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Highlighted articles Atherosclerosis April 2016 Issue

Friday 15 April 2016   (0 Comments)
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Volume 247 Issue April  2016

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief)

Issue highlights

Review article

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

The growing worldwide prevalence of overnutrition and underexertion threatens the gains made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). Individuals with this syndrome also exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and – crucially – hyperinsulinemia.

Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway-selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyperinsulinemia does something bad in a tissue or organ, that effect remains responsive in the atherometabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects.

In their in-depth review, the authors discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance causing obesity.

They also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. The dysfunction of this oxide transport chain (abbreviated ‘NSAPP’ after its five major proteins) during chronic overnutrition results in the harmful pattern of SEIRR.

Moreover, the origins of widespread, chronic overnutrition are reviewed. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us to overcome these foes of good health and solve this man-made epidemic.

Highlighted articles

The carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis

γ-butyrobetaine (γBB) is a metabolite from dietary carnitine involved in the gut microbiota-dependent conversion from carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). In experimental studies in mice, orally ingested γBB has a pro-atherogenic effect, however, γBB has not been investigated in relation to atherosclerosis in humans.

With this study, the authors aimed at evaluating the association between serum levels of γBB, TMAO and their common precursors (carnitine and trimethyllysine (TML)) and carotid atherosclerosis and adverse outcome.

To this purpose, serum γBB, carnitine, TML and TMAO were quantified by high-performance liquid chromatography in patients with carotid artery atherosclerosis and healthy controls.

The authors showed that serum γBB and carnitine, but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or carnitine, were independently associated with cardiovascular death also after adjustment for age and eGFR.

In conclusion, patients with carotid atherosclerosis have increased serum levels of γBB. Elevated levels of γBB and its precursor TML are associated with cardiovascular mortality.
Long-term clinical studies of γBB as a cardiovascular risk marker and safety studies on dietary supplementation of γBB are warranted.

Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling

Endothelial dysfunction contributes to cardiovascular disease in diabetes mellitus. Autophagy is a multistep mechanism for the removal of damaged proteins and organelles from the cell. Under diabetic conditions, inadequate autophagy promotes cellular dysfunction and insulin resistance in non-vascular tissue.

The authors hypothesized that impaired autophagy contributes to endothelial dysfunction in diabetes mellitus. To validate this hypothesis, they therefore measured autophagy markers and endothelial nitric oxide synthase (eNOS) activation in freshly isolated endothelial cells from diabetic subjects and non-diabetic controls.

They showed that p62 levels are higher in cells from diabetics subjects, indicating reduced autophagic flux. Moreover, bafilomycin inhibited insulin-induced activation of eNOS in cells from controls, confirming that intact autophagy is necessary for eNOS signaling.

In endothelial cells from diabetics, activation of autophagy with spermidine restored eNOS activation, suggesting that impaired autophagy contributes to endothelial dysfunction.

Indicators of autophagy initiation, including the number of LC3-bound puncta and beclin 1 expression, were similar in diabetics and controls, whereas an autophagy terminal phase indicator, the lysosomal protein Lamp2a, was higher in diabetics. In addition, in endothelial cells under diabetic conditions, the beneficial effect of spermidine on eNOS activation was blocked by the autophagy inhibitors bafilomycin or 3-methyladenine.

Blocking the terminal stage of autophagy with bafilomycin increased p62 in cells from diabetics to a lesser extent than in cells from controls, suggesting ongoing, but inadequate autophagic clearance.

In conclusion, the authors demonstrated that inadequate autophagy contributes to endothelial dysfunction in patients with diabetes and may be a target for therapy of diabetic vascular disease.

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