Metabolic effects of low glycaemic index diets

Observational studies indicate that the GI of the diet may be an important determinant of metabolic risk. The major sources of carbohydrate in the Western diet (highly-refined cereal and potato products) tend to have high GI values, which has been linked to the widespread occurrence of type 2 diabetes and CVD [23].

GI has been shown to be positively associated with the prevalence of the metabolic syndrome and insulin resistance in a cross -sectional study of 2834 subjects from the Framingham Offspring cohort [24]. Odds of having metabolic syndrome were reported to be 41% higher in the highest quintile of dietary GI compared with the lowest quintile (median GI values 84 and 72 respectively), and insulin resistance was found to be increased across quintiles (p < 0.001) [23].

Associations have also been reported between GI and both unfavorable lipid profiles and raised inflammatory status. In 280 women aged 45–70 years from the Nurses Health Study fasting triacylglycerol levels were shown to be positively related to GI [25]. Serum HDL levels have been found to be negatively related to GI in 1420 subjects aged 18–64 years from the 1986–7 Survey of Britain Adults 18–64 years [26], in which GI was the only dietary factor found to be significantly associated with HDL levels in multiple linear-regression analysis. Plasma levels of high-sensitivity C-reactive protein, a sensitive marker of systemic inflammation, were found to be positively associated with both GI and GL in 244 women from the Nurses' Health Study, aged 45–82 years, with a stronger relationship in overweight women than in normal-weight women [27].

Fig. 1. Low GI diets and metabolic syndrome.

Weight loss is an additional potential mechanism by which low-GI diets may contribute to reduced risk of metabolic syndrome.

Induction of a rapid initial weight loss with low-carbohydrates diets may be partly explained by a reduction in overall caloric intake, which may be the result of a great limitation of food choices by the requirements of minimizing carbohydrates intake [28, 29], to the initial increase in circulating β-hydroxybutyrate, which may suppress appetite [30] and to the satiating effect of low-carbohydrates diets containing relatively high amounts of protein [31, 32]. Some of the initial weight loss may also be explained by a reduction of glycogen stores from liver (5% of liver weight) and muscle (1% of muscle weight). Each gram of glycogen is stored with approximately 3 g of water [33]. Therefore a weight loss of 1–2 kg can theoretically be achieved within the first week of the diet because of substantial glycogen reductions in liver and muscle and excretion of the liberated water in urine [15]. Depending on the rate of glycogen depletion, this process may last up to 7–14 days, after which weight loss slows [34]. It should be noticed in this respect that loss of glycogen and water is not a true measure of weight loss, as their stores will be replenished once the diet is stopped [15].

The rapid large rise in blood glucose following consumption of high-GI food triggers a large insulin response and strongly inhibits glucagons release. For most foods, a good correlation exists between glucose and insulin responses, with high-GI foods eliciting large insulin responses [35], which trigger rapid uptake of nutrients by insulin-responsive tissues and suppress nutrient mobilization. Glucose uptake and glycogen synthesis in skeletal muscle and liver, and lipogenesis in adipose tissue, are increased. Simultaneously, gluconeogenesis and glucose out put by liver and lipolysis are suppressed.

Low-GI diets give a more stable diurnal profile, reducing postprandial hyperglycaemia and hyperinsulinaemia, and attenuating late postprandial rebounds in circulating free fatty acids, all factors that exacerbate various components of the metabolic syndrome [23].

High circulating free fatty acids levels result in lipid accumulation in skeletal muscle and liver, causing insulin resistance in these normally insulin-responsive tissues [36, 37], which reduces insulin-stimulated glycogen synthesis in skeletal muscle (the primary pathway for non-oxidative glucose disposal in normal subjects [38] and decrease the ability of insulin to suppress hepatic glucose production and output.

Insulin sensitivity may be negatively affected in the long term as low- carbohydrates, high-fat diets favor an increase of plasma circulating free fatty acids [39, 40], which under usual dieting conditions is typically associated with many insulin-resistant states in humans [41, 42]. Altered fatty acid metabolism contributes to insulin resistance because of alterations in the partitioning of fat between the adipocytes and muscle or liver [15]. Accumulation of fatty acid and fatty acid metabolites in these insulin-responsive tissues leads to acquired insulin signaling defects and insulin resistance resulting in a reduced glucose transport [43]. The later is thought to results from fatty-acid-induced alterations in upstream insulin signaling events, resulting in decreased GLUT 4 translocation to the plasma membrane. Increased level of intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA's, or ceramides activates a serine/threonine kinase cascade, possibly initiated by protein kinase CӨ. The latter leads to a non-desired phosphorylation of serine/threonine sites on insulin receptor substrates, which then fail to associate with or to activate PI 3-kinase, resulting in decreased activation of glucose transport and other downstream events [15].

Fig. 2 Regulation of insulin secretion by glucose and lipids (adapted by Brand et al. (2004). Free Radic. Biol. Med.).

It is observed an inverse relationship between adiponectin and insulinsensivity. Adiponectin is similar in structure to TNF-α (tumor necrosis factor α) which paradoxically appears to be increased in abdominal adipose tissue. Increases in proinflammatory cytokines (interleukine 6, TNF-α, resistin, C- reactiv protein – CRP) reflect overproduction by the expanded adipose tissue mass [44, 45]. All of these factors contribute to the exaggerated release of free fatty acids from abdominal adipocytes into the portal system. Free fatty acids have deleterious effects on insulin uptake by the liver and contribute to the increased hepatic gluconeogenesis and hepatic glucose release observed in central obesity [46].

High glucose levels have a glucotoxic effect on β-cells, probably as a result of free radical oxidative damage [47]. Hyperinsulinaemia may reduce β-cell function by causing excess amyloid deposits [48]. High free fatty acids levels lead to triacylglycerol accumulation in β-cells, which reduces insulin secretion [49]. Accordingly, by reducing hyperglycaemia, hyperinsulinemia and free fatty acids levels, low-GI foods may decrease the factors contributing to β-cell failure [23].

Hyperinsulinaemia and insulin resistance are significantly correlated to dyslipidaemia and contribute to the characteristic alteration of plasma lipid profile associated with obesity.

Low-GI diets may reduce insulin-stimulated activity of 5-hydroxi-3-methylglutaryl-CoA reductase, the rate-limiting enzyme involved in cholesterol synthesis, by reducing insulin levels. Dietary fiber tends to reduce bile acid and cholesterol re-absorption from the ileum, which may inhibit hepatic cholesterol synthesis [47].

Low-carbohydrates diets as well as low-fat diets significantly decreased several biomarkers of inflammation (CRP, TNF-α, IL-6), which play a key role in all stages of the pathogenesis of atherosclerosis [15].

Hyperglicaemia is a continuous risk factor for CVD morbidity and mortality.

The effects of cytokines on peripheral tissues with increased intracellular lipids also lower cellular insulin sensitivity: the surge in lipids promotes proliferation of the vasa vasorum of the arterial media and apoptosis by the medial macrophages with a further release of cytokines. There is an additional complex relationship through an associated pro-inflammatory state and alterations in coagulation. A rise in blood viscosity is induced by the release of profibrinogen and plasminogen activator inhibitor 1 from adipocytes with a fall in plasminogen activator. These changes may explain the role of obesity as a promoter of intracellular inflammatory processes that result in arterial damage. Ethnic differences in CRP may explain some of the variation observed in insulin resistance across populations with comparable weight gain and associated medical complications [46].

A low-GI diet may have beneficial effects on thrombolytic function. The activity of plasminogen activator inhibitor-1, a thrombolytic factor that increases clot and plaque formation, has been found to be 53% lower after 24 days on a low -GI diet compared with a high-GI diet in twenty subjects with type 2 diabetes [50].

Long-term studies are clearly required, as recently, an increased plasma homocysteine level (+6.6%) was observed in individuals that follow strictly a low- carbohydrates diet for several months [51]. In contrast, a low-fat diet induced a decrease of plasma homocysteine by 6–8%. This may be an important observation as the relationship between total plasma homocysteine and CVD is dose dependent and independent of other risk factors. In humans, the effects of homocysteine on endothelial and vascular function and blood coagulation provide explanations for increased CVD risk [15, 52, 53].

The effects of increased body fatness on cardiovascular function can be predicted. Total body oxygen consumption is increased because of an expanded lean tissue mass and metabolically active adipose tissue, and this is accompanied by an absolute increase in cardiac output. The total blood volume in obesity is increased in proportion to body weight. This increase in blood volume contributes to an increase to the left ventricular pre-load and an increase in resting cardiac output. The increased demand for cardiac output is achieved by an increase in stroke volume: an increase in stroke volume results from an increase in diastolic filling of the left ventricle. This thickening of the wall with dilatation results in eccentric hypertrophy. The cardiovascular adaptation to the increased intravascular volume of obesity may not completely restore normal homodynamic function. Marked systolic dysfunction occurs when the ventricle can no longer adapt to volume overload. Dilatation of the left ventricle cavity radius leads to a decline in ventricular contractility. A combination of systolic and diastolic dysfunction progresses to heart failure [46, 54]. Hyperglicaemia exacerbates oxidative stress, which is associated with inflammation, increased blood pressure, accelerated clot formation and decreased endothelium-dependent blood flow [47, 55], and which may also worsen insulin resistance [56].