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Understanding the cellular and molecular mechanisms underlying glycemic index health benefits

  • Autores: Simona Maria Giardina
  • Directores de la Tesis: Mònica Bulló Bonet (dir. tes.), Jordi Salas Salvadó (codir. tes.)
  • Lectura: En la Universitat Rovira i Virgili ( España ) en 2018
  • Idioma: español
  • Tribunal Calificador de la Tesis: Ulf Risérus (presid.), Joan Vendrell Ortega (secret.), José Manuel Fernández Real Lemos (voc.)
  • Programa de doctorado: Programa de Doctorado en Nutrición y Metabolismo por la Universidad Rovira i Virgili
  • Materias:
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  • Resumen
    • There has always been considerable debate about the effects of carbohydrate intake. The American Dibetes Association has recommended for years to reduce carbohydrate intake, especially in weight reduction dietary strategy, to manage blood glucose levels and other metabolic disorders. Despite the speculation on carbohydrate and diseases, evidences have suggested that carbohydrate quality rather than absolute intake is associated with risk of chronic diseases. In fact, carbohydrates with different physical forms, chemical structures, particle sizes, and fiber contents induce distinct plasma glucose and insulin responses. To quantify this physiological response to carbohydrate, it has been introduced the Glycemic Index.

      In the last few years evidences have showed the potential health benefits of low-glycemic index diets. In fact, it has been established that low-GI (LGI) diets improve glucose/insulin metabolism in people with diabetes or pre-diabetes, reduce lipids in hyperlipidemic individuals, and improve inflammatory parameters. Furthermore, diets rich in low-glycemic index foods are considered favorable in terms of health, particularly for the prevention and management of type 2 diabetes (T2D) and cardiovascular disease (CDV). These diets have also been found to be more effective for weight loss and improving insulin sensitivity in overweight and obese subjects, as showed in the GLYNDIET study, carried out by our group. But the exact mechanisms that link dietary GI and its beneficial effects on human health are still unclear.

      The physiological event that may mediate the beneficial effect of LGI have been related to the lower glycemic and insulin response, so regulating blood pressure, serum lipid, coagulation factors, inflammatory mediators and endothelial function. LGI diet seems to regulate the expression of the hepatic PPAR-alpha gene and adipocyte PPAR-gamma gene, and have been related to lower concentration of pro-inflammatory biomarkers, such as ultra-sensitive C-reactive protein, fibrinogen, interleukin-6 and tumor necrosis factor, and reduce oxidative state, even if evidences are controversial. Also, evidences have highlighted the positive effects of LGI diet on satiety, even if the whole topic needs more studies. During the past decades, metabolomics has appeared as a new discipline in system biology. The non-invasive nature of metabolomics and its close link to the phenotype make it an ideal tool for studying changes in the humane metabolome due to physiological and/or pathological condition. Furthermore, as metabolomics allows the simultaneous characterization of large numbers of chemicals in biological matrices, it is a strategy for acquiring a far more detailed and comprehensive picture of the molecular biological consequences of different diet.

      We proposed new unexplored potential mechanisms that could contribute to explain the health benefits attributed to the LGI diets. These mechanisms includes the modulation of cell membrane fatty acids composition since it is closely involved in cell function, the modulation of epigenetic tags such as miRNAs and the modulation of circulating metabolome.

      In view of the important functions carried out by cellular membrane, it is not surprising that alteration in its structure have been linked to the initiation and development of disease processes. Being mostly composed of fatty acids, the structure, and therefore the functions, of cellular membrane are strongly affected by diet. Also, in the last few years microRNAs (miRNAs) have been identify as implicated in the majority of biological processes, playing a key role not only in the normal cellular and tissues homeostasis but also in the development of diseases and chronic conditions. Recent studies have pointed out the regulatory effect of dietary intervention on circulating and tissue miRNAs profile, despite the lack of information on it.

      This thesis project aimed at clarifying the cellular and molecular mechanisms that could explain the beneficial role of LGI diets observed in epidemiological studies and clinical trials. Owing to that, within the frame of the GLYNDIET study, we studied the effect of two moderate carbohydrates diets and a low fat diet with different GIs on fatty acids erythrocytes membrane composition, circulating miRNAs profile and the expression of several miRNAs of subcutaneous adipose tissue, and the circulating metabolome.

      To study the effectiveness of a moderate-carbohydrate and low-GI diet versus a moderate-carbohydrate and high-GI diet and a low-fat diet, in the frame of the GLYNDIET study, the following analysis were conducted: 1. Changes in fatty acids erythrocyte membrane composition reflecting modulation of membrane structure,using gas chromatography and ELISA assay; 2. Modulation of concentration of circulating miRNAs selected by genome-wide analysis; 3. Modulation of expression of subcutaneous adipose tissue miRNAs selected by both genome-wide analysis and computerized search of miRNAs previously linked to obesity, adipose tissue development and glucose metabolism; 4. Modulation of circulating metabolome, mostly comprised of lipid species and amino acids, using three different approaches: gas chromatography/quadrupole time-of-flight, liquid chromatography/Q-TOF and Nuclear Magnetic Resonance.

      Our results suggest that in a energy-restricted dietary pattern with a moderate amounts of healthy fat, a diet with a low glycemic index maintain a favourable erythrocyte membrane fatty acid profile. However, whether these changes are related to better functionality of cell membrane was not clarified.

      According to the findings, energy-restricted diet with different amount and quality of carbohydrates, does not seem to be a factor that modulates the expression of the subcutaneous adipose tissue miRNAs here analyzed that have been associated with obese-related complications. Dietary effect may be hidden by changes in some of the anthropometric parameters of obesity, especially how the fat is distributed, that was found a significant and relevant role in regulating adipose tissue miRNA expression.

      The consumption of a low glycemic index diet, in a dietary weight loss intervention, seems to provide a better circulating miRNA profile that could be related to a reduction of cardiovascular disease risk.

      Following a low-glycemic index diet may help to improve circulating levels of amino acids and specific lipid families related to several metabolic disorders.


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