mdl-100907 and Insulin-Resistance

Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is a potential antiplatelet agent. We performed a randomized study to evaluate the effect of sarpogrelate on vascular health in Korean patients with diabetes.. Forty diabetic patients aged 58.6 ± 6.8 years with 10-75% coronary artery stenosis, as assessed by coronary computed tomography angiography, were randomly assigned to sarpogrelate 300 mg/day plus aspirin 100 mg/day (SPG + ASA group) or aspirin 100 mg/day alone (ASA group) for 6 months. The primary endpoint of this study was the change in coronary artery disease including the calcium score (CACS), maximal stenosis, and plaque volume (calcified vs. noncalcified). The secondary endpoints were changes in biochemical parameters related to glucose and lipid metabolism, and in subclinical atherosclerosis assessed by ankle-brachial index and pulse wave velocity.. After 6-month treatment, there was no significant difference in the changes in CACS, coronary stenosis, ankle-brachial index, and pulse wave velocity, between groups. The total plaque volume decreased from 82.4 ± 14.5 mm. The present study demonstrated that sarpogrelate treatment may decrease coronary artery plaque volume, particularly the noncalcified portion, in patients with diabetes.

Topics: Adult; Aged; Ankle Brachial Index; Anti-Inflammatory Agents; Aspirin; Biomarkers; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Coronary Vessels; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Insulin Resistance; Male; Middle Aged; Multidetector Computed Tomography; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Pulse Wave Analysis; Republic of Korea; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Succinates; Time Factors; Treatment Outcome; Vascular Calcification

There is considerable interest in the pleiotropic pharmacological action of sarpogrelate hydrochloride, a novel selective serotonin 2A receptor antagonist. In the present study the persistent insulin-sensitizing effects of sarpogrelate were investigated in non-diabetic and non-medicated diabetic patients with peripheral artery disease (PAD).. Indices of insulin resistance (IR) (fasting immunoreactive insulin (IRI) and calculated homeostasis model assessment (HOMA-R)) and adiponectin were measured before and after 2 weeks of sarpogrelate administration (300 mg/day) in 24 patients (19 men, 76+/-9 years) with PAD. Sixteen of the 24 patients were examined after 3 months of treatment for assessment of the chronic effect of sarpogrelate on IR. After 2 weeks of treatment, significant decreases in fasting IRI (p=0.03) and HOMA-R (p=0.024), but not in adiponectin, were observed. After 3 months of treatment, significant decreases in fasting IRI (16.0+/-10.3 vs 9.2+/-2.0 microU/ml, p=0.03) and HOMA-R (4.30+/-2.83 vs 2.40+/-0.74, p=0.025) were maintained. Furthermore, adiponectin was significantly increased (8.11+/-4.13 vs 9.64+/-4.37 microg/ml, p=0.027). All of the examined HOMA-R had a significant correlation with all of the examined adiponectin (p<0.001, r=-0.441).. Sarpogrelate has a persistent insulin-sensitizing effect through adiponectin modification and might be beneficial for anti-atherosclerotic therapy, at least, in non-diabetic and non-medicated diabetic patients with PAD.

Topics: Adiponectin; Aged; Aged, 80 and over; Atherosclerosis; Blood Pressure; Female; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Peripheral Vascular Diseases; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates

Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.

Topics: 14-3-3 Proteins; 3T3-L1 Cells; Adipocytes, White; Animals; Cytosol; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microsomes; Protein Stability; Protein Transport; Proteolysis; Proto-Oncogene Proteins c-akt; Receptor, Serotonin, 5-HT2A; RNA Interference; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Ubiquitination