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The Journal of Nutrition Vol. 128 No. 2 February 1998,
pp. 333S-336S
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
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ABSTRACT |
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Abstract
Introduction
References
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Although mild abnormalities of amino acid metabolism frequently exist in conventionally treated insulin-dependent diabetes mellitus (IDDM), their physiologic and nutritional importance is uncertain. We tested whether a tendency toward body N loss can be either masked or revealed in insulin-treated IDDM by changing the level of protein in the diet. After adaptation to a protein-free diet adequate in all other nutrients, obligatory urinary N excretion of intensively treated IDDM subjects was significantly greater than normal, indicating an impaired ability to recycle endogenous amino acids during protein restriction. When the preceding diet was high in protein, urea N production after consumption of a mixed test meal matched the amount of N consumed for both normal and diabetic subjects. However, when the test meal was preceded by 5 d of protein restriction, conventionally treated IDDM subjects failed to adaptively reduce postprandial urea production as effectively as normal or intensively treated IDDM subjects. Thus, even during insulin treatment, the ability to maximally recycle endogenous amino acids is impaired in IDDM, as is the ability to adaptively increase dietary amino acid retention in response to protein restriction.
KEY WORDS: nutrition · malnutrition · urea · amino acids · fed state
Protein wasting has long been known to accompany untreated or poorly treated insulin-dependent diabetes mellitus (IDDM) (Bliss 1982 Protein wasting does not occur in adults with insulin-treated IDDM (Rosenfalck et al. 1994 It is easy to understand how a mild defect in the ability to suppress amino acid oxidation could be masked by a high protein intake. A person whose protein intake is above the requirement level will normally catabolize amino acids at the same rate at which they are consumed. Because most people consume about twice the normal protein requirement, there is no physiologic need to conserve dietary amino acids efficiently to maintain protein balance. To detect subtle defects in protein metabolism, it is first necessary to reduce habitual protein consumption to near or below the requirement level.
The factorial method was the first technique systematically used to estimate the adult protein requirement (Munro 1985 Although the factorial method can be a sensitive research tool for detecting subtle impairments of metabolic adaptation, it does not represent a realistic clinical situation. Moreover, it assumes that amino acids lost from the body can be replaced with perfect efficiency from the diet. In reality, there is considerable variation in the retention of dietary amino acids during their initial distribution and metabolism in the body (Millward 1994
These results indicate that adaptation to dietary protein restriction involves an increase in endogenous amino acid reutilization and increased dietary amino acid retention after a standard mixed meal. This latter process is impaired during conventional IDDM treatment, but not during intensive treatment. Maximum endogenous amino acid reutilization is impaired even during intensive diabetic therapy, and it varies intimately with the deviation from fully physiologic insulin replacement. Because a high efficiency of dietary amino acid retention and endogenous amino acid recycling becomes necessary only when dietary protein intake is restricted, diabetic adults whose protein intake is ample will normally be protected from protein wasting. The precise combination of protein restriction and imperfect metabolic control that will result in clinical protein wasting cannot be predicted from this research. Both, however, are important.
INTRODUCTION
Abstract
Introduction
References
), but only in recent years has a detailed metabolic description of this phenomenon begun to emerge. Modern tracer studies reveal that even transient insulin withdrawal induces intense and prolonged body protein catabolism (Nair et al. 1983 and 1987, Umpleby et al. 1986). After insulin was introduced into clinical medicine, cases of extreme insulin lack and protein-wasting in IDDM became rare (Bliss 1982). Nevertheless, even modern intensive insulin regimens do not fully normalize insulin physiology, and the conventional twice-daily insulin therapy still used by the majority of diabetic persons is frequently associated with biochemical abnormalities of amino acid and energy metabolism (Carlson and Campbell 1993, Gebre-Medhin et al. 1985, Rudolf et al. 1982, Tamborlane et al. 1979). Are these abnormalities physiologically or nutritionally important?
); thus the physiologic consequences of residual abnormalities of protein metabolism in treated IDDM, if indeed there are any, must either be subtle and difficult to detect, or they emerge only in certain situations. In our research, we predicted that a tendency toward protein wasting in IDDM could be either masked or revealed if we varied the major factor that normally regulates body protein economy: the level of protein consumption.
PROTEIN REQUIREMENT OF NORMAL AND DIABETIC SUBJECTS MEASURED BY THE FACTORIAL METHOD
). It is so named because it involves adding the factors (urinary, fecal and other) that contribute to body N loss. These losses are measured after several days of adaptation to a protein-free diet on the assumption that the lowest rate of endogenous amino acid catabolism and N excretion the body can achieve under these conditions
its "obligatory" N lossis the minimum amount of protein needed from the diet to maintain N balance. Urinary obligatory N is by far the most important factor contributing to total obligatory N, and it has been found to be highly constant when measured in many different studies (FAO/WHO/UNU Expert Consultation 1985).
). All subjects lived in the metabolic unit for the duration of the study; the blood glucose level of the diabetic subjects was measured at least seven times daily and regulated by using a portable continuous subcutaneous insulin infusion pump. Our intention was to normalize the blood glucose level of these subjects to the maximum extent possible in a clinically plausible scenario. As a result of this approach, the blood glucose parameters of our diabetic subjects fell well within published guidelines for intensive insulin therapy (DCCT Research Group 1986). Metabolic adaptation was measured by using two different methods. The first was postabsorptive plasma leucine oxidation, which was measured after adaptation to each of the diets and (for the diabetic subjects) during strict euglycemia maintained by an intravenous insulin infusion. The second was daily urinary N excretion, which had reached an apparent steady state after 7 d of adaptation to the protein-free diet, and hence represented obligatory urinary N excretion. Because the urinary measurement indicated amino acid oxidation over the entire day, it accounted for variations in amino acid oxidation associated with a clinically feasible intensity of diabetic control. These effects would not be revealed during a short-term tracer leucine oxidation study conducted during strict euglycemia.
, FAO/WHO/UNU Expert Consultation 1985). This N excretion rate was also appropriate for the total amino acid oxidation rate indicated by their short-term postabsorptive leucine oxidation data (Lariviere et al. 1992). This confirmed that the urinary N excretion of normal people consuming a protein-free diet is constant over the entire day (Steffee et al. 1981).
FED STATE PROTEIN METABOLISM AFTER PROTEIN RESTRICTION
). This explains why the average daily protein requirement indicated by the factorial method (0.34 g protein/kg adult body weight) is substantially less than the value of 0.60 g/kg indicated by more detailed studies that include several test levels of protein intake (FAO/WHO/UNU Expert Consultation 1985).
). We named this test by analogy with the glucose tolerance test. Because an abnormal glucose tolerance test indicates impaired disposal of an oral glucose load, abnormal "protein tolerance" would be indicated by abnormal disposal of a protein load, resulting in an abnormally high post-prandial urea production rate.
). Amino acid oxidation was inferred from urinary urea excretion over the 9 h after the test meal was consumed, with a correction for changes in the body urea pool size. Net protein utilization (NPU) was calculated as (Nin 
urea N production)/Nin. It should be noted that this measurement of urea production ignores the fact that some newly synthesized urea is hydrolyzed in the gut and hence is not detected by a nonisotopic method based on urinary urea excretion (Taveroff et al. 1993). However, by including a tracer dose of [13C]urea in several of the test meals and measuring its recovery in urine and plasma, we determined that neither dietary condition nor the presence of hyperglycemia affected this source of unmeasured urea loss. (Approximately 75% of the [13C]urea in each test meal was recovered in urine and plasma under all conditions.) In each test meal, we also included a tracer of the rapidly transaminated amino acid, [15N]alanine, in order to estimate "first-pass" dietary amino acid catabolism, with resulting appearance of the label in plasma and urinary urea (Freyse et al. 1987).
View this table:
Table 1.
Effect of prior adaptation to protein restriction on the metabolic response to a test meal1
CLINICAL IMPLICATIONS
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
Introduction
References
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