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Title: Inactivity as a key factor inducting insulin resistance and metabolic syndrome
Authors: Mazzucco, Sara
Supervisore/Tutore: Biolo, Gianni
Issue Date: 28-Apr-2011
Publisher: Università degli studi di Trieste
Introduction. The metabolic syndrome is a cluster of alterations, including insulin resistance, dyslipidaemia, hypertension, hyperglycaemia, abdominal obesity, hyperhomocysteinemia, inflammation and oxidative stress, leading to type II diabetes and cardiovascular disease. The metabolic syndrome is usually associated with sedentary lifestyle and overweight, while regular physical activity and weight loss can counteract these alterations and prevent type II diabetes and cardiovascular disease.
Aim of the Thesis. In order to define the net role of inactivity as key factor inducing insulin resistance and metabolic syndrome independently from changes in body fat we have investigated the net impact of experimental bed rest on human metabolism. Experimental bed rest in healthy, young, lean subjects represents a suitable model to determine the effects of inactivity on physiology, avoiding potential interferences and confounding effects of diseases, ageing, energy unbalance and excess body fat. We have focused on inactivity-related development of insulin resistance, dyslipidaemia, hypertension as well as inflammation and oxidative stress. These aspects have been investigated during four different experimental bed rest protocols, lasting 2 months (WISE-Toulouse, France) and 5 weeks (Valdoltra, Slovenia 2006–2007–2008). Energy requirements and intakes were strictly controlled to avoid changes in fat mass.
Results and discussion. Muscle atrophy. Muscle atrophy was evidenced after three weeks of bed rest and was worsened by prolonged exposure to inactivity (WISE, Valdoltra studies). However, muscle loss rate was higher in the first 5 weeks of bed rest while it decreased in the second month of inactivity (WISE). Time-course analysis of insulin resistance development. Insulin resistance, measured by an oral glucose tolerance test, rapidly developed in the first week of inactivity and was maintained after 5 weeks of bed rest, as assessed by the ISI-Belfiore index of insulin sensitivity (Valdoltra 2008). Cardiovascular regulation. In the first week of bed rest, baroreflex sensitivity decreased indicating that, in an early phase, alterations in the sympatovagal balance paralleled changes in insulin resistance development. At the end of 5 week-bed rest, heart rate and heart rate variability as well as systolic blood pressure variability, indexes of cardiovascular regulation, were also impaired (Valdoltra 2008). Plasma lipids and lipid metabolism. Five weeks of bed rest induced a decrease in high-density lipoprotein (HDL) cholesterol. During inactivity, cholesteryl ester transfer protein (CETP), a key enzyme involved in HDL metabolism, was up-regulated and changes in CETP inversely correlated with changes in HDL-to-non-HDL cholesterol ratio. Conversely, changes in CETP and HDL were not directly correlated to insulin resistance (Valdoltra studies). Cell membrane lipids. Bed rest reduced monounsaturated FAs, enhanced n-6 polyunsaturated FA total contents and affected activities of both Δ-5 and Δ-9 desaturases, enzymes involved in FA metabolism. These data further support that membrane FA composition and activities of Δ-5 and Δ-9 desaturases are predictive indicators of metabolic syndrome development. Moreover, arachidonic-to-eicosapentaenoic acid ratio, reflecting the competitive role of these FAs in the modulation of inflammatory processes, was shifted towards pro-inflammatory state (Valdoltra studies). Oxidative stress and glutathione kinetics. Bed rest induced oxidative stress as showed by enhanced muscle protein carbonylation, a marker of tissue exposure to oxidative damage, and increased muscle glutathione absolute synthesis, as assessed by a new one-sample, double-isotope tracers infusion method (Valdoltra 2007). Homocysteinemia and homocysteine kinetics. Plasma homocysteine level was increased by bed rest, due to a decrease in homocysteine clearance related to remethylation (WISE). Hyperhomocysteinemia is a further evidence of inactivity-mediated oxidative stress and increased cardiovascular risk.
Conclusions. Physical inactivity in healthy young subjects is a suitable model to define the net impact of physical inactivity on the development of metabolic alterations observed in patients with the metabolic syndrome. Our results indicate that inactivity is directly involved in insulin resistance development, low-grade systemic inflammation, dyslipidaemia, hyperhomocysteinemia, oxidative stress and autonomic-cardiovascular abnormalities.
Ciclo di dottorato: XXIII Ciclo
Keywords: Insulin resistanceOxidative stressMuscle atrophyMetabolic syndromePhysical inactivity
Type: Doctoral
Language: en
NBN: urn:nbn:it:units-9103
Appears in Collections:Scienze biologiche

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