocardiogram and myocardial perfusion scintigraphy.

The assessment of residual myocardial viability in infarcted areas is relevant for subsequent management and prognosis but requires expensive technology. To evaluate the possibility that simple, easily obtainable clinical markers may detect the presence of within-infarct viable tissue, the significance of exercise-induced ST elevation occurring in leads exploring the area of a recent Q wave myocardial infarction was assessed. Twenty-five patients with recent (less than 6 months) myocardial infarction were studied. All had angiographically documented coronary artery disease, diagnostic Q waves (n = 24) or negative T waves (n = 25) on the rest 12-lead electrocardiogram and exhibited during exercise greater than or equal to 1.5 mm ST segment elevation (n = 17) or isolated T wave pseudonormalization (n = 8) in the infarct-related leads. ST-T wave changes were reproduced in all patients during thallium-201 exercise myocardial scintigraphy. A fixed perfusion defect was observed in 24 of the 25 patients. A reversible defect was seen in 16 (94%) of 17 patients who exhibited transient ST elevation during exercise but in only 4 (50%) of the 8 patients who had only T wave pseudonormalization. In conclusion, in patients with recent myocardial infarction, analysis of simple ST segment variables obtained during exercise testing may allow a first-line discrimination of those who may potentially benefit from a revascularization procedure.     

Acylation-stimulating protein: effect of acute exercise and endurance training

INTRODUCTION: Acylation-stimulating protein (ASP) is an adipocyte-derived protein that contributes to fatty acid clearance. Regular exercise training improves fatty acid handling. OBJECTIVE: To examine the effect of acute exercise and short-term endurance training on ASP levels. SUBJECTS: Eight untrained men (age: 23.5+/-3.4 y; maximal power output (Wmax): 3.7+/-0.6 W/kg body weight). DESIGN: Subjects were trained for 2 weeks. Before and after training, blood was sampled during a 3-h exercise test, and insulin sensitivity was assessed by an insulin tolerance test. RESULTS: Before training, ASP levels decreased during exercise (from 17.9+/-2.9 to 15.5+/-3.7 nmol/l at t=0 vs 180, P<0.05). Endurance training decreased fasting ASP levels significantly (17.9+/-2.9 vs 13.4+/-2.3 nmol/l pre- and post-training, P<0.001). Interestingly, after 2 weeks of endurance training, ASP levels tended to increase during exercise (from 13.4+/-2.3 to 17.2+/-4.5 nmol/l at t=0 vs 180, P=0.09). Baseline ASP levels correlated negatively with insulin sensitivity both before (r=-0.86, P<0.01) and after training (r=-0.82, P<0.05). CONCLUSION: Short-term endurance training reduces baseline ASP levels. These data fit with the hypothesis that reduced ASP levels indicate improved ASP sensitivity.     

Plasma acylation-stimulating protein,adiponectin, leptin,and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects

We examined fasting plasma insulin, acylation-stimulating protein (ASP), leptin, adiponectin, ghrelin, and metabolic/cardiovascular risk profile before and 15 +/- 6 months after isolated Roux-en-Y gastric bypass surgery in 50 morbidly obese subjects. Average preoperative plasma lipids were mostly normal, whereas ASP, insulin, and leptin were elevated, and adiponectin and ghrelin were decreased. Postoperatively, body weight decreased significantly (-36.4 +/- 9.6%) and was best predicted by preoperative adiponectin concentration in weight-stable subjects (r = -0.59; P = 0.02). Plasma lipids and insulin resistance improved, leptin and ASP decreased (-76.3 +/- 14.6% and -35.9 +/- 52.2%; P < 0.001), and adiponectin increased (50.1 +/- 47.0%; P < 0.001). The decrease in apolipoprotein B was best predicted by the decrease in ASP (r = 0.55; P = 0.009), whereas the improved postoperative insulin sensitivity was best predicted by the increase in adiponectin (r = 0.70; P = 0.01). Despite bypassing 95% of the stomach and isolating the fundus from contact with ingested nutrients, circulating ghrelin did not decrease after surgery. In fact, plasma ghrelin increased postoperatively in the subset of subjects undergoing active weight loss (+60.5 +/- 23.2%; P < 0.001); ghrelin, however, remained unchanged in weight-stable subjects. In summary, 1) preoperative adiponectin concentrations may be predictive of the extent of weight loss; 2) changes in ASP and adiponectin are predictive of decreased apolipoprotein B and improved insulin action, respectively; and 3) plasma ghrelin increases after gastric bypass surgery in patients experiencing active weight loss.     

Acylation stimulating protein reduction precedes insulin sensitization after BPD-DS bariatric surgery in severely obese women

Objective:

The mechanisms involved in early resolution of insulin resistance and type 2 diabetes mellitus after biliopancreatic diversion with duodenal switch (BPD-DS) surgery are still unknown. We evaluated early effects of BPD-DS on plasma acylation stimulating protein (ASP), an adipokine involved in lipid and glucose metabolism.

Subjects:

32 non-diabetic and 22 diabetic severely obese women (BMI⩾40 kg m⁻²) were evaluated for body composition and plasma parameters before, 24 h, 5 days, 6 and 12 months after surgery.

Results:

Within the early postoperative period (24 h), ASP decreased 25 and 30% in non-diabetic and diabetic women, respectively (P<0.001). Twenty-four hours after surgery, triglyceride, cholesterol, HDL-Chol, LDL-Chol and C3 also decreased, while glucose, insulin and high-sensitivity C-reactive protein (hsCRP) increased (all P<0.001). By 5 days, without significant weight loss, the decreases in ASP, cholesterol, HDL-Chol and LDL-Chol levels were all maintained. At this time, glucose, insulin and HOMA-IR also decreased 11 to 52% (all P<0.001). At 6 and 12 months, with pronounced weight loss and decreased per cent fat mass, there were further decreases in ASP (maximal −56% non-diabetic, −61% diabetic, P<0.001), as well as in glucose, insulin, HOMA-IR, triglyceride, cholesterol, LDL-Chol, HDL-Chol and hsCRP levels. Improved insulin resistance/diabetes at 5 days was predicted by 24 h changes as follows: per cent change ASP, HDL-Chol, hsCRP and total cholesterol predicted HOMA-IR (5 days) (r²=0.454, P<0.001), and per cent change ASP, HDL-Chol and hsCRP predicted change (5 days vs baseline) in HOMA-IR (r²=0.351, P<0.001).

Conclusion:

Acute postoperative decreases in ASP are associated with early improvement of insulin resistance/diabetes after BPD-DS surgery.     

Autoantibodies against oxidized low density lipoproteins in patients with stable angina, unstable angina or peripheral vascular disease; pathophysiological implications.

BACKGROUND: Antibody antioxidized low density lipoproteins (oxLDL) might play a role both in atherogenesis and in the pathogenesis of acute coronary syndromes. METHODS AND RESULTS: Antibody titres to oxLDL and levels of C-reactive protein were compared in unstable angina, stable angina or peripheral artery disease. Antibody titres to LDL oxidated by CuSO(4)for 2, 4 and 18 h (Cu-oxLDL-Ab(2-4-18)) or by peroxidase (HRP-oxLDL-Ab) were assessed by ELISA. Cu-oxLDL-Ab(2-4-18)were consistently higher in peripheral artery disease than in unstable angina (P<0.001, P<0.001, P=0.01, respectively) or in stable angina (P<0.001, P=0.01, P=ns) but similar in unstable and stable angina. Accordingly, HRP-oxLDL-Ab were higher in peripheral artery disease than in unstable angina (P<0.001) or stable angina (P=0.04) but similar in unstable and stable angina. The number of arterial stenoses was higher in peripheral artery disease than unstable and stable angina (P<0.01). Cu-oxLDL-Ab and HRP-oxLDL-Ab correlated with the severity of atherosclerosis (P<0.01, R=0.4;P=0.02, R=0.3 respectively). Conversely, C-reactive protein levels were higher in unstable than in stable angina (P<0.001) or in peripheral artery disease (P<0.03) but similar in stable angina and peripheral artery disease and did not correlate with the severity of atherosclerosis. CONCLUSION: The autoimmune response to oxLDL is likely to play an important role in atherogenesis but not in precipitating acute coronary syndromes.     

Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI

Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG- and PA-mediated signaling. We previously showed that Src-dependent activation and plasma membrane recruitment of DGKα are required for growth-factor-induced cell migration and ruffling, through the control of Rac small-GTPase activation and plasma membrane localization. Herein we unveil a signaling pathway through which DGKα coordinates the localization of Rac. We show that upon hepatocyte growth-factor stimulation, DGKα, by producing PA, provides a key signal to recruit atypical PKCζ/ι (aPKCζ/ι) in complex with RhoGDI and Rac at ruffling sites of colony-growing epithelial cells. Then, DGKα-dependent activation of aPKCζ/ι mediates the release of Rac from the inhibitory complex with RhoGDI, allowing its activation and leading to formation of membrane ruffles, which constitute essential requirements for cell migration. These findings highlight DGKα as the central element of a lipid signaling pathway linking tyrosine kinase growth-factor receptors to regulation of aPKCs and RhoGDI, and providing a positional signal regulating Rac association to the plasma membrane.