Amino Acids In Health and Disease: New Perspectives, pages 369-382@ 1987 Alan R. Liss, Inc. )

PLASMA AMINO ACID LEVELS IN OBESITY:EFFECTS OF INSULIN RESISTANCE

Benjamin Caballero, Nicholas Finer1and Richard J. Wurt man

Department of Applied Biological Sciences andClinical Research Center

Massachusetts Institute of TechnologyCambridge, !\fA 02142

ABSTRACT The decreased insulin sensitiVity of. obesity,besides its w~n-known effects on glucose metabolism, isalso responsible for the elevated plasma amino acid levelsobserved in many obese persons. This hyperaminoacidemia ismost evident for valine, leucine, lsoleucine, tyrosine andphenylalanine. The plasma amino acid response t(f. foodIntake is also different in obese subjects; carbohydratemeals do not cause the expected fall in branched chainamino acids, causing a distorted postprandial amino acidprot:ile~

INTRODUCTION.'

Most moderately obese persons have a normal oral glucosetolerance test (OGTT), but they exibit an excessive insulin riseIn response to glucose intake, consistent with their lower tissueresponsiveness to insulin. This hyperinsulinemia of obesity wasfirst described qver 20 years ago (1), and is associated with adecre.ased glucose ptetabolic rate, excessive hepatic basal glucoseproduction, and inadequate suppression ot hepatic glucose outputby insulin (2). O~e persons may thus be chronically exposed tohigh plasma insulin concentrations, which may be necessary tosustain their normal blood glucose levels, but which may be---------1. Present address: Depart ment ot fAedicine, Guy's Hospital

Medical School, University of London, London, England

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370 Caballero, Finer, and Wurtman

either insuf!icient. or excessive for other insulin-dependentprocesses.

The decreased tissue sensitivity to insulin of obesityinvolves receptor and postreceptor defects. Studies in obesehumans and in ani mal models of obesity have shown a decreasednumber of insulin receptors in a variety of tissues: skeletal

muscle (3, 4), adipocytes '{.5), thymic lymphocytes (6), hepatocytes(7, 8) and circulating monocytes (9). Studies in humans have alsodemonstrated a correlation between the number of receptors incirculating monocytes and insulin sensitivity measured by theinsulin clamp technique (10). Regional perfusion studies in obesehumans shows that insulin resistance is present in muscle(quantitatively the most important) (11), adipose tissue, liver (2)and the splanchnic bed (12, 13). Since under normal conditionsonly a small number of receptors must be active to exert insulinactions, most obese subjects exibit a normal maximal insulinstimulated glucose disposal rate when sufficient insulin isadministered (14). On the other hand, some obese persons cannotreach the maximum glucose output even when receiving veryhigh amounts of insulin, presumably reaching receptor saturationwithout exibit1ng an insulin effect (15, 16).. These obese personsare characterized as having postreceptor defects, and in somestudies the magnitude of this defect is correlated with fastingplasma insulin concentrations (16).

INSULIN AND PLASMA AMINO ACID LEVELS IN OBESITY

Normal insulin effects on plasma amino acids

Insulin regulates protein synthesis at the transcriptional,translational and post-translational processing steps U 7, 18); itcan also indirectJy modulate protein synthesis by controlling therate of amino acid uptake into the cell. Insulin promotes theincorporation ot branched chain amino acids into muscle, inhibitsleucine oxidation (19), and decreases protein degradation (20). In1928, Luck et al. (21) were the first to demonstrate that theinjection of insulin to man produces a significant decrease in

. total amino N in plasma. In the following decades, an inversecorrelation between plasma insulin and branched chain aminoacid concentrations over a wide range of insulin levels have beenreported, from very low, such as in diabetes, to very high, as infunctioning insulinoma (22). A dose of 0.1 U/kg of insulin in anadult causes a significant fall in branched chain amino acids 20minutes atter injection (23); carbohydrate intake produces similar

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Plasma AmiJlo Acid Levels in Obesity 371

effects (24). This insulin effect is most likely due to astimulation of peripheral amino acid uptake, particularly intomuscle tissue (25). In a recent study, Fukagawa et al. (26) usedthe euglycemic clamp technique to quantify the sensitivity ofthe branched chain amino acids, tyrosine and phenylalanine toinsulin in normal men. They reported that insulin levels for half-maximal amino acid decljease are within the range of half-maximal glucose disposal.

Insulin and plas ma amino acids in obesity

Several years ago, Felig et al. and others (27, 28)demonstrated that the insulin-dependent fall in plasma BCAA wasimpaired in obese subjects; in their study, obese subjectsshowed significantly higher fasting plasma levels of valine,leucine, isoleucine, tyrosine and phenylalanine. After i. v.administration of 0.5 g/kg of glucose, the percent fall in. neutralamino acids was significantly lower in obese, although theabsolute fall for each of these amino acids was similar in lean

and obese.. Felig ~ al. suggested that this hyperaminoacidemiacould constitute a feedback signal to increase insulin productionin face of the lower insulin sensitivity, given the known ab~lityof most amino acids to stimula~e pancreatic beta cell output(29). An alternative interpretation is that this elevated plasmaamino acid levels result from the accumulation of amino acidswithin the plasma compartment, secondary to a decrease in theirinsulin-mediated uptake into peripheral tissues. Thisinterpretation assumes that insulin resistance affects similarlyglucose and amino acid metabolism. Although in normal humansthe plasma insulin level for half-maximal glucose metabolic rateand half-maximal decrease in plasma amino acid levels is similar(26), it is not known if this is the case in insulin-resistantstates. Indeed, it has been shown that there is a dissociationbetween the responsiveness to insulin of glucose and ofpotassium and free fatty acids (30). Insight in the mechanism ofinsulin resistance obtained from the study of other diseases alsosuggest that the reponsiveness of glucose and amino acid uptaketo insulin may not necessarily be parallel (Table 1). For example,the insulin resistance of ure mia is associated with a decreasedmetabolic rate for glucose, but amino acid uptake is normal, tothe point that the high plas ma insulin response frequentlyproduce a markedly low plasma level of branched chain aminoacids (31, 32).

372 Caballero. Finer. and Wurtman

TABLE 1INSULIN ACTIONS IN OBESITY, UREMIA

AND TYPE I DIABETES

OBESITY UREMIA DIABETES

;.lI

GLUCOSEPlasma levelOral GTTDisposal rate

Nor malNormalDecreased

HighImpairedDecreased

HighAbnormalDecreased

INSULINPlasma levelSensiti vity

IncreasedDecreased

IncreasedDecreased

D ecreas edNormal/Decr.

AMINO ACIDS (BCAA)Plas ma level IncreasedUptake Decreased

.DecreasedIncreased

IncreasedDecreased

Likewise, aging is associated with a progressive decline inthe glucose metabolic response to insulin, while the amino acidresponse is preserved (33). In obesity, results from other studiesshow that the hyperaminoacidemia is not a constant feature ofinsulin resistance (34, 35). In contrast to Felig et !!,., studies byForlani et al. (34) and Iieraiet et al. (35) found normal fastingplasma ieVels of branched chainamino acids in obese, whichwere 'unrelated to plas ma insulin concentrations. A study thatco mpared the rate of disappearance fro m plas ma of an 1.v.valine dose in lean and obese adults, found that the metabolicclearance rate of the amino acid was the same in both groups,and that the obese actually had lower valine levels during thefirst 90 minutes of the study (36). Conversely, Forlani et al. (34)found a reduced fall in plasma branched chain amino acidln theobese during an euglycemic insulin clamp. These investigatorsused a nonpri med insulin infusion and assu med a steady-statecondition after only 30 minutes, factors that may haveco mplicated the interPretation of results.

If the degree of hyperinsullnemia of an obese person isinsufficient to support a normal amino acid metabolism, thisperson would be in a situation of relative insulin deficiency (asfar as amino acids are concerned), similar to that of an insulin-

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Plasma Amino Acid Lev4;1sin Obesity 373

depri ved type I diabetic. In this latter condition, there is anincrease in the plasma concentration of BCAA, as well as in therate of leucine flux and oxidation (37). Kinetic stu"dies in obesityusing stable isotopes alSo suggest that leucine flux may be abovecontrol levels. Vazquez et al. (38) studied a group of obese

persons using a primed, 3-h~r J,4C-leucine infusion, and reporteda mean leucine flux (Q) ot 8.7 "~moles/hour. A similar result(8.44 mmoles/hour) was tound by Clugston et !!: (39) in 10 obese

women infused with 14C-leucin~ for 24 hours. Using a constant10-hour infusion ot the same tracer, Garlicl( et aL (40) tound amean Q of 10.2 mmoles/hour (97.3 umoles/kg/hour) in five obeseadults. These values are higher than those tound by Fukagawa et

aL (20) in five lean adults using 13C-leucine and a similar -ldnetic model: 5.7 mmoles/hour (76.8 umoles/kg/hour). However,comparisons between different studies should be made withcaution, since differences in methods and/or theoretic.alassumptions in the kinetic parameters may produce diUerencesunrelated to the physiological state of the subj~cts. Ideally, data

. fro m obese subjects should be co mpared only with a carefullyma"tched group of lean subjects studied under the same.conditions. Furthermore, as 'with other values of substrateconcentrations in obese, results can vary dra matically dependingon whether they are expressed per kg of body weight, or leanbody mass or surface area, and most studies on amino acidkinetics do not assess body composition.

Effects ot body composition on plasma amino acids

The correlation between tat mass and insulin sensitivity hasbeen shown in several studies. Bjorntorp et ale (41) found a

I --sign1!1cant correlation between fasting insulin levels and fat celldiameter in obese persons, and the correlation of fasting insulinwith body fat and with percent excess of IB W has also beenreported by other investigators (42, 43). Measuring insulinsensitivity with the euglycemic clamp technique, Yki-Jarvinenand Koivisto (44) reported a signiricant negative correlationbetween percent body fat (estimated by skinfold thicknessmensurements) and insulin sensitivity. Bogardus et aL (45) alsoreported a nonlinear correlation between insulin sensitivity andfat mass measured by underwater weighing, with a cut-off pointat approximately 28% oC body Cat. Using the steady state plasmaglucose approach, Nagulesparan et a1. (46) found a significant., --

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374 Caballero, "'iner, and Wurtman

negative correlation between body mass index and insulinresponse.

. Leono Obese,

r ·0.83

80 90

FIG URE 1. Corr.elation between the sum of plasma Val, He,Leu, Tyr and Phe levels and lean body mass. From Holm etaL (47).

Plasma amino acid levels in obesity also appears to beaffected by body composition. Lean tissue is the main site ormetabolism of branched chain amino acids, and obesity is usuallyassociated with an increase in lean body mass that may compriseas much as 4096 of the excess weight (48). One study showed asignificant correlation betwee~ plasma amino acids and insulinlevels and ponderal index of obesity (49). In another study inobese subjects before and after a 6-week period or physicaltraining, a significant positive correlation was found between

lean body mass (measured by 40K) and the sum of branchedchain amino acids, tyrosine and phenylalanine, both before andafter the training (47) ,(Figure 1).

0.9I

" 0

0.8-1 I-::i:E- 0.7a..

I 0 ./ 0

..J

..: 0.6-1 - ........ .;::'0E O.:JVI

M0.330 40 50 60 70

Leon body moss, kg

Plasma Amino Acid ~vels in Obesity 375

Plasma amino acid levels and brain serotonin in obesity

High plasma levels of large neutral amino' acids (LNAA) -ofwhich the branched chain comprise a large fraction- may affect

the regulation of food 'intake and other behavioral andneuroendocrine processes invC!lvingthe neurotransmitter serotonin.

The synthesis of serotonin in-,the brain is dependent on the

availabilityof its precursor a'mino acid tryptophan, which entersthe brain at a rate determined by its plasma concentration

relativeto the other large neutralamino acids (LNAA: valine,

leucine, isoleucine,tyrosine, phenylalanine and methionine) (50).This plasma Trp/LNAA ratio, therefore, predicts the availabilityof tryptophan to the brain (51), which in turn determines its

serotonin output in animals, and presumably in humans (52, 53).

TABLE 2CARBOHYDRATE~NDUCED FALL1N PLASMA NEUTRAL

AMINO ACIDS IN OBESEMean % decrease from basal levels

The insulin resistance of obese persons diminish the insulin-

mediated fallin pla.'JmaLNAA and thereforeblocks'the normalrise in the Trp/LNAA ratio produced by carbohydrate ingestion.Thus, less tryptophan would be available to the brain, and lessserotonin win be released after a carbohydrate meal. Sinceserotonin agonists have ,been shown to selectively decreasecarbohydrate intake in obese "carbohydrate cravers" (54), and

tryptophan administration decreases appetite and energy intake innormal humans (55, 56), the "carbohydrate craving" described in

some obese persons (54) may be teleologicallyinterpreted as the

failure of the brain to produce enough serotonin to suppress

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Lean Obese

Val 46 18lIe 57 31Leu 53 25Phe 45 22Tyr 52 24Trp 50 24

376 Caballero, Finer. and Wurtman

carbohydrate intake. To assess the magnitude of this impairedTrp/LNAA "signal"to the brain in obese subjects, we compared

the plasma amino acid profile in lean and obese alter ingestion

of carbohydrate snacks at mid-afternoon. Seven" obese persons (%

of ideal body weight between 135 and 190) and six lean controls

received a standard breakfas~ at 7:30 AM, and a 400 kcal lunch(1596 protein, 55 % carbohydrate and 30 % fat) at noon. Two hours

laterthey received a 30g glucose drink. Plasma amino acids,glucose and insulin were measured at hourly intervals until 6

PM. The plasma glucose response in the obese was similar tocontrols, but the obese showed a significantlyhigher insulinreponse (peak level, mean + SD: 73 + 37 mUlL, vs. 13 + 4m U/L in controls). In spite-of this higher insulin output;- the fallin plasma neutral amino acids was markedly blunted (Table 2).

As a consequence of this blunted amino acid response, obese"subjects exibited only a 696 rise in their Trp/LNAA ratio inresponse .to carbohydrate ingestion, reaching a peak ratio of0.107 .::0.013, as compared to 0.150 in lean controls.

CONCL USIONS

Most obese persons show elevated plasma insulin levels, in"order to compensate for the very frequent insulin resistanceassociated with obesity. This hyperinsulinemia is usually .

sufficient to sustain a nor mal plas ma glucose concentration, but"this is not the case for pl!lSma amino acids, which are usuallyelevated, particularly the branched chain, tyrosine andphenylalanine. In contrast, plasma tryptophan tend to be belowcontrol levels. The net result is a decreased ratio of Trp to theother neutral amino acide; in plasma, and thus a lowera vai lability of Trp to the brain. Thus, the degree of insulinresistance of an obese person, besides its efCects on glucosemetabolis m, may also affe"ct serotonin-mediated brain functionsby limiting the supply of the precursor amino acid t.o the centralnervous system. These data suggest that treatments that improvethe amino a~d response to insulin of obese persons,or thatprovide tryptophan supple ments may be useful coadjuvants in tJ:1edietary treatment of obesity. .

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Plasma Amino Acid Levels In Obesity 377

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