PREVENTION OF STARCH UTILIZATION WITH a-AMYLASE INHIBITORS.
The composition of the ideal weight loss diet has been much discussed, and controversy exists over whether such diets should be high in carbohydrate or not, though public opinion is gradually leaning in the direction of low carbohydrate, and rightfully so. One obstacle to the use of low carbohydrate diets has been the popular misconception that unless a diet contains substantial amounts of carbohydrate, it will inevitably result in tired and listless patients who have no "zip". A simplistic approach teaches that the body uses glucose for energy, which leads directly to the assumption that carbohydrate must be consumed if one is to feel energetic!
The full story is much more complex. Digestion of food results in simple sugars from carbohydrate (such as glucose), amino acids from protein and fatty acids from fat entering the blood stream (ignoring fine detail like lymphatic absorption), and thus becoming available to the tissues. Apart from some direct utilization for storage or function (fatty acids into fat, glucose into glycogen, amino acids into protein), and some utilization for special purposes (essential amino acids, essential fatty acids), any sugar or fatty acid, and many amino acids, can be broken down to a basic biochemical unit, acetyl-Coenzyme A, which can be oxidized to give energy or rebuilt into certain storage nutrients (particularly fat). Simply put, the body can equally well use protein, fat or carbohydrate for energy! Increasing the amount of carbohydrate in the diet results in more acetyl-Coenzyme A being formed, and the surplus, instead of giving more energy, will be turned into fat, which is not exactly the intent for patients on a diet.
When it comes to energy sources, the body tissues are not too selective; most will use glucose, free fatty acids, free amino acids and ketone bodies interchangeably. In fact, muscle prefers free fatty acids under some circumstances, while brain tissue likes ketone bodies if they are available.
There is, of course, nothing wrong about having carbohydrate in a diet, provided there is still sufficient protein, but since calories must be restricted, once the requisite amount of protein and a certain amount of fat has been allowed for, there is no space for a lot of carbohydrate. More can be added "on top", of course, but it will have a negative effect on weight loss, will not improve "energy", and may even cause sensations of hunger.
Research has shown that the carbohydrate content of low calorie diets makes the smallest contribution to weight loss, and that the protein content makes the greatest contribution to maintaining the ability to perform physical exertion (keeps the "zip" in the patient). A few scientists have examined this subject directly. For example, Rabast et al. (1979) showed that carbohydrate in a diet diminishes weight loss; these investigators gave two comparable groups of obese subjects isocaloric diets (1000 kilocalories per day), one of which was low carbohydrate (25 g per day) and high in fat, the other high carbohydrate (170 g per day) and low fat.
Both contained 46 g protein per day. Over a 50 day period, weight loss was 14.0 kg in the group given the low carbohydrate diet, but only 9.8 kg in the group receiving the high carbohydrate diet.
Racette et al. (1995), in a study of the combination of diet and exercise on weight loss and fat loss, confirmed that the combination of exercise and diet increases the proportion of fat in the weight lost and maintains, or even increases, total daily energy expenditure, even allowing for the energy utilized in the aerobic exercise. They also showed that the composition of the 1200 kilocalorie diet, low fat or low carbohydrate, controlled weight loss, which was greater (10.6 ± 2.0 kg; about 23 lbs) on the low carbohydrate high fat diet than on the high carbohydrate low fat diet (8.1 ± 3.0 kg; about 18 lbs). Thus on average, rates of weight loss were almost half a pound better per week on the low carbohydrate high fat diet. This confirms the results of previous studies which have shown that excessive reductions in fat intake slow weight loss or may even cause weight gain. The reason for this observation, which flies counter to commonly held perceptions of fat as being a bad thing, is obscure, but it may relate to both essential fatty acid deficiency and a negative impact of a high carbohydrate load on metabolic efficiency.
The energy cost to the body of digesting, absorbing and "processing" carbohydrate is about the same as that for fat under normal conditions, and both are much lower than the equivalent energy costs for protein. These energy costs form part of "diet induced thermogenesis" (DIT).
Those who have a tendency to put on weight have a reduced thermogenic response to glucose (Heleniak and Aston, 1989; Jéquier, 1987, 1989), but apparently not to fat. In low fat diets (and low fat/no fat products), carbohydrate generally takes the place of the fat, so such persons actually require less calories when on such a diet. Since this may not be obvious from direct caloric comparisons, high carbohydrate diets can at the least diminish rates of weight loss, and at the worst may even result in weight gain.
Thus when food eaten does not contain much fat, but contains adequate amounts of carbohydrate, the body converts carbohydrate (glucose) to fat very efficiently (see any standard textbook of biochemistry). Adequate insulin levels facilitate this conversion, and the rate at which glucose is converted to fat increases as fat intake falls. Thus whereas some dietary fat is incorporated almost directly into storage fat, reducing fat in the diet, far from reducing the amount stored, actually increases it. This is, of course, a natural mechanism; when a diet contains enough fat, conversion of glucose to fat is reduced, and any surplus glucose is converted into glycogen. Glycogen is, however, only a short-term energy store (enough for 18 - 24 hours of normal use), and if carbohydrate intake is high, the glycogen stores are most likely to be full. Stored fat is a long-term energy reserve, and fat is also a better way of storing energy, preferred by the body.
Testing body performance in exercise tests may be a way of quantifying "zip". Davis and Phinney (1990) compared the effects of two diets on aerobic and anaerobic function. They found that all functional parameters were maintained on a Protein Sparing Modified Fast (PSMF) of 550 kilocalories per day, providing 1.5 g protein/kg ideal body weight/day and less than 10 g carbohydrate, but that significant decreases in all parameters occurred on a Very Low Calorie Diet of 420 kilocalories per day providing 70 g protein and 30 g carbohydrate. Interestingly, despite the extra calories in the group given the high protein, low carbohydrate diet, the weight losses in both groups were similar.
The psychological state of the patient (particularly attitudes to food) may also relate to carbohydrate content of the diet. There has been little comparative research on this topic, but Wadden et al. (1985) did compare groups of patients on isocaloric ketogenic (low carbohydrate) and non-ketogenic formula diets. They found that patients on the ketogenic diet had significantly less hunger, and were also much less pre-occupied with food (a behavioural parameter that should be considered very beneficial). Anderson et al. (1990) revealed that a conventional (not high protein) diet reduced plasma tryptophan levels in women and reduced brain serotonin metabolism; serotonin is a hormone derived from tryptophan, low levels of which may result in depression and abnormal eating behaviour.
Other negative effects of high-carbohydrate diets have been reported. Roust et al. (1994) investigated changes in body composition and plasma lipids occurring when fat in a diet was partially replaced by complex carbohydrate. Their study was performed in 23 premenopausal women, who were classified as upper-body obese (7), lower-body obese (8), or non-obese (8).
After weight maintenance was achieved on a diet providing 43% calories from fat, 37% from carbohydrate and 20% from protein, the contribution of fat was reduced to 27% of calories, and the carbohydrate contribution was increased to 53%. As a result of the dietary change, plasma triglyceride levels increased in the upper-body obese women, but did not change significantly in the other groups. There were no significant changes in any of the other parameters studied.
Though the exact reason for the increase in triglyceride levels is obscure, it is tempting to assume that it may reflect an increase in fat synthesis caused by reducing fat intake in favor of carbohydrate. The finding that body fat distribution affects response to dietary change is of interest, and emphasizes the importance of assessing fat distribution when predicting the outcome of treatment.
To summarize, high
carbohydrate diets do not necessarily make patients more energetic,
and result in poor weight loss. Furthermore, such diets may cause loss
of vital tissues, do nothing to suppress hunger, and may even result
in deposition of extra fat.
While it is reasonable to formulate weight loss diets that are adequate in protein, essential fatty acids and micronutrients, but low in carbohydrate, it is theoretically possible to achieve similar results by increasing protein and essential fatty acid intake and reducing the availability of carbohydrate, and in particular the availability of starch, in the diet. This is potentially feasible either by providing specially formulated foods containing amylase-resistant starch, or by administration of an a-amylase inhibitor (present in many unprocessed plant materials, including beans and cereal grains). The latter approach has the merit that the dieting patient can continue to eat conventional starchy foods, which often (but not always) contain significant amounts of dietary fibre (a valuable adjunct in weight loss diets), and both approaches also benefit from the fact that starch that is unavailable (for any reason) actually behaves in the gastrointestinal tract like dietary fibre.
Reducing the availability of starch also has merit for the diabetic subject, giving greater control of metabolic swings without the need for excessive caution in determining the carbohydrate composition of ingested food.
THE USE OF a-AMYLASE INHIBITORS:
The enzyme a-amylase found in the duodenum of the gastrointestinal tract acts upon large linear polymers at internal bonds. The hydrolytic products have an a-configuration. Specifically, a-amylase catalyzes the hydrolysis of internal a-1,4-glucan links in polysaccharides containing 3 or more a-1,4-linked D-glucose units, yielding a mixture of maltose and glucose. Amylolytic activity is present in all living organisms, but the enzymes vary remarkably, even from tissue to tissue within a single species.
A protein fraction from various plants, though usually prepared from beans (particularly Great Northern and red kidney beans), is capable of inhibiting the action of a-amylase in vitro. As prepared from red kidney beans, this protein fraction is a glycoprotein with a molecular weight of 49,000 (Houglam and Chappell, 1984). It is destroyed by acid (pH < 3.0) and by chymotrypsin (a proteolytic enzyme present in the duodenum), but not by pepsin (a proteolytic enzyme present in the stomach) or trypsin (a proteolytic enzyme in the duodenum) (Andriolo et al., 1984). It has also been noted that the protein may be readily oxidized.
Initial clinical studies gave disappointing results. For example, Bo-Linn et al. (1982) showed no effect on faecal calorie excretion after administration of a commercial "starch blocker", while Garrow et al. (1983) failed to show any changes in insulin or blood sugar levels after administration of two different commercial "starch blockers". Carlson et al. (1983) also failed to show effects on blood glucose, insulin or breath hydrogen after administration of a commercial product with verified in vitro activity.
Granum et al. (1983), however, determined that actual amounts of a-amylase inhibitor present in one commercial "starch blocker" product, though capable of inhibiting a-amylase in vitro, were too small to exert an effect in vivo, and that the degree of concentration or purification of the a-amylase inhibitor was apparently minor (to the extent that one tablet contained no more protein than a single bean).
Hollenbeck et al. (1983) came to the conclusion that while commercial "starch blockers" might inhibit pancreatic amylase, they appeared to be ineffective against the amylolytic enzyme present in the brush border cells lining the small intestine, which though it performs the same actions is in fact a different enzyme.
Later studies (Layer et al., 1984; Rosenfeld et al., 1984; Layer et al., 1985; Layer et al., 1986) showed that a-amylase inhibitors from beans were effective in preventing starch digestion in vivo if they were sufficiently purified. For example, administration of a concentrated a-amylase inhibitor with increased activity substantially reduced increases in plasma glucose and insulin after a test meal containing starch in both normal subjects and in those with diabetes (Layer et al., 1986).
Umoren and Kies (1992) tested a commercially available starch blocker derived from soybeans in rats fed potato starch, and though they demonstrated a small but non-significant decrease in body weight over a 4-week period, they did show significant increases in faecal copper and zinc excretion, the reason for which was not apparent but may have related to some degree of impairment of starch absorption.
In retrospect, it appears that many of the commercial "starch blockers" available in the early 1980's contained essentially unconcentrated bean protein and had little intrinsic activity, such that they could be predicted to be ineffective. Use of more highly concentrated material, however, did give clinically significant results. The sensitivity of the a-amylase inhibitor to acid, and possibly also to atmospheric oxygen, also indicates that the time of administration, and the sophistication of the formulation containing the inhibitor, are critical to the achievement of a significant degree of "starch blocking".
It should be understood, of course, that even when all these criteria are satisfied, "starch blockers" can only work when the diet contains starch; they have no effect on the absorption of simple sugars. In this respect, it has been reported that starch provides from 500 to 700 kilocalories per day in the average American adult diet.
In practice, therefore, to be effective a "starch blocker" must meet the following criteria for content and use:
While in vitro tests may indicate, for example, that an a-amylase inhibitor is capable of inhibiting the hydrolysis of as much as 1.5 grams of starch per mg of inhibitor over a relatively short period of time, it is unlikely that activity will reach more than a fraction of this level under in vivo conditions.
However, even when in vivo activity is only 2% of the in vitro level, inhibitor of this potency can still reduce availability of many grams of starch.
Exposure of the inhibitor to atmospheric oxygen is likely to result in severe loss of activity, therefore capsules are an inappropriate vehicle.
It is essential that the inhibitor is not exposed to gastric acid before admixture with the food, and it is also essential that the inhibitor passes into the duodenum together with the food. The objective is to inhibit the effect of pancreatic amylase on the starch in the meal, and for this purpose, the inhibitor must be present when the starch is first exposed to the pancreatic amylase.
The inhibitor only prevents the enzymatic hydrolysis of the starch (amylolysis), and NOT the absorption of simple sugars.