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Background and Aims Primary Focal Segmental Glomerulosclerosis (FSGS) is the most common primary glomerular disease in patients with end stage renal disease in the United States. Current treatment regimens target reduction in proteinuria, but may have limited response or exhibit disease recurrence. CCX140 is an orally-administered selective small molecule inhibitor of the C-C chemokine receptor 2 (CCR2) under investigation for the treatment reduction of proteinuria in patients with FSGS. The primary objectives of this study were to evaluate the safety and efficacy of CCX140 in patients with FSGS and a urine protein to creatinine ratio (UPCR) of ≥1 g/g. Efficacy was assessed by the change in UPCR. Method Forty-six adult patients with primary or genetic FSGS were randomized into a double-blind, placebo-controlled Phase 2 dose-ranging study designed to evaluate the safety and efficacy of CCX140. Changes of urinary protein excretion estimation (UPCR) from baseline to Week 12 were measured in four blinded treatment groups (three active CCX140 doses of 5 mg once daily, 10 mg and 15 mg twice-daily (BID) vs placebo). Starting at Week 12, all subjects including those in the placebo group received the CCX140, 15 mg BID for an additional 12 weeks, and UPCR changes from Week 12 to Week 24 were assessed. There was a 4-week follow-up period from Week 24 to Week 28 where no CCX140 was administered. Results In the intent to treat (ITT) analysis of UPCR changes at Week 12 relative to baseline, the 15 mg BID CCX140 group exhibited the greatest reduction of UPCR (median reduction from baseline 0.9 g/g or approximately 30%, and approximately 25% reduction from baseline for the geometric mean), but that did not differ significantly from the placebo group (median reduction from baseline 0.45 g/g; or approximately 22%, and approximately 23% reduction from baseline for the geometric mean). Also, after crossover of the blinded portion of the trial to 15 mg BID active dosing, the previous placebo group did not appear to exhibit an additional reduction of UPCR. CCX140 at all doses was well-tolerated, with no serious adverse events (SAEs) during the blinded trial and a numerically lower rate of treatment-emergent adverse events in the CCX140 treatment groups. Conclusion In the study, CCX140 did not demonstrate a therapeutically meaningful reduction in proteinuria relative to the control group after 12 weeks of blinded treatment. The study provides insights into the natural disease progression of patients with primary or genetic FSGS as part of a clinical trial setting.

In the ABSORB II trial, comparing Absorb™ bioresorbable vascular scaffold with metallic XIENCE™ everolimus-eluting stent (EES), a difference was found in site-reported new or worsening angina using adverse event (AE) reporting. However, the clinical relevance of this site-reported angina is unclear. The aim of the present study was therefore to investigate the clinical relevance of site-reported angina by evaluating its relation with cardiac endpoints, cardiovascular resource utilization (including diagnostics and treatment), positive exercise stress tolerance tests (ETTs), and Seattle Angina Questionnaire (SAQ).Site-reported new or worsening angina was captured on cardiac AE forms. There was a wide variation in the total number of days with site-reported angina (overall interquartile range 35-279 days). Patients with site-reported angina showed higher rates of cardiovascular events [including the patient-oriented composite endpoint of all deaths, all myocardial infarctions (MI), or all revascularizations (21.1 vs. 4.2%, P0.0001), all MIs (2.3 vs. 0%, P = 0.03), and all revascularizations (21.1 vs. 0.7%, P0.0001)], cardiovascular resource utilization (including stress tests, anti-anginal medication, diagnostic angiographies, and hospitalization), and positive ETTs (51.9 vs. 14.9%, P0.001), compared with those without site-reported angina. Furthermore, an event-based analysis of the SAQ showed that patients with ongoing angina within the recall period of 4 weeks prior to the SAQ assessment have clinically and statistically significant decrements of14 points in SAQ scores compared with those with no reported angina.We showed that the site-reported angina through AE reporting may be clinically relevant because of their relation with cardiovascular events (mostly repeat revascularizations), cardiovascular resource utilization, ETT, and SAQ.https://clinicaltrials.gov/ct2/show/NCT01425281; Unique identifier: NCT01425281.

The Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) is designed to reduce chronic adverse cardiovascular events that may occur from the permanent presence of a metallic stent and/or durable polymer. The systemic pharmacokinetic (PK) profile of BVS has not been

GS-9667, a new selective, partial agonist of the A(1) adenosine receptor (AR), may represent an effective therapy for Type 2 diabetes (T2DM) and dyslipidemia via lowering of free fatty acids (FFA). The objectives of the studies were to evaluate the effects of single and multiple doses of GS-9667 on plasma FFA concentrations, its pharmacokinetics (PK) and safety/tolerability. Two studies were conducted. In the single ascending dose study, healthy, non-obese, and obese subjects received a single oral dose of GS-9667 (30-1,800 mg). In the multiple, ascending dose study, healthy, obese subjects received GS-9667 (600-2,400 mg QD, 1,200 mg BID, or 600 mg QID) for 14 days. Blood and urine samples were collected for lipid profiling and PK analyses. The ECG, vital signs, and subject tolerability were monitored. Doses of GS-9667 ≥300 mg caused dose-dependent reductions in FFA levels that were reproducible over 14 days without evidence of desensitization or rebound. All doses were well tolerated. GS-9667 was rapidly absorbed and distributed; Steady-state concentrations were achieved within 3-5 days. The A(1) AR partial agonist GS-9667 reduced plasma FFA, exhibited linear kinetics, and was well-tolerated in healthy non-obese and obese subjects.

Selective serotonin reuptake inhibitors (SSRIs) may be associated with electrocardiographic effects. The electrocardiographic pharmacodynamics of dapoxetine, a short-acting SSRI being developed for the treatment of premature ejaculation, are compared with those of placebo and moxifloxacin (positive control) in 2 single-center, randomized, crossover studies in healthy men. In study 1, subjects receive 2 doses of dapoxetine 120 mg, given 3 hours apart; a single dose of moxifloxacin 400 mg; and 2 doses of placebo, given 3 hours apart. In study 2, subjects receive single doses of dapoxetine 60 mg, dapoxetine 120 mg, moxifloxacin 400 mg, and placebo. Moxifloxacin significantly increases QT and corrects QT intervals (QTc) compared with placebo in both studies (eg, Bazett-corrected QTc of 11.90 milliseconds [95% confidence interval, 2.68 to 21.11] and 5.06 [95% confidence interval, -2.26 to 12.38]). Dapoxetine 60, 120, and 240 mg do not prolong the QT/QTc interval and have no clinically significant electrocardiographic effects. Dapoxetine and moxifloxacin pharmacokinetics are similar to previous reports. Adverse events are generally mild in severity; nausea is the most common. The results demonstrate that dapoxetine does not have electrocardiographic effects at doses of 60, 120, and 240 mg.

Aims Theoretically, bioresorbable vascular scaffolds (BVSs) may provide superior long-term results compared with permanent metallic drug-eluting stents (DESs). However, whether BVSs are as safe and effective as metallic DESs prior to complete bioresorption is unknown. Methods and results ABSORB Japan was a single-blind, multicentre, active-controlled, randomized trial designed to support regulatory approval of the Absorb BVS in Japan. Eligible patients with one or two de novo lesions in different epicardial vessels were randomized at 38 Japanese sites in a 2:1 ratio to Absorb BVS vs. cobalt-chromium everolimus-eluting stents (CoCr-EESs). The primary endpoint was target lesion failure [TLF: a composite of cardiac death, myocardial infarction attributable to target vessel, or ischaemia-driven target lesion revascularization (ID-TLR)] at 12 months, powered for non-inferiority. The major secondary endpoint was angiographic in-segment late lumen loss (LLL) at 13 months. A total of 400 patients were randomized to BVSs (266 patients and 275 lesions) or CoCr-EESs (134 patients and 137 lesions). TLF through 12 months was 4.2% with BVSs and 3.8% with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.39% (3.95%); P non-inferiority < 0.0001]. Definite/probable stent/scaffold thrombosis at 12 months occurred in 1.5% of the patients with both devices ( P = 1.0), and ID-TLR for restenosis was infrequent (1.1% with BVSs and 1.5% with CoCr-EESs, P = 1.0). With 96.0% angiographic follow-up, in-segment LLL at 13 months was 0.13 ± 0.30 mm with BVSs and 0.12 ± 0.32 mm with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.01 (0.07); P non-inferiority < 0.0001). Conclusion In the ABSORB Japan randomized trial, 12-month clinical and 13-month angiographic outcomes of BVSs were comparable to CoCr-EESs. Clinical registration ClinicalTrials.gov, number [NCT01844284][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01844284&atom=%2Fehj%2Fearly%2F2015%2F08%2F28%2Feurheartj.ehv435.atom

Despite rapid dissemination of an everolimus-eluting bioresorbable scaffold for treatment for coronary artery disease, no data from comparisons with its metallic stent counterpart are available. In a randomised controlled trial we aimed to compare an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent. Here we report secondary clinical and procedural outcomes after 1 year of follow-up. In a single-blind, multicentre, randomised trial, we enrolled eligible patients aged 18-85 years with evidence of myocardial ischaemia and one or two de-novo native lesions in different epicardial vessels. We randomly assigned patients in a 2:1 ratio to receive treatment with an everolimus-eluting bioresorbable scaffold (Absorb, Abbott Vascular, Santa Clara, CA, USA) or treatment with an everolimus-eluting metallic stent (Xience, Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetes status and number of planned target lesions. The co-primary endpoints of this study are vasomotion (change in mean lumen diameter before and after nitrate administration at 3 years) and difference between minimum lumen diameter (after nitrate administration) after the index procedure and at 3 years. Secondary endpoints were procedural performance assessed by quantitative angiography and intravascular ultrasound; composite clinical endpoints based on death, myocardial infarction, and coronary revascularisation; device and procedural success; and angina status assessed by the Seattle Angina Questionnaire and exercise testing at 6 and 12 months. Cumulative angina rate based on adverse event reporting was analysed post hoc. This trial is registered at ClinicalTrials.gov, number NCT01425281. Between Nov 28, 2011, and June 4, 2013, we enrolled 501 patients and randomly assigned them to the bioresorbable scaffold group (335 patients, 364 lesions) or the metallic stent group (166 patients, 182 lesions). Dilatation pressure and balloon diameter at the highest pressure during implantation or postdilatation were higher and larger in the metallic stent group, whereas the acute recoil post implantation was similar (0.19 mm for both, p=0.85). Acute lumen gain was lower for the bioresorbable scaffold by quantitative coronary angiography (1.15 mm vs 1.46 mm, p

Acute or chronic activation of AMP-activated protein kinase (AMPK) increases insulin sensitivity. Conversely, reduced expression and/or function of AMPK might play a role in insulin resistance in type 2 diabetes. Thus protein expression of the seven subunit isoforms of AMPK and activities and/or phosphorylation of AMPK and acetyl-CoA carboxylase-β (ACCβ) was measured in skeletal muscle from obese type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Protein expression of all AMPK subunit isoforms (α1, α2, β1, β2, γ1, γ2, and γ3) in muscle of obese type 2 diabetic subjects was similar to that of control subjects. In addition, α1- and α2-associated activities of AMPK, phosphorylation of α-AMPK subunits at Thr172, and phosphorylation of ACCβ at Ser221showed no difference between the two groups and were not regulated by physiological concentrations of insulin. These data suggest that impaired insulin action on glycogen synthesis and lipid oxidation in skeletal muscle of obese type 2 diabetic subjects is unlikely to involve changes in AMPK expression and activity.

Udgivelsesdato: 2003-Oct AIMS: In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action. METHODS: We studied seven obese Type 2 diabetic patients twice: once with (+ ON) and once without (- ON) prior overnight insulin infusion. Glucose turnover rates were quantified by adjusted primed-constant 3-3H-glucose infusions, and insulin action was assessed in 4-h euglycaemic, hyperinsulinaemic (40 mU m-2 min-1) clamp studies using labelled glucose infusates (Hot-GINF). RESULTS: Basal plasma glucose levels (mean +/- sd) were 5.5 +/- 0.5 and 10.7 +/- 2.9 mmol/l in the + ON and - ON studies, respectively, and were clamped at -5.5 mmol/l. Basal rates of glucose production (GP) were similar in the + ON and - ON studies, 83 +/- 13 vs. 85 +/- 14 mg m-2 min-1 (NS), whereas basal rates of glucose disappearance (Rd) were lower in the + ON than in the - ON study, 84 +/- 8 vs. 91 +/- 11 mg m-2 min-1 (P = 0.02). During insulin infusion in the clamp period, rates of GP, 23 +/- 11 vs. 25 +/- 10 mg m-2 min-1, as well as rates of Rd, 133 +/- 32 vs. 139 +/- 37 mg m-2 min-1, were similar in the + ON and - ON studies, respectively (NS). CONCLUSIONS: Apart from basal rates of Rd, assessment of glucose turnover rates in euglycaemic clamp studies of Type 2 diabetic patients is not dependent on the method by which plasma glucose levels are lowered.

Several problems limit quantification of gluconeogenesis. We applied in vitro 2H-nuclear magnetic resonance (NMR) spectroscopy to simultaneously measure 2H in all glucose carbons for direct assessment of gluconeogenesis. This method was compared with 2H measurement in carbons 5 and 2 using gas chromatography–mass spectrometry (hexamethylenetetramine [HMT]) and with in vivo 13C magnetic resonance spectroscopy (MRS). After 14 h of fasting, and following 2H2O ingestion, blood was obtained from nine healthy and seven type 2 diabetic subjects. Glucose was purified, acetylated, and analyzed for 2H in carbons 1–6 with 2H-NMR. Using 5:2 ratios, gluconeogenesis increased (P < 0.05) over time and mean gluconeogenesis was lower in control subjects than in type 2 diabetic patients (63 ± 3 vs. 75 ± 2%, P < 0.01). 13C-MRS revealed higher hepatic glycogenolysis in control subjects (3.9 ± 0.4 vs. 2.3 ± 0.2 μmol · kg−1 · min−1) yielding mean contribution of gluconeogenesis of 65 ± 3 and 77 ± 2% (P < 0.005). Measurement of gluconeogenesis by 2H-NMR correlated linearly with 13C-MRS (r = 0.758, P = 0.0007) and HMT (r = 0.759, P = 0.0007). In an additional protocol, 2H enrichments demonstrated a fast decline of gluconeogenesis from ∼100 to ∼68% (P < 0.02) within 4 h of galactose infusion after 40–44 h of fasting. Thus, in vitro 2H-NMR offers an alternative approach to determine fractional gluconeogenesis in good agreement with standard methods and allows monitoring of rapid metabolic alterations.

Udgivelsesdato: 2003-Feb We have recently reported a progressive decline in the expression of glucose transporter isoform 4 (GLUT4) from control subjects through obese non-diabetics to obese type 2 diabetic subjects, indicating that the reduced GLUT4 in slow twitch fibres could be secondary to obesity. In this study we investigate the association of GLUT4 expression with the intracellular triglyceride (TG) content in the same muscle fibres and with plasma lipid parameters. We used histochemistry and stereology to study the relationship between TG content and GLUT4 expression in muscle fibres from obese, obese type 2 diabetic subjects, and young lean controls. TG density was significantly higher in slow compared to fast fibres in all studied subjects (p0.05). Plasma TG and FFA did not correlate with GLUT4 expression in slow or fast fibres (p>0.05). In conclusion, TG content was increased in diabetic slow fibres with a reduced GLUT4 expression. The GLUT4 expression was not associated with an increased intracellular triglyceride content or with increased plasma FFA levels. Thus, intracellular TG content and circulating FFA may not influence glucose transport directly through GLUT4 expression.

BACKGROUND Protein phosphatase 2A (PP2A) acts on a number of enzymes involved in the insulin regulation of glucose uptake and glycogen synthesis. This study was carried out to investigate the effect of insulin on PP2A expression in skeletal muscles of type 2 diabetic and control subjects. MATERIAL AND METHODS Ten type 2 diabetic and 10 matched, control subjects were studied using the euglycaemic-hyperinsulinaemic clamp technique combined with indirect calorimetry. Immunoreactive protein levels of the catalytic alpha subunit of PP2A (PP2A-C alpha) were measured in biopsies from the vastus lateralis muscle obtained in the basal and insulin-stimulated state. RESULTS In type 2 diabetic subjects insulin-mediated glucose disposal, glucose oxidation and nonoxidative glucose metabolism were reduced, whereas lipid oxidation was increased (all P < 0.05). Insulin down-regulated PP2A-C alpha expression in skeletal muscle of the control subjects (P < 0.05) but not in the type 2 diabetic subjects. In the control subjects, the insulin-mediated decrease in PP2A-C alpha correlated with the insulin-mediated increase in glucose disposal, glucose oxidation, nonoxidative glucose metabolism (all P < 0.05) and decrease in lipid oxidation (P < 0.01). In the type 2 diabetic subjects these relationships were absent. CONCLUSIONS Down-regulation of PP2A-C alpha expression by insulin in skeletal muscle seems to be associated with a normal insulin action on glucose storage, glucose and lipid oxidation. Impaired down-regulation of PP2A-C alpha expression by insulin may be a marker for insulin resistance and contribute to the pathogenesis of type 2 diabetes.

Based on recent studies, including our own, using what we consider to be an appropriate technique to estimate rates of hepatic glucose production (HGP), this article can be summarized as follows: 1) HGP in the overnight fasted state is near normal in obese type 2 diabetes (T2D) subjects, i.e., it may be increased by a mean of 12% compared to matched control subjects. 2) Suppression of HGP by insulin shows a rightward shift of the dose response curve (reduced insulin sensitivity) but normal maximal suppression (no maximum velocity defect). 3) In the overnight fasted state, gluconeogenesis is responsible for two thirds of HGP in T2D subjects and is about 5% to 10% increased compared to healthy subjects. 4) Suppression of HGP during a meal is close to normal. 5) The slightly increased HGP values throughout the 24-hour period together with reduced metabolic clearance rate (peripheral insulin resistance) and increased carbohydrate intake is responsible for the increase in fasting plasma glucose values. 6) Hypothetically, the role of the liver in nondiabetic and T2D subjects may be to produce the amount of glucose needed for metabolism in peripheral tissues. If insulin-mediated glucose uptake in skeletal muscle is reduced, plasma glucose will increase due to the "nonsuppressed" HGP values. Plasma glucose continues to rise until glucose-mediated glucose uptake compensates completely for the reduction in insulin-mediated glucose uptake.

Selective serotonin reuptake inhibitors (SSRIs) may be associated with electrocardiographic effects. The electrocardiographic pharmacodynamics of dapoxetine, a short-acting SSRI being developed for the treatment of premature ejaculation, are compared with those of placebo and moxifloxacin (positive control) in 2 single-center, randomized, crossover studies in healthy men. In study 1, subjects receive 2 doses of dapoxetine 120 mg, given 3 hours apart; a single dose of moxifloxacin 400 mg; and 2 doses of placebo, given 3 hours apart. In study 2, subjects receive single doses of dapoxetine 60 mg, dapoxetine 120 mg, moxifloxacin 400 mg, and placebo. Moxifloxacin significantly increases QT and corrects QT intervals (QTc) compared with placebo in both studies (eg, Bazett-corrected QTc of 11.90 milliseconds [95% confidence interval, 2.68 to 21.11] and 5.06 [95% confidence interval, -2.26 to 12.38]). Dapoxetine 60, 120, and 240 mg do not prolong the QT/QTc interval and have no clinically significant electrocardiographic effects. Dapoxetine and moxifloxacin pharmacokinetics are similar to previous reports. Adverse events are generally mild in severity; nausea is the most common. The results demonstrate that dapoxetine does not have electrocardiographic effects at doses of 60, 120, and 240 mg.

To compare the effects of age, gender, body mass index, and diabetes on the safety and efficacy of regadenoson stress myocardial perfusion imaging, and to assess the noninferiority of regadenoson to adenosine for the detection of reversible myocardial perfusion defects.Previous reports have shown that a fixed unit bolus of regadenoson is safe and noninferior to adenosine for the detection of reversible perfusion defects by radionuclide imaging.Using a database of 2,015 patients, we evaluated the effects of age, gender, body mass index, and diabetes on the safety and efficacy of regadenoson compared to adenosine.For detection of ischemia relative to adenosine, noninferiority was demonstrated for all patients (agreement rate difference 0%, 95% CI -6.2% to +6.8%). The average agreement rate between adenosine-adenosine and adenosine-regadenoson were 0.62 +/- 0.03 and 0.63 +/- 0.02. Detection of ischemia was also comparable in specific subgroups. Agreement was less for both agents in women versus men with moderate and large areas of ischemia. Compared to adenosine, regadenoson had a lower combined symptom score and less chest pain, flushing, and throat, neck, or jaw pain, but more headache and gastrointestinal discomfort. This was true in nearly all subgroups. Regadenoson patients reported feeling more comfortable (1.7 +/- .02 vs. 1.9 +/- 0.03, p0.001). Based on the overall tolerability score, women felt less comfortable than men with both stress agents. Image quality was rated good or excellent in 92% for both agents.Regadenoson can be safely administered as a fixed unit bolus and is as efficacious as adenosine in detecting ischemia regardless of age, gender, body mass index, and diabetes. Regadenoson is better tolerated overall and across various subgroups.

The effect of increased glycogenolysis, simulated by galactose's conversion to glucose, on the contribution of gluconeogenesis (GNG) to hepatic glucose production (GP) was determined. The conversion of galactose to glucose is by the same pathway as glycogen's conversion to glucose, i.e., glucose 1-phosphate → glucose 6-phosphate → glucose. Healthy men ( n = 7) were fasted for 44 h. At 40 h, hepatic glycogen stores were depleted. GNG then contributed ∼90% to a GP of ∼8 μmol·kg−1·min−1. Galactose, 9 g/h, was infused over the next 4 h. The contribution of GNG to GP declined from ∼90% to 65%, i.e., by ∼2 μmol·kg−1·min−1. The rate of galactose conversion to blood glucose, measured by labeling the infused galactose with [1-2H]galactose ( n = 4), was also ∼2 μmol·kg−1·min−1. The 41st h GP rose by ∼1.5 μmol·kg−1·min−1and then returned to ∼9 μmol·kg−1·min−1, while plasma glucose concentration increased from ∼4.5 to 5.3 mM, accompanied by a rise in plasma insulin concentration. Over 50% of the galactose infused was accounted for in blood glucose and hepatic glycogen formation. Thus an increase in the rate of GP via the glycogenolytic pathway resulted in a concomitant decrease in the rate of GP via GNG. While the compensatory response to the galactose administration was not complete, since GP increased, hepatic autoregulation is operative in healthy humans during prolonged fasting.

Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.

The objective of the study is identify and document drug-related problems and other possible quality problems in primary care through a pharmacist-run medication review and screening service. GPs’ acceptance and implementation rates of the pharmacist’s recommendations are evaluated. A community pharmacist worked 20 h per week for 18 months in a GP practice with three GPs. The pharmacist completed 40 reviews and identified 103 drug-related problems. GPs had a high rate of acceptance of the pharmacist’s suggested interventions (83%), and 77% of the recommendations had been implemented. 765 (12.5%) possible quality problems were identified after screening 6094 medical records. The physicians accepted 86% of the recommendations to initiate low dosage ASA and treatment was implemented for 63% of the patients. 76% of the recommendations to initiate Statin treatment were agreed on and 56% were implemented. The pharmacist was able to identify drug-related problems and other possible quality problems with regard to quality assurance of individual patient’s drug treatment. The GPs accepted and implemented the pharmacist’s recommendations. It was feasible to implement the services and to establish well-functioning co-operation between the pharmacist and the GPs.

Udgivelsesdato: 2003-Jun In type 2 diabetes, insulin activation of muscle glycogen synthase (GS) is impaired. This defect plays a major role for the development of insulin resistance and hyperglycemia. In animal muscle, insulin activates GS by reducing phosphorylation at both NH(2)- and COOH-terminal sites, but the mechanism involved in human muscle and the defect in type 2 diabetes remain unclear. We studied the effect of insulin at physiological concentrations on glucose metabolism, insulin signaling and phosphorylation of GS in skeletal muscle from type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Analysis using phospho-specific antibodies revealed that insulin decreases phosphorylation of sites 3a + 3b in human muscle, and this was accompanied by activation of Akt and inhibition of glycogen synthase kinase-3alpha. In type 2 diabetic subjects these effects of insulin were fully intact. Despite that, insulin-mediated glucose disposal and storage were reduced and activation of GS was virtually absent in type 2 diabetic subjects. Insulin did not decrease phosphorylation of sites 2 + 2a in healthy human muscle, whereas in diabetic muscle insulin infusion in fact caused a marked increase in the phosphorylation of sites 2 + 2a. This phosphorylation abnormality likely caused the impaired GS activation and glucose storage, thereby contributing to skeletal muscle insulin resistance, and may therefore play a pathophysiological role in type 2 diabetes.

Defects in hepatic insulin action in type 2 diabetes and its possible underlying mechanisms were assessed in euglycemic-hyperinsulinemic clamp studies, using improved tracer methods (constant specific activity technique). Ten obese diabetic patients (age 54 years, BMI 29 ± 0.5 kg/m2) and ten matched control subjects were studied at baseline (after an overnight fast) and during insulin infusions of 20- and 40-mU · m–2 · min–1. In the diabetic patients, plasma glucose levels were normalized overnight before the studies by low-dose insulin infusion. Hepatic sinusoidal insulin levels were estimated, and plasma levels of free fatty acids (FFAs) and glucagon were determined to assess the direct and indirect effects of insulin on hepatic glucose production (HGP) in type 2 diabetes. Baseline rates of HGP (86 ± 3 vs. 76 ± 3 mg · m–2 · min–1, P < 0.05) were slightly elevated in the diabetic patients compared with control subjects, despite much higher hepatic sinusoidal insulin levels (26 ± 3 vs. 12 ± 2 mU/l, P < 0.001). Consequently, a marked defect in the direct (hepatic) effect of insulin on HGP appeared to be present at low insulin levels. However, in response to a small increase in baseline hepatic sinusoidal insulin levels of 11 mU/l (26 ± 3 to 37 ± 3 mU/l, P < 0.05) in the 20-mU clamp, a marked suppression of HGP was observed in the diabetic patients (86 ± 3 to 32 ± 5 mg · m–2 · min–1, P < 0.001), despite only minimal changes in FFAs (0.33 ± 0.05 to 0.25 ± 0.05 mmol/l, NS) and glucagon (14 ± 1 to 11 ± 2 pmol/l, P < 0.05) levels, suggesting that the impairment in the direct effect of insulin can be overcome by a small increase in insulin levels. Compared with control subjects, suppression of HGP in the diabetic patients was slightly impaired in the 20-mU clamp (32 ± 5 vs. 22 ± 4 mg · m–2 · min–1, P < 0.05) but not in the 40-mU clamp (25 ± 2 vs. 21 ± 3 mg · m–2 · min–1, NS). In the 20-mU clamp, hepatic sinusoidal insulin levels in the diabetic patients were comparable with control subjects (37 ± 3 vs. 36 ± 3 mU/l, NS), whereas both FFA and glucagon levels were higher (i.e., less suppressed) and correlated with the rates of HGP (R = 0.71, P < 0.02; and R = 0.69, P < 0.05, respectively). Thus, at this insulin level impaired indirect (extrahepatic) effects of insulin seemed to prevail. In conclusion, hepatic insulin resistance is present in obese type 2 diabetic patients but is of quantitative significance only at low physiological insulin levels. Defects in both the direct and the indirect effects of insulin on HGP appear to contribute to this resistance.

Udgivelsesdato: 2000-Nov Prompted by our recent observations that GLUT-1 is expressed in fetal muscles, but not in adult muscle fibers, we decided to investigate whether GLUT-1 expression could be reactivated. We studied different stimuli concerning their ability to induce GLUT-1 expression in mature human skeletal muscle fibers. Metabolic stress (obesity, non-insulin-dependent diabetes mellitus), contractile activity (training), and conditions of de- and reinnervation (amyotrophic lateral sclerosis) could not induce GLUT-1 expression in human muscle fibers. However, regenerating muscle fibers in polymyositis expressed GLUT-1. In contrast to GLUT-1, GLUT-4 was expressed in all investigated muscle fibers. Although the significance of GLUT-1 in adult human muscle fibers appears limited, GLUT-1 may be of importance for the glucose supplies in immature and regenerating muscle.

To measure possible changes in basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from insulin-resistant individuals, soluble and particulate muscle fractions were prepared from biopsies taken before and after a 3-h hyperinsulinaemic euglycaemic clamp in eight non-insulin-dependent diabetic (NIDDM) patients and nine control subjects. We used a sensitive sandwich-immunofluorescence assay and the human insulin receptor as the substrate. PTPase activity was expressed as percentage of dephosphorylation of phosphotyrosyl-residues in immobilized insulin receptors per 2 h incubation time per 83 micrograms and 19 micrograms muscle fraction protein (soluble and particulate fraction, respectively). In the diabetic soluble muscle fractions, the basal PTPase activity was decreased compared with that of control subjects (11.5 +/- 5.5 vs 27.5 +/- 3.3, p0.04, mean +/- SEM). In the particulate muscle fractions from the control subjects, PTPase activity was increased after 3 h hyperinsulinaemia (20.0 +/- 3.2 vs 30.2 +/- 3.6, p0.03) and in the corresponding soluble fractions PTPase activity seemed decreased (27.5 +/- 3.3 vs 19.9 +/- 5.9, NS). No effect of insulin on PTPase activity was found in NIDDM patients (25.1 +/- 4.1 vs 27.2 +/- 5.2, 11.5 +/- 5.5 vs 15.1 +/- 4.5 [particulate and soluble fractions], NS). In conclusion, we found that the basal PTPase activity in soluble muscle fractions was decreased in NIDDM patients; furthermore, insulin stimulation was unable to increase PTPase activities in the particulate fractions, as opposed to the effect of insulin in control subjects.

To gain further insight into the mechanisms underlying muscle insulin resistance, the influence of obesity and type 2 diabetes on GLUT4 immunoreactivity in slow and fast skeletal muscle fibers was studied. Through a newly developed, very sensitive method using immunohistochemistry combined with morphometry, GLUT4 density was found to be significantly higher in slow compared with fast fibers in biopsy specimens from lean and obese subjects. In contrast, in type 2 diabetic subjects, GLUT4 density was significantly lower in slow compared with fast fibers. GLUT4 density in slow fibers from diabetic patients was reduced by 9% compared with the weight-matched obese subjects and by 18% compared with the lean control group. The slow-fiber fraction was reduced to 86% in the obese subjects and to 75% in the diabetic subjects compared with the control group. Estimated GLUT4 contribution from slow fibers was reduced to 77% in the obese subjects and to 61% in type 2 diabetic patients compared with the control subjects. We propose that a reduction in the fraction of slow-twitch fibers, combined with a reduction in GLUT4 expression in slow fibers, may reduce the insulin-sensitive GLUT4 pool in type 2 diabetes and thus contribute to skeletal muscle insulin resistance.

The safety and performance of the Absorb Bioresorbable Vascular Scaffold (Absorb, Abbott Vascular, Santa Clara, CA) has been previously demonstrated with clinical data up to 5 years (Cohort A), 3 years (Cohort B), 2 years (EXTEND). ABSORB FIRST is designed for post-approval surveillance of Absorb