scholarly journals Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

Metabolomics ◽  
2021 ◽  
Vol 17 (6) ◽  
Author(s):  
Wenyi Wang ◽  
Ko Willems van Dijk ◽  
Carolien A. Wijsman ◽  
Maarten P. Rozing ◽  
Simon P. Mooijaart ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Insulin Infusion ◽  
Low Dose ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
High Dose ◽  
Mixed Effect ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Branched Chain

Abstract Background Insulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants. Methods We assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures. Results After low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e−4), among which glycerol (beta [Confidence Interval] =  − 1.41 [− 1.54, − 1.27] s.d., p = 1.28e−95) and three-hydroxybutyrate (− 1.22 [− 1.36, − 1.07] s.d., p = 1.44e−61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters. Conclusion Metabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.

scholarly journals Rationales and uncertainties for aspirin use in COVID-19: a narrative review

2021 ◽  
Vol 9 (2) ◽  
pp. e000741
Author(s):  
Hazem A Sayed Ahmed ◽  
Eric Merrell ◽  
Mansoura Ismail ◽  
Anwar I Joudeh ◽  
Jeffrey B Riley ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Low Dose ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Narrative Review ◽  
Cochrane Library ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dose Aspirin ◽  
Hospitalised Patients ◽  
Low Dose Aspirin

ObjectivesTo review the pathophysiology of COVID-19 disease, potential aspirin targets on this pathogenesis and the potential role of aspirin in patients with COVID-19.DesignNarrative review.SettingThe online databases PubMed, OVID Medline and Cochrane Library were searched using relevant headlines from 1 January 2016 to 1 January 2021. International guidelines from relevant societies, journals and forums were also assessed for relevance.ParticipantsNot applicable.ResultsA review of the selected literature revealed that clinical deterioration in COVID-19 is attributed to the interplay between endothelial dysfunction, coagulopathy and dysregulated inflammation. Aspirin has anti-inflammatory effects, antiplatelet aggregation, anticoagulant properties as well as pleiotropic effects on endothelial function. During the COVID-19 pandemic, low-dose aspirin is used effectively in secondary prevention of atherosclerotic cardiovascular disease, prevention of venous thromboembolism after total hip or knee replacement, prevention of pre-eclampsia and postdischarge treatment for multisystem inflammatory syndrome in children. Prehospital low-dose aspirin therapy may reduce the risk of intensive care unit admission and mechanical ventilation in hospitalised patients with COVID-19, whereas aspirin association with mortality is still debatable.ConclusionThe authors recommend a low-dose aspirin regimen for primary prevention of arterial thromboembolism in patients aged 40–70 years who are at high atherosclerotic cardiovascular disease risk, or an intermediate risk with a risk-enhancer and have a low risk of bleeding. Aspirin’s protective roles in COVID-19 associated with acute lung injury, vascular thrombosis without previous cardiovascular disease and mortality need further randomised controlled trials to establish causal conclusions.

scholarly journals High Dose Statins: Is it Beneficial over Conventional Dose of Statin in Acute Coronary Syndrome?

1970 ◽  
Vol 2 (2) ◽  
pp. 245-251
Author(s):  
AEM M Islam ◽  
AAS Mazumder
Keyword(s):  
Acute Coronary Syndrome ◽  
Heart Disease ◽  
Statin Therapy ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Surgical Care ◽  
High Dose ◽  
Coronary Syndrome ◽  
Conventional Dose ◽  
Coronary Events

Increasing burden of cardiovascular disease risk factors has led to increase in the incidence in the coronary artery disease (CAD). Advancements in medical and surgical care of patients with heart disease have led to a large number of people surviving acute coronary events. Patients with acute coronary syndrome (ACS) are at high risk for recurrent coronary events, sudden death, and all cause mortality. Conventional revascularization therapies reduce the risk of further ischaemia but do not affect the underlying atherosclerotic disease. Statins have a proven record in the secondary prevention of coronary heart disease. Furthermore, statins have been shown to exert various pleotropic effects, which may stabilize vulnerable atherosclerotic plaques. Therefore, initiating, statin therapy in patients with established CAD is both beneficial and more cost effective. Trials conducted in recent times have addressed the issue of whether higher dose statin therapy provides further reductions in the risks of cardiovascular events following an acute coronary syndrome diagnosis, over and above that provided by a conventional dose statin regimen. However, recent trials of high dose statin therapy in patients with acute coronary syndromes have yielded conflicting results. The aim of this article is to provide a critical and up-to-date summary of the findings of clinical trials of intensive statin therapy, including a brief overview of safety and efficacy of such treatments. Keywords: Statin; Acute coronary syndrome. DOI: 10.3329/cardio.v2i2.6648Cardiovasc. j. 2010; 2(2) : 245-251

4328Short-term effects of dapagliflozin versus canagliflozin on acute decompensated heart failure in patients with type 2 diabetes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Nakagaito ◽  
S Joho ◽  
R Ushijima ◽  
M Nakamura ◽  
T Hirai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Glucose ◽  
Repeated Measures ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Fasting Blood Glucose ◽  
Urine Volume ◽  
P Value ◽  
Urine Glucose

Abstract Background The CANVAS program and DECLERE-TIMI 58 reported that SGLT2i had been demonstrated to reduce hospitalization for heart failure (HF) in type 2 diabetic mellitus (T2DM) patients with high cardiovascular disease risk. However, it remains unclear whether the effectiveness of SGLT2i on acute decompensated HF is also observed in T2DM patients irrespective of acting types of SGLT2i. Methods In this single center, open-label, prospective study, fifty-eight T2DM patients hospitalized due to decompensated HF were enrolled (mean age 73 years, HbA1c 7.2%). After treatment for HF, 5mg/day of dapagliflozin (n=24, from February 2016 to February 2017) or 100mg/day of canagliflozin (n=34, from March 2017 to July 2018) was administered and clinical parameters about HF and T2DM were followed for 7 days. Statistical comparison of parameters between groups taking dapagliflozin or canagliflozin was performed using the two-way repeated measures analysis of variance (MANOVA). Results In both groups, urine glucose excretion increased significantly after administration of SGLT2i. Fasting blood glucose level tended to be decreased in both groups. Urine volume increased significantly one day after administration of SGLT2i, and returned to the baseline after one week in both groups. Interestingly, urine volume one day after administration of SGLT2i tended to increase more in the group taking canagliflozin than in the group taking dapagliflozin (interaction P value = 0.088). Importantly, plasma BNP levels and Nt-proBNP levels were decreased significantly in both groups. Parameters before and after treatment Baseline Day 7 (Day 1) P value Interaction P value Fasting blood glucose, mg/dL All 137±57 122±51 0.013 0.900 Dapa 144±64 133±53 0.089 Cana 128±64 118±40 0.069 log BNP All 5.31±1.11 4.91±1.09 <0.001 0.102 Dapa 5.48±1.04 4.94±1.00 <0.001 Cana 5.20±1.15 4.89±1.16 <0.001 log Nt-proBNP All 7.25±1.35 6.96±1.41 <0.001 0.735 Dapa 7.54±1.16 7.22±1.25 0.048 Cana 7.04±1.45 6.79±1.50 0.005 Urine volume (Day 1), mL/24h All 1218±523 1584±614 <0.001 0.088 Dapa 1261±564 1486±568 0.038 Cana 1186±498 1654±644 <0.001 Urine volume (Day 7), mL/24h All 1218±523 1305±408 0.128 0.428 Dapa 1261±564 1295±468 0.700 Cana 1186±498 1313±367 0.097 Urine glucose, g/24h All 1.6±5.5 23.7±23.5 <0.001 0.330 Dapa 1.7±6.8 20.3±21.7 <0.001 Cana 1.5±4.6 26.0±24.7 <0.001 Conclusion SGLT2i are useful for correcting volume overload and recovering from the decompensated state in HF patients with T2DM irrespective of acting types of SGLT2i.

scholarly journals Finasteride Reduces Total Cholesterol in LDLR-Deficient Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 35-35
Author(s):  
James McQueen ◽  
Ivan Pinos ◽  
Jaime Amengual
Keyword(s):  
Cardiovascular Disease ◽  
Body Weight ◽  
Total Cholesterol ◽  
Atherosclerotic Plaque ◽  
Dose Group ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
The Other ◽  
High Dose ◽  
Prostate Size

Abstract Objectives Androgen imbalance is associated with cardiovascular disease risk but the exact impact on lipid and glucose profile is unknown. Finasteride (FIN) prevents the conversion of testosterone to its active metabolite dihydrotestosterone (DHT) by inhibiting the type II 5alpha-reductase. Our objective is to examine the impact of FIN on cardiovascular disease risk. We hypothesize that FIN delays the progression of atherosclerosis by ameliorating hyperglycemia and dyslipidemia. Methods We used the low-density lipoprotein receptor (LDLR)-deficient (Ldlr−/−) mouse model as a widely regarded model of atherosclerotic plaque development in rodents. Four-week-old male mice (n = 9–15/group) were fed a Western-diet containing 41% fat +0.3% cholesterol with increasing doses of FIN (10 mg/kg, 100 mg/kg, and 1000 mg/kg diet) for 12 weeks. Littermates fed Western-diet without FIN were used as a control group. A week before tissue harvest, mice were subjected to a glucose tolerance test (GTT). At the end of the experiment, mice were sacrificed, and their tissue and body weights were analyzed. A total cholesterol assay was performed at 0, 4, 8, and 12 weeks. Results We examined prostate size, whose growth is DHT dependent, as an indicator of the effect of finasteride in our experimental model. We observed a dose-dependent effect of FIN on prostate size for all the doses (P &lt; .0001), indicating FIN had a physiological impact on these mice. No changes in food intake or circulating transaminase levels were observed, discarding any evidence of food intolerability or hepatic toxicity. FIN did not alter GTT among experimental groups or any other biometric parameter. However, we observed a significant reduction in body weight gain in the high dose group (P = .0027) in comparison to the other experimental groups. Total cholesterol levels at the time of the sacrifice were significantly reduced in the high dose group (P &lt; .0001) in comparison to the other experimental groups. Future experiments will include atherosclerotic plaque characterization of both size and composition. Conclusions Our findings suggest that a high dose of FIN is associated with a reduction of total plasma cholesterol and body weight in Ldlr−/− mice. Funding Sources USDA multistate hatch project (W4002)

Abstract 139: Vascular Endothelin-1 Activity Increases with Age in Hypertensive Patients

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Andrew E Berdy ◽  
Vijaywant Brar ◽  
Julio A Panza ◽  
Umberto Campia
Keyword(s):  
Essential Hypertension ◽  
Repeated Measures ◽  
Disease Risk ◽  
Population Aging ◽  
Pearson Correlation ◽  
Cardiovascular Disease Risk ◽  
Prospective Clinical Study ◽  
Hypertensive Patients ◽  
Association Analyses ◽  
Endothelin 1

Background: Vascular endothelin-1 (ET-1) dependent vasoconstriction is elevated in patients with hypertension. The effect of increasing age on ET-1 activity is unknown. This study investigated the hypothesis that age is directly associated with ET-1 activity in hypertensive patients. Methods: Retrospective analysis of data collected in a prospective clinical study that investigated vascular ET-1 activity in patients with essential hypertension (BP>140/90mmHg). Endothelin-1 activity was expressed as forearm blood flow (FBF) responses as measured by strain-gauge plethysmography during the intra-arterial infusion of the selective endothelin type-A receptor antagonist BQ-123 (100 nmol/min) for 60 minutes. Changes in FBF from baseline in response to BQ-123 were assessed by one-way ANOVA for repeated measures. Association analyses were performed with use of the Pearson correlation coefficient. Results: Data from 40 patients were included in the current analyses. The baseline characteristics of the study population are reported in the table. Infusion of BQ-123 induced a significant increase in FBF from baseline (p<0.001). The percent increase in FBF from baseline at 60 minutes of BQ-123 infusion was significantly directly associated with age (r=0.435; p=0.006), but not with blood pressure, parameters of glucose and lipid metabolism, markers of endothelial activation, and adipocytokine levels (p=NS for all). Conclusions: In patients with essential hypertension, ET-1 activity is directly associated with age. Our findings suggest that, in this population, aging may contribute to vascular damage and cardiovascular disease risk through an enhanced activation of the ET-1 system. Further study is needed to elucidate the mechanisms underlying the association between age and vascular ET-1 activity.

Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia

2002 ◽  
Vol 283 (5) ◽  
pp. E1002-E1007 ◽  
Author(s):  
Neehar Gupta ◽  
Harmanjit Sandhu ◽  
Tracy Goh ◽  
Keyur Shah ◽  
Stephanie R. Wiesenthal ◽  
...  
Keyword(s):  
Direct Effect ◽  
Indirect Effects ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Direct And Indirect Effects ◽  
Euglycemic Clamp ◽  
Glycemic Level ◽  
Hyperinsulinemic Euglycemic Clamp

In our previous studies in nondiabetic dogs and humans, insulin suppressed glucose production (GP) by both an indirect extrahepatic and a direct hepatic effect. However, insulin had no direct effect on GP in diabetic depancreatized dogs under conditions of moderate hyperglycemia. The present study was designed to investigate whether insulin can inhibit GP by a direct effect in this model under conditions of euglycemia. Depancreatized dogs were made euglycemic (∼6 mmol/l), rather than moderately hyperglycemic (∼10 mmol/l) as in our previous studies, by basal portal insulin infusion. After ∼100 min of euglycemia, a hyperinsulinemic euglycemic clamp was performed by giving an additional infusion of insulin either portally (POR) or peripherally at about one-half the rate (½ PER) to match the peripheral venous insulin concentrations. The greater hepatic insulin load in POR resulted in greater suppression of GP (from 16.5 ± 1.8 to 12.2 ± 1.6 μmol · kg−1 · min−1) than ½ PER (from 17.8 ± 1.9 to 15.6 ± 2.0 μmol · kg−1 · min−1, P < 0.001 vs. POR), consistent with insulin having a direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP.

Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs

1998 ◽  
Vol 274 (2) ◽  
pp. E346-E356 ◽  
Author(s):  
Richard H. McCall ◽  
Stephanie R. Wiesenthal ◽  
Z. Qing Shi ◽  
Kenneth Polonsky ◽  
Adria Giacca
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Insulin Infusion ◽  
Low Dose ◽  
Glucose Production ◽  
High Rate ◽  
High Dose ◽  
Insulin Levels ◽  
Predominant Effect

To determine whether the predominant effect of insulin in suppressing tracer-determined glucose production (Ra) is hepatic or peripheral, we infused insulin peripherally (PER) and portally (POR) at both low (0.75 pmol ⋅ kg−1 ⋅ min−1) and high physiological rates (2.7 pmol ⋅ kg−1 ⋅ min−1) during euglycemic clamps in normal dogs. We also infused insulin peripherally at one-half these rates (1/2 PER) to match the peripheral insulin levels in POR and thus obtain a selective POR vs. 1/2 PER difference in hepatic insulin levels. At the high-rate insulin infusion, peripheral insulin levels were greatest with PER (PER = 212 ± 10 pM, n = 5; POR = 119 ± 5 pM, n = 6; 1/2 PER = 122 ± 5 pM, n = 6). Calculated hepatic insulin levels were greatest with POR (POR = 227 ± 13 pM, PER = 206 ± 19 pM, 1/2 PER = 123 ± 8 pM). High-dose PER yielded a greater suppression of Ra than POR (79 ± 18 vs. 56 ± 6%, P < .001). Ra was only suppressed by 45 ± 6% with 1/2 PER ( P< 0.01 vs. POR on 6 paired experiments). Free fatty acid (FFA) was suppressed by 57 ± 8% with PER and only by 33 ± 5 and 37 ± 2% with POR and 1/2 PER, respectively. The low-dose PER and POR yielded an equal Ra suppression (PER = 46 ± 9%, POR = 43 ± 4%). Only 1/2 PER was associated with a lower suppression of Ra (36 ± 8, P < 0.05 vs. POR). FFA showed similar suppression in all three groups (∼25%). Using both insulin infusion rates, the percent Ra suppression per unit difference in peripheral insulin was approximately twofold greater than that per unit difference in hepatic insulin. These results suggest that, during euglycemic clamps without somatostatin in normal dogs, Ra suppression is mediated by both peripheral and hepatic effects of insulin and that peripheral insulin, at least at high physiological infusion rates, is more potent than hepatic insulin in suppressing Ra.

scholarly journals LIFESTYLE PHYSICAL ACTIVITY IN OLDER WOMEN: ASSOCIATIONS OF CHANGE, SELF-EFFICACY, AND WELL-BEING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S171-S171
Author(s):  
Leanne L Lefler ◽  
Shelly Y Lensing ◽  
Kimberly K Garner
Keyword(s):  
Physical Activity ◽  
Clinical Trial ◽  
Older Women ◽  
Self Efficacy ◽  
Repeated Measures ◽  
Social Role ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Well Being ◽  
Lifestyle Physical Activity

Abstract Reduction of cardiovascular disease risk in undeserved populations, such as older women, is a top priority of the U.S. Our innovative trial tested a new approach to PA promotion for older women—motivational interviewing (MI), shifting the paradigm from structured exercise to self-selected activities. We present data comparing stage of change (SOC), self-efficacy for exercise (SEE), and well-being: 8 dimensions (physical, social, role limitations, emotional, general mental health, vitality, health perceptions and pain) and associations with physical activity outcomes in the Lifestyle Physical Activity for Women (LPAW) clinical trial. Methods: 106 women, &gt; 60 years old, who did not engage in regular PA, and were not frail, participated in a clinical trial of a tailored MI intervention to increase PA. We report baseline, 3 and 6 month repeated measures and PA associations with SOC, SEE, and well-being (SF36). Results: Of 106 women, 36% were Black and 63% White, with a mean age of 69. Significant improvement in SOC in both arms noted but the proportion in action/maintenance was significantly higher in the PA arm at 3 mos (78% vs. 55%, P=0.045) and 6 mos (79% vs. 50%, P= 0.019). A decrease in SEE for control (p=.001), but not for PA arm (p=.45); at 6 months, The PA arm had greater SEE compared to control. There were significant arm difference for physical component scores of SF36 (p=.02), but not for mental scores. Associations with PA will be tabulated. Conclusions: Preliminary results support the PA intervention, more data to be presented.

scholarly journals Modeling statin myopathy in a human skeletal muscle microphysiological system

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242422
Author(s):  
Anandita Ananthakumar ◽  
Yiling Liu ◽  
Cristina E. Fernandez ◽  
George A. Truskey ◽  
Deepak Voora
Keyword(s):  
Cardiovascular Disease ◽  
Fixed Effects ◽  
Disease Risk ◽  
Ex Vivo ◽  
Cardiovascular Disease Risk ◽  
Muscle Fibers ◽  
Musculoskeletal Symptoms ◽  
Growth Media ◽  
Mixed Effect ◽  
Donor Type

Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62–64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5μM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.

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