Children with familial hypercholesterolemia display changes in LDL and HDL function : A cross-sectional study

Publisher Copyright: © 2021 The Association for the Publication of the Journal of Internal Medicine.Background: The functional status of lipoprotein particles contributes to atherogenesis. The tendency of plasma low-density lipoprotein (LDL) particles to aggregate and the ability of igh-density lipoprotein (HDL) particles to induce and mediate reverse cholesterol transport associate with high and low risk for cardiovascular disease in adult patients, respectively. However, it is unknown whether children with familial hypercholesterolemia (FH) display lipoprotein function alterations. Hypothesis: We hypothesized that FH children had disrupted lipoprotein functions. Methods: We analyzed LDL aggregation susceptibility and HDL-apoA-I exchange (HAE), and activity of four proteins that regulate lipoprotein metabolism (cholesteryl ester transfer protein, lecithin–cholesterol acyltransferase, phospholipid transfer protein, and paraoxonase-1) in plasma samples derived from children with FH (n = 47) and from normocholesterolemic children (n = 56). Variation in lipoprotein functions was further explored using an nuclear magnetic resonance-based metabolomics profiling approach. Results: LDL aggregation was higher, and HAE was lower in FH children than in normocholesterolemic children. LDL aggregation associated positively with LDL cholesterol (LDL-C) and negatively with triglycerides, and HAE/apoA-I associated negatively with LDL-C. Generally, the metabolomic profile for LDL aggregation was opposite of that of HAE/apoA-I. Conclusions: FH children displayed increased atherogenicity of LDL and disrupted HDL function. These newly observed functional alterations in LDL and HDL add further understanding of the risk for atherosclerotic cardiovascular disease in FH children.Peer reviewe

LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

Published version. Source at http://dx.doi.org/10.1007/s00125-016-4036-y Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR). Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Characteristics of Glucose Metabolism in Nordic and South Asian Subjects with Type 2 Diabetes

Background: Insulin resistance and type 2 diabetes are more prevalent in people of South Asian ethnicity than in people of Western European origin. To investigate the source of these differences, we compared insulin sensitivity, insulin secretion, glucose and lipid metabolism in South Asian and Nordic subjects with type 2 diabetes. Methods: Forty-three Nordic and 19 South Asian subjects with type 2 diabetes were examined with intra-venous glucose tolerance test, euglycemic clamp including measurement of endogenous glucose production, indirect calorimetry measuring glucose and lipid oxidation, and dual x-ray absorptiometry measuring body composition. Results: Despite younger mean ± SD age (49.7±9.4 vs 58.3±8.3 years, p = 0.001), subjects of South Asian ethnicity had the same diabetes duration (9.3±5.5 vs 9.6±7.0 years, p = 0.86), significantly higher median [inter-quartile range] HbA1c (8.5 [1.6] vs 7.3 [1.6] %, p = 0.024) and lower BMI (28.7±4.0 vs 33.2±4.7 kg/m2, p<0.001). The South Asian group exhibited significantly higher basal endogenous glucose production (19.1 [9.1] vs 14.4 [6.8] µmol/kgFFM⋅min, p = 0.003). There were no significant differences between the groups in total glucose disposal (39.1620.4 vs 39.2617.6 µmol/kgFFM⋅min, p = 0.99) or first phase insulin secretion (AUC0–8 min: 220 [302] vs 124 [275] pM, p = 0.35). In South Asian subjects there was a tendency towards positive correlations between endogenous glucose production and resting and clamp energy expenditure. Conclusions: Subjects of South Asian ethnicity with type 2 diabetes, despite being younger and leaner, had higher basal endogenous glucose production, indicating higher hepatic insulin resistance, and a trend towards higher use of carbohydrates as fasting energy substrate compared to Nordic subjects. These findings may contribute to the understanding of the observed differences in prevalence of type 2 diabetes between the ethnic groups

Kon-Tiki2 Expedition 2015-2016 Scientific Cruise Report

The Kon-Tiki2 Expedition was partly an anthropogenic exploration and partly an interdisciplinary oceanic and atmospheric research expedition. As a research expedition it was unique for three reasons: 1) The type of vessel used, 2) the timing of the expedition, and 3) the geographical location. The scientific program was run onboard the ancient design balsa rafts, powered by solar power only, with almost no possibility of stopping the raft, during a year with the strongest El Niño recorded in human history, in the midst of the center of that El Niño, namely in the area between Peru, Easter Island and the Chilean mid-latitudinal coast. The scientific expedition planned and organized as a cooperation between the NIVA and NTNU in Norway. It was divided in two legs: the transect from Peru to Easter island and from Easter Island until the expedition concluded with the organized evacuation of the rafts. Instruments were brought on board the rafts and procedures were specifically developed for this cruise to study 1) climate change and ocean acidification, 2) marine litter, 3) El Niño and operational weather forecasting and 4) marine life. The rafts were built following the designs of archeological studies on an Ecuadorian maritime culture known as the Manteno. They were built in Peru, with help from volunteers from all over the world as well as from the national Peruvian Navy. Building efforts were delayed by logistic issues, but Leg 1 departed Callao on November 7th 2015 and reached the Easter Island as planned 6 weeks later, on December 19th 2015. After a change of crew and a full overhaul of the rafts and equipment in Easter Island, Leg 2 departed Easter Island January 6 and ended March 17 2016. The crew was multinational, gender-mixed, synergetic and multidisciplinary experienced. Each raft on each leg had 7 members on board. Only four members were present during both legs. There was a one scientist on board on each leg representing either of the organizing institutions. Both rafts were instrumented for research. Each had an electrical installation with capacity calculated according to the payload of instruments that would be operated from it. Wind was the main source of energy to transport the vessels while photovoltaic cells transformed solar into electric energy for the electronics onboard. The sensor payloads can be classified into three categories: atmospheric, oceanographic and ecological. Optical sensors to measure light, together with physical sensors to measure atmospheric conditions were combined with crew observations to describe the meteorological situation in the raft. A combination of echosounders and cameras were used to describe the macrofauna biodiversity present around the rafts. DNA and Chlorophyll a filtering aimed to study the microdiversity. The physical parameters like temperature, salinity, pH, levels of carbon dioxide described the climatic conditions in the region were the cruise sailed. Finally, both conventional and state-of-the-art technology were used to observe macro and micro plastics in this remote area of the world oceans. Currently, the material collected on the cruise is subject of analysis in different laboratories. Kon-Tiki2, due to its unique nature, has been the subject of interest to a wide range of audiences. In addition to the general scientific interest, the expedition has given a much louder voice to the oceans than any regular research expedition could have given. For instance, the expedition coincided with the Climate Summit in Paris in December 2015 (COP21), a coincidence that we utilized to its fullest. The outreach efforts of the expedition participants have raised awareness about the science as well as about the expeditions sponsors. Most importantly, it has promoted cultural awareness across many state borders. The Kon-Tiki2 Expedition combined science with adventure and challenge. Its organization was not simple, however, the outcome is of highest value, both from a professional scientific point of view, for the originator and sponsors of the expedition idea and for each and every project participant. Kon-Tiki2 aimed to double-down on Thor Heyerdahl's Kon-Tiki voyage (1947) by sailing two rafts from South America to Polynesia and then back. No one has done this in modern history. Kon-Tiki2 was an unparalleled voyage of survival, science and exploration. Although one of the strongest El Niño ever recorded stopped us from sailing all the way to South America, Kon-Tiki2 substantiates the ancient Pacific pathway for both Polynesians and South Americans. We know both cultures had rafts. Polynesians probably used their superior double hulled canoe for exploration and rafts for migrations. Kon-tiki2 showed how Polynesians could have sailed to South America and back, and how South Americans could have done the same in the opposite direction

Kon-Tiki2 Expedition 2015-2016 Scientific Cruise Report

The Kon-Tiki2 Expedition was partly an anthropogenic exploration and partly an interdisciplinary oceanic and atmospheric research expedition. As a research expedition it was unique for three reasons: 1) The type of vessel used, 2) the timing of the expedition, and 3) the geographical location. The scientific program was run onboard the ancient design balsa rafts, powered by solar power only, with almost no possibility of stopping the raft, during a year with the strongest El Niño recorded in human history, in the midst of the center of that El Niño, namely in the area between Peru, Easter Island and the Chilean mid-latitudinal coast. The scientific expedition planned and organized as a cooperation between the NIVA and NTNU in Norway. It was divided in two legs: the transect from Peru to Easter island and from Easter Island until the expedition concluded with the organized evacuation of the rafts. Instruments were brought on board the rafts and procedures were specifically developed for this cruise to study 1) climate change and ocean acidification, 2) marine litter, 3) El Niño and operational weather forecasting and 4) marine life. The rafts were built following the designs of archeological studies on an Ecuadorian maritime culture known as the Manteno. They were built in Peru, with help from volunteers from all over the world as well as from the national Peruvian Navy. Building efforts were delayed by logistic issues, but Leg 1 departed Callao on November 7th 2015 and reached the Easter Island as planned 6 weeks later, on December 19th 2015. After a change of crew and a full overhaul of the rafts and equipment in Easter Island, Leg 2 departed Easter Island January 6 and ended March 17 2016. The crew was multinational, gender-mixed, synergetic and multidisciplinary experienced. Each raft on each leg had 7 members on board. Only four members were present during both legs. There was a one scientist on board on each leg representing either of the organizing institutions. Both rafts were instrumented for research. Each had an electrical installation with capacity calculated according to the payload of instruments that would be operated from it. Wind was the main source of energy to transport the vessels while photovoltaic cells transformed solar into electric energy for the electronics onboard. The sensor payloads can be classified into three categories: atmospheric, oceanographic and ecological. Optical sensors to measure light, together with physical sensors to measure atmospheric conditions were combined with crew observations to describe the meteorological situation in the raft. A combination of echosounders and cameras were used to describe the macrofauna biodiversity present around the rafts. DNA and Chlorophyll a filtering aimed to study the microdiversity. The physical parameters like temperature, salinity, pH, levels of carbon dioxide described the climatic conditions in the region were the cruise sailed. Finally, both conventional and state-of-the-art technology were used to observe macro and micro plastics in this remote area of the world oceans. Currently, the material collected on the cruise is subject of analysis in different laboratories. Kon-Tiki2, due to its unique nature, has been the subject of interest to a wide range of audiences. In addition to the general scientific interest, the expedition has given a much louder voice to the oceans than any regular research expedition could have given. For instance, the expedition coincided with the Climate Summit in Paris in December 2015 (COP21), a coincidence that we utilized to its fullest. The outreach efforts of the expedition participants have raised awareness about the science as well as about the expeditions sponsors. Most importantly, it has promoted cultural awareness across many state borders. The Kon-Tiki2 Expedition combined science with adventure and challenge. Its organization was not simple, however, the outcome is of highest value, both from a professional scientific point of view, for the originator and sponsors of the expedition idea and for each and every project participant. Kon-Tiki2 aimed to double-down on Thor Heyerdahl's Kon-Tiki voyage (1947) by sailing two rafts from South America to Polynesia and then back. No one has done this in modern history. Kon-Tiki2 was an unparalleled voyage of survival, science and exploration. Although one of the strongest El Niño ever recorded stopped us from sailing all the way to South America, Kon-Tiki2 substantiates the ancient Pacific pathway for both Polynesians and South Americans. We know both cultures had rafts. Polynesians probably used their superior double hulled canoe for exploration and rafts for migrations. Kon-tiki2 showed how Polynesians could have sailed to South America and back, and how South Americans could have done the same in the opposite direction

Differences in insulin sensitivity, lipid metabolism and inflammation between young adult Pakistani and Norwegian patients with type 2 diabetes: a cross sectional study

Background Immigrants from South Asia to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM). We explored pathogenic factors that might contribute to the high risk of T2DM in Pakistani immigrants to Norway. Methods A cross-sectional study was performed in 18 Pakistani and 21 Norwegian men and women with T2DM (age 29 – 45 years), recruited from two hospital out-patient clinics. Anthropometrics and a two-step euglycemic, hyperinsulinemic clamp with measurements of non-esterified fatty acids (NEFA) during clamp, was performed in all patients. Insulin sensitivity, given as the Glucose Infusion Rate (GIR) and Insulin Sensitivity Index (ISI), was calculated from the two euglycemic clamp steps. Fasting adipokines and inflammatory mediators were measured. Continuous variables between groups were compared using Student’s t test or Mann–Whitney U test as appropriate. Spearman’s correlation coefficient and multiple linear regression analyses were used. Results Despite having a lower BMI, Pakistani patients were more insulin resistant than Norwegian patients, during both low and high insulin infusion rates, after adjustment for sex and % body fat: median (interquartile range) GIR(low insulin): 339.8(468.0) vs 468.4(587.3) µmol/m2/min (p=0.060), ISI(low insulin): 57.1(74.1) vs 79.7(137.9) µmol/m2/min (p=0.012), GIR(high insulin): 1661.1(672.3) vs 2055.6(907.0) µmol/m2/min (p=0.042), ISI(high insulin): 14.2(7.3) vs 20.7(17.2) µmol/m2/min (p=0.014). Pakistani patients had lower percentage NEFA suppression 30 minutes into clamp hyperinsulinemia than Norwegians: 41.9(90.6)% vs 71.2(42.1)%, (p=0.042). The relationship of ISI to BMI, leptin and interleukin-1 receptor antagonist also differed between Norwegians and Pakistanis. Conclusions Compared with Norwegian patients, Pakistani patients with T2DM had lower insulin sensitivity, affecting both glucose and lipid metabolism. The relation of insulin sensitivity to BMI and some adipokines also differed between the groups. Keywords: Ethnicity; South Asian; Insulin sensitivity; Anthropometry; NEFA; Adipokines; Inflammatio