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reduced plasma GSH/GSSG ratio was found; this was negatively associated with the levels of fasting FFA (r = -0.53; p < 0.05) (49). In an experimental study with healthy volunteers, ' 'metabolic oxidative stress'' was induced by infusion of intralipid and heparin, resulting in a marked rise of FFA levels. This was associated with an increase of indicators of oxidative stress, as reflected by increased TBARS and a reduced GSH/GSSG ratio (28). In contrast, the infusion of glutathione diminished the negative effect of the sustained elevation of FFA; although FFA were elevated, the alteration of both oxidative stress and insulin-stimulated glucose uptake were markedly attenuated when glutathione was coinfused with intralipid. In addition, glutathione even improved insulin sensitivity and oxidative stress in the control experiment in which no intralipid was given (28).

Ammon et al. (77) showed that the administration of acetyl-cysteine, a compound that could increase endogenous formation of glutathione, improved glucose disposal in healthy volunteers; this was associated with an improved GSH/GSSG ratio. Furthermore, experimental studies indicate a protective role of glutathione on endothelial function (78).

3. Vitamin E

A large epidemiological study indicates that a low level of vitamin E confers a marked risk for the development of a type 2 diabetes mellitus (26). Low levels of vitamin E are also documented in patients with coronary artery disease (20). A regular intake of higher doses of vitamin E was associated with a marked decline in vascular events in coronary artery disease patients (79). These observations suggest a role for vitamin E and/or oxidative stress in these chronic diseases.

In experimental studies, it was shown that vitamin E has beneficial effects on insulin sensitivity. Fructose feeding induces insulin resistance and hypertension in rats; this is also associated with an increase in radical oxygen species formation (80). Vitamin E administration prevented not only the diet-induced alterations in insulin sensitivity but also reduced oxidative stress. Finally, several clinical studies by Paolisso's group suggest that vitamin E intake improves insulin sensitivity as measured by the glucose clamp technique in healthy and diabetic subjects (81-84).

Vitamin E could also modulate insulin sensitivity by indirect effects because it can improve endothelial function. It was shown that in diabetes mellitus endothelial dysfunction is present (1,4), and it is suggested that oxidative stress reduces vasodilatation (3,85,86). Vitamin E administration restores this defect (3,85,86).

If endothelial dysfunction is involved in modulating insulin's action, a restoration of endothelial function should also augment insulin sensitivity (see III.A and Table 2, Fig. 4). Furthermore, vitamin E improves insulin secretion in experimentally induced (type 1) diabetes mellitus (87). At present, however, there are no data concerning the effect of vitamin E on ß-cell function in type 2 diabetes mellitus.

4. Vitamin C

There are a few studies indicating a role for vitamin C in modulating insulin sensitivity. Epidemiological data identify low serum levels of the vitamin as a risk factor for the development of type 2 diabetes mellitus (27). Experimental data describe a protective role of vitamin C on the age-associated deterioration of insulin sensitivity (88). Clinical studies describe an enhanced insulin-stimulated glucose uptake in a glucose clamp study after acute vitamin C treatment in healthy subjects and in those with type 2 diabetes (89,90); the beneficial effects on insulin sensitivity were closely associated with the increases in the plasma levels of the vitamin C (90). Experimental studies indicate also a beneficial effect on endothelial function in experimental polyneuropathy (3). Clinical studies also describe an improvement of endothelial dysfunction (91).

Oxidative stress

Oxidative stress

^peripheral blood flow

Insulin resistance.

Glucose T

Glucose T

Negative mod ' of the insulin signalling cha

Negative mod ' of the insulin signalling cha

Antioxidant??

Figure 4 Decrease of insulin resistance by antioxidants (hypothetical mechanisms).

5. a-Lipoic Acid

Thioctic acid, also known as a-lipoic acid, was found to improve insulin action in various experimental models (92-95). Its action seems to involve interaction with the insulin receptor signaling cascade and potentially also insulin-independent steps (see Chaps. 18 and 19). In vivo experimental studies found an improvement of insulin sensitivity and glucose tolerance after the administration of the racemic mixture (95,96).

Clinical pilot trials suggest that this compound might also have beneficial effects in humans, because insulin resistance was improved after acute or chronic intravenous administration of a-lipoic acid (97-99). Recently, a small placebo-controlled pilot trial found an improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration (100). The changes in insulin sensitivity seen after the active treatment was significantly different from that seen in placebo: whereas insulin sensitivity decreased in the control group, it improved after a-lipoic acid. Furthermore, thioctic acid improves endothelial function (101) and microcirculation by reducing adhesion molecules (102) and preserves endothelial structure (103).

6. Other Compounds

There are several other compounds with antioxidant activity also shown to have a beneficial effect on insulin sensitivity. Two groups of antihypertensive agents are known to improve insulin sensitivity and oxidative stress.

Angiotensin-converting enzyme inhibitors increase the availability of kinins by inhibition of kininase II (104) and consequently NO (47). They were shown to augment insulin-stimulated glucose uptake in clinical and experimental studies (104,105). Recent data suggest that treatment with Ramipril has pronounced effects on NO synthase expression and NO formation and a concomitant decrease in superoxide accumulation, which was associated with an extended lifespan in the angiotensin-converting enzyme treated rats (47).

The vasodilating beta-blockers carvedilol and celiprolol have a marked antioxidant capacity (46,106,107) and were found to improve endothelial function (108). In clinical studies they increased insulin sensitivity as documented by the glucose clamp (109-111).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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