Structure And Mode Of Action Of Agis

The concept of AGI was developed by Puls et al. (14), as a method of controlling the release of glucose from starch and sucrose—the major carbohydrate components in western diet. Inhibition affects both degradation of complex carbohydrates and digestion of disaccharides. An appropriate agent (acarbose) of microbial origin (culture filtrates of actinoplanes) was first described in 1977 by Schmidt et al. (13), and this inhibitor was introduced onto the market in 1990. Three AGIs are now in therapeutic use worldwide (Fig. 1), and are frequently prescribed in Central and south Europe and Asia.

Acarbose is a pseudotetrasaccharide with a nitrogen bound between the first and second glucose unit. This modification of a natural tetrasaccharide is important for its high affinity for active centers of alpha-glucosidases of the brush border of the small intestine, and for its stability. 1-Desoxynojirimycin is the parent compound of other AGIs such as miglitol which, in contrast with acarbose, is a small molecule, similar to glucose. Voglibose is produced by reductive alkylation of valiolamine (16,17).

TABLE 1 Determinants of Postprandial Glucose Excursion

Fasting plasma glucose

Insulin secretion (early phase)

Hepatic gluconeogenesis

Insulin sensitivity of target tissues

Meal composition and quantity

Additives to meal (alcohol, spices, fibers)

Gastric emptying, intestinal digestion and absorption

Duration of the meal

Gut hormones (enteroinsular axis)

Medication affecting insulin sensitivity (beta-blockers, angiotensin converting-enzyme inhibitors, etc.) Physical activity

AGIs act as competitive inhibitors because of their high affinity for alpha-glucosidases, they block the enzymatic reaction particularly because of their nitrogen component. Thus, AGIs must be present at the site of enzymatic action at the same time as the carbohydrates. The effect on postload glucose excursion and insulin after a starch-containing mixed meal is shown in Figure 2. In principle, all three AGIs act in the same way, by inhibiting alpha-glucosidase enzymes in the brush border of the upper part of the small intestine. There are, however, some differences with respect to the inhibitory efficiency on various alpha-glucosidases, which may be responsible for differences in the frequency of side effects. Acarbose is most effective on glucoamylase, followed by sucrase, maltase, and dextranase (15). It also has a degree of inhibition of alpha-amylase, but has no effect on beta-glucosidases, such as lactase. Miglitol is a more potent inhibitor of disaccharide digesting enzymes, such as sucrase and maltase, than acarbose, and is also active on isomaltase but has no effect on alpha-amylase (18). It also weakly interacts as a pseudomonosaccharide with the intestinal sodium-dependent glucose transporter, without having a clinically relevant effect on glucose absorption (19). Voglibose is isolated from Streptomyces culture broths. It is a strong AGI with little effect on alpha-amylase.


Acarbose is poorly absorbed (0.5-1.7%), and is degraded in the large intestine by bacterial enzymes into glucose, maltose, and acarviosine. A nonabsorbed fraction of 60% to 80% is excreted via feces (Table 2). About 35% of an oral dose appears as degradation products in the urine (16); this may be clinically relevant in cases of impaired kidney function. Miglitol is rapidly absorbed and transported in the intestine in the same way as glucose. It is



FIGURE 1 Structures of AGIs in clinical use.

TABLE 2 Summary of Pharmacological Characteristics of AGIs in Clinical Use
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