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The Journal of Nutrition Vol. 128 No. 2 February 1998,
pp. 337S-339S
Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago, IL 60612-7333
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ABSTRACT |
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Abstract
References
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The effects of dietary protein deprivation in insulin-dependent diabetes mellitus (IDDM) have been investigated in a merely rudimentary fashion in human subjects. Moderate dietary protein restriction of 0.6 g/(kg ideal body weight·d) over 3 mo in free-living IDDM patients produces increased adiposity during weight maintenance and decreased muscle strength. These effects might have been predicted from studies of protein deprivation in diabetic subjects, indicating impairment of nitrogen retention. The clinical consequences of dietary protein restriction in IDDM may be more complex than described to date. This is suggested by the overriding paradox that the actions of insulin on protein synthesis are inconsistent among in vitro, animal and human in vivo models. The inconsistency and the observation that insulin deficiency in humans accelerates both proteolysis and protein synthesis imply that knowledge about insulin, diabetes and protein metabolism in humans is inadequate and should be studied in increasing detail. Better understanding of the clinical consequences of dietary protein restriction in diabetes, both beneficial and adverse, is likely to come from future studies incorporating clinically relevant levels of insulin deficiency and protein deprivation into studies of bodily function, clinical outcomes and specific examination of the metabolism of individual proteins.
KEY WORDS: protein metabolism · skeletal muscle · amino acids · body composition
The observations of Walter Kempner in the mid 1940s that limiting dietary consumption to rice and fruit reduced some of the complications of hypertension and diabetes remained a curiosity for decades, open to criticism as a result of the multiple experimental alterations in American food consumption induced by his "rice diet" (Kempner 1945 Understanding the nutritional consequences of protein restriction in diabetic nephropathy posed unique challenges and brought an examination of previous research from two disciplines involved in the study of human protein metabolism. The first was the study of human adaptation to varying levels of dietary protein restriction. The second was the investigation of the regulation of protein metabolism by insulin.
Clinical studies establishing the benefit of dietary protein restriction for patients with diabetic nephropathy employed diets with a protein content of 0.6 g/(kg·d) (Walker et al. 1989 It seemed possible that insulin-deficient diabetic patients consuming protein-restricted diets would be at greater risk for loss of body proteins than those without diabetes, given the abnormalities of protein metabolism that have been reported during insulin deficiency (Nair et al. 1995 We examined body composition and muscle strength in six insulin-dependent diabetic subjects with early nephropathy before and after a 3-mo trial of a 0.6 g/(kg ideal body weight/d) protein intake (Brodsky et al. 1992 Our study suggested that conventional methods of detecting undernutrition in the clinical setting, such as measurement of body weight, are insensitive. Similarly, serum albumin concentration in the study participants was normal. Although serum albumin concentration is commonly used as a nutritional indicator, it is known to have poor predictive characteristics as a test for nutritional risk (Detsky et al. 1984 The full spectrum of clinical pathophysiology to be found with combined dietary protein restriction and IDDM remains to be elucidated. Similarly, the mechanisms underlying the clinical disturbances already noted have not been defined. For these reasons, studies of clinical function and the metabolism in vivo of individual proteins should be undertaken in an attempt to clarify these items. Pursuit of the mechanisms underlying the clinical disturbances might begin with examination of skeletal muscle proteins. Our isokinetic dynamometry and hydrodensitometry measurements suggested that skeletal muscle is particularly affected by decrements in function and perhaps mass when restricted dietary protein is superimposed on insulin-deficient diabetes (Brodsky et al. 1992 When skeletal muscle is considered a representative tissue affected by the combination of insulin deficiency and dietary protein restriction, it is clear that present knowledge about human skeletal muscle protein metabolism is incomplete. Studies performed in rat muscle suggest that insulin stimulates protein synthesis and inhibits protein degradation (Flaim et al. 1980 The difference in insulin's effects in different mammalian species may have nutritional implications and lessons for future investigation. In vivo studies of diabetic humans have examined synthesis and breakdown of mixtures of muscle proteins rather than specific proteins during insulin deprivation or supplementation; thus, on the basis of known physiology, one cannot predict the influence of altered insulin availability on muscle function. Synthesis and degradation of minority proteins that regulate muscle function may be affected by insulin action, but such effects may be unrecognized when they are obscured by more abundant proteins that are less sensitive to insulin.
Examining the metabolism of specific muscle proteins in diabetes might explain better the effect of diabetes on muscle function. The genes for certain proteins are known to have recognizable insulin regulatory sequences. These include phosphoenolpyruvate carboxykinase, insulin-like growth factor binding protein 1, and apolipoprotein C3. However, there are other, recently recognized ways in which insulin can exert specific regulation of protein synthesis. Examples include the following: 1) the ability of insulin to increase the availability of eukaryotic initiation factor 4E, promoting translation of uniquely configured mRNA, which encodes proteins regulated by insulin (Proud 1994 As with our poor knowledge concerning the effects of insulin, there is a general lack of information about the effects of protein nutrition on the metabolism of specific muscle proteins in humans. Much of the knowledge about the clinical response to protein deprivation is clouded by the effects of energy undernutrition, metabolic diseases such as renal failure and inflammatory illness with which protein deprivation often coincides. Isolated dietary protein restriction in humans does not consistently inhibit whole-body protein synthesis; inhibitory effects are exhibited in some studies (Motil et al. 1981 In rats, both synthesis and degradation of muscle proteins are decreased during dietary protein restriction, thereby allowing lower protein turnover and a preservation of muscle mass (Tawa and Goldberg 1992 Given the scant information available about the metabolism of individual proteins in humans with insulin-deficient diabetes or those deprived of dietary protein, it is not surprising that we cannot explain the subtle clinical changes of body composition and muscle strength noted in IDDM patients consuming protein-restricted diets. Studies examining regional metabolism of IDDM patients during moderate dietary protein restriction have noted that the balance of amino acids across the forearm, a largely muscular region, remains normal in IDDM patients during protein restriction as long as euglycemia is maintained (Brodsky and Devlin 1996 The elevated rate of leucine appearance clearly indicates that protein degradation is elevated in forearm tissues of IDDM subjects. The increased leucine disposal may represent augmented utilization of leucine in the forearm either for protein synthesis or for enhanced terminal oxidation of leucine. Because whole-body leucine oxidation was not increased in our IDDM subjects under the euglycemic condition studied and forearm alanine de novo synthesis (a product of leucine transamination in muscle) was not increased, we believe that this enhanced leucine disposal is due to increased protein synthesis. This suggests that IDDM subjects maintain elevated rates of both protein degradation and protein synthesis in muscular regions during normal and protein-restricted dietary conditions.
Given the methodology used in these studies, we do not know which proteins are excessively degraded and which are excessively synthesized. It is clearly possible that amino acids released from forearm and perhaps other muscular regions in IDDM subjects are not recycled into the same types of proteins from which they were liberated. The nutritional consequences of these observations depend on whether specific proteins are uniquely accumulated or depleted in muscle of IDDM patients. The introduction of dietary protein deprivation to IDDM subjects does not appear to amplify the accelerated forearm leucine release and disposal. However, this does not mean that there are not qualitative differences between IDDM and non-diabetic subjects in the adaptation of muscle protein composition to dietary protein restriction. Rather, it underscores the inability of the methods used to detect the spectrum of changes in protein metabolism that could have clinical consequences.
In conclusion, to advance the understanding of the clinical, nutritional implications of dietary protein restriction, insulin-dependent diabetes and their combination, future studies will have to employ two approaches. First, studies should address relevant clinical outcomes and function among IDDM patients consuming diets with lowered protein content. Studies of muscle function could be extended to include studies of immune function and similarly important assessments. Second, studies of human protein metabolism under these clinical circumstances should be directed toward the scrutiny of the metabolism of individual, clinically relevant proteins. These two approaches may bring into focus those aspects of whole-body functioning that are of intuitive medical importance and those aspects of protein metabolism that can provide new insight into the in vivo cellular biology of our patients. Two sayings of the Taoists (Lao-tzu 1989) may sum up the unresolved questions: "We look at it but do not see it" and "To know you do not know is best."
). Spurred by the investigations of Giordano and Giovanetti, indicating that low protein diets could forestall progression of renal dysfunction to end stage, the 1960s brought interest in the use of dietary protein restriction to treat renal disease (Giordano et al. 1966, Giovanetti and Maggiore 1964). This difficult dietary treatment was felt to be unnecessary with the advent of dialysis. However, when it became clear in the 1980s that dialysis was an imperfect renal replacement approach, interest in the use of dietary protein restriction to forestall progression of renal dysfunction again increased. This was accompanied by an interest in its nutritional consequences.
, Zeller et al. 1991), an intake recommended to meet the average minimum requirement for healthy adults (FAO/WHO/UNU 1985).
). Protein breakdown is accelerated during insulin deficiency and can be measured as an increase in net whole-body protein degradation and amino acid oxidation. The enhanced protein breakdown and loss of essential amino acids can be reversed by prolonged maintenance of near-euglycemia, generally requiring an elevated concentration of insulin in the peripheral circulation (Luzi et al. 1990, Nair et al. 1987, Tessari et al. 1986, Umpleby et al. 1986). Because prolonged euglycemia is difficult to achieve in clinical practice, one might anticipate that enhanced protein catabolism in insulin-deficient diabetes would be a common occurrence, necessitating an increased dietary protein intake for counterbalance.
). Despite maintenance of a constant body weight, subjects experienced an 11% increase in body fat (as measured by hydrodensitometry). This resulted in a 10% decline in lean/fat mass ratio, confirming the increase in adiposity. Muscle strength [measured by isokinetic dynamometry (Cybex II, Ronkonkoma, NY) as gravity-corrected, maximum, quadriceps-generated torque] declined by nearly 7% during the 3-mo moderate dietary protein restriction. These results confirmed that insulin-dependent diabetic patients experience clinical evidence of undernutrition while consuming a diet with a protein content similar to that prescribed for the treatment of diabetic nephropathy.
). James and Hay (1968) have shown that serum albumin concentration is maintained in children consuming a low protein diet even when total body albumin mass is decreased. These children would normally be considered to be at high risk for kwashiorkor with additional physiological stress, yet serum albumin concentrations do not predict this.
). Thus, skeletal muscle is a reasonable tissue for further investigation into the regulation of human protein metabolism in vivo by the interaction of insulin and dietary amino acids.
, Jefferson 1980, Pain et al. 1983). These studies stand in contrast to in vivo studies of amino acid metabolism in skeletal muscle or muscular body regions of adult humans, suggesting that insulin is solely an inhibitor of protein degradation and plays no role in the promotion of protein synthesis (Nair et al. 1987). These contradictory results have been attributed to the inhibition of protein synthesis by low circulating concentrations of amino acids that occur when studies are performed with systemic insulin administration. However, studies using a forearm perfusion technique, which avoids hypoaminoacidemia, also indicate that inhibition of proteolysis is the dominant anabolic action of insulin in the muscle of adult humans (Gelfand and Barrett 1989).
) and 2) the ability of insulin to interact intracellularly with the insulin degrading enzyme, which mediates some functions of the steroid receptor family (Duckworth et al. 1997). Advances in technology for measurement of amino acid tracers may make investigation of minority proteins in human subjects currently feasible. Such studies should be less sensitive than the study of mixed proteins to variation in proportional expression of proteins among species or preparations.
) but not in others (Brodsky and Devlin 1996, Picou and Taylor-Roberts 1968, Steffee et al. 1976). Similarly, some studies indicate that whole-body protein degradation decreases during protein deprivation (Motil et al. 1981) (Brodsky and Devlin 1996), whereas others suggest an increase (Steffee et al. 1976). It is not clear what to expect clinically from examining whole-body responses. Lean tissue estimated by total body potassium counting appears to be lost during long-term (>80 d) moderate dietary protein restriction in healthy adults (Garza et al. 1977), but it is not clear which lean tissues are most affected and how much can be attributed to muscle.
). The specific muscle proteins whose turnover is affected are largely unknown. The implications of the available data for responses of human muscle to moderate dietary protein restriction are also unclear.
). Interestingly, IDDM patients maintaining euglycemia maintain normal amino acid balance while displaying a consistent elevation of forearm amino acid turnover, evidenced by persistently high rates of leucine appearance and disposal. This increased turnover persists after adaptation to moderate dietary protein restriction under conditions of near euglycemia.
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
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