Metabolic Response to Human Growth

Hormone during Prolonged Starvation

PHiLp FELIG, ERROLB. MARLIss, and GEORGEF. CAHILL, JR.

From the Department of Medicine, Harvard Medical School, and the PeterBent Brigham Hospital, and the Joslin Diabetes Foundation, Inc., Boston,Massachusetts 02215, and the Department of Internal Medicine, YaleUniversity School of Medicine, NewHaven, Connecticut 06510

A B S T R A C T The metabolic response to human growthhormone (HGH) was studied in five obese subjects inthe fed state and during prolonged (5-6 wk) starvation.In the fed state (three subjects), HGHinduced an ele-vation in basal serum insulin concentration, a minimalincrease in blood and urine ketone levels, and a markedreduction in urinary nitrogen and potassium excretionresulting in positive nitrogen and potassium balance.

In prolonged fasting (four subjects), HGHadminis-tration resulted in a 2- to 3-fold increase in serum in-sulin which preceded a 50% elevation in blood glucose.Persistence of the lipolytic effects of HGHwas indicatedby a rise in free fatty acids and glycerol. The responsediffered markedly from the fed state in that blood P-hy-droxybutyrate and acetoacetate levels rose by 20-40%,resulting in total blood ketone acid concentrations of10-12 mmoles/liter, ketonuria of 150-320 mmoles/day,and increased urinary potassium loss. The subjects com-plained of nausea, vomiting, weakness, and myalgias.Despite a 50% reduction in urea excretion during HGHadministration, total nitrogen loss remained unchangedas urinary ammonia excretion rose by 50% and corre-lated directly with the degree of ketonuria.

It is concluded that in prolonged starvation (a) HGHmay have a direct insulinotropic effect on the beta cellindependent of alterations in blood glucose concentration,(b) persistence of the lipolytic action of HGHresults in

This work was presented in part at the Fifty-first An-nual Meeting of the Endocrine Society, New York, June1969.

Dr. Felig was formerly a U. S. Public Health ServiceSpecial Postdoctoral Fellow (5-F3-AM-36-069) and is nowa Teaching and Research Scholar of the American Collegeof Physicians in the Department of Internal Medicine,Yale University School of Medicine, New Haven, Conn.06510. Dr. Marliss was a Fellow of the Medical ResearchCouncil of Canada.

Received for publication 14 August 1970 and in revisedform 5 October 1970.

severe exaggeration of starvation ketosis and interfereswith its anticatabolic action by necessitating increasedurinary ammonia loss, and (c) failure of HGHto reducenet protein catabolism in starvation suggests that thishormone does not have a prime regulatory role in con-serving body protein stores during prolonged fasting.

INTRODUCTIONIn recent years growth hormone has been implicated inthe regulation of body fat mobilization (1) and in bloodglucose homeostasis (2). With regard to protein metabo-lism, it has been postulated that growth hormone is notonly responsible for the anabolism characteristic of younggrowing individuals, but also plays a role in fully grownsubjects in conserving body protein stores during periodsof starvation or restricted food intake (3).

Recent studies from our laboratory have demonstratedthat obese subjects undergoing prolonged therapeuticstarvation do, indeed, conserve body protein as indicatedby a reduction in urinary nitrogen excretion from levelsof 10-15 g/day in the 1st wk of fasting to levels of 3-5g/day after 5 wk of starvation (4). Furthermore, asdemonstrated by indirect calorimetry, these subjectsutilize no carbohydrate stores but derive almost all theircaloric requirements from dissolution of body fat (5).While this constellation of enhanced fat utilization, di-minished carbohydrate consumption, and minimal proteincatabolism is consistent with the known effects of ex-ogenous growth hormone in the fed state (6), no sig-nificant elevation in serum growth hormone is demon-strable in the starved obese subjects (4). Similarly innonobese individuals, after a transient increase in serumlevels, growth hormone concentration returns to base lineas fasting is extended beyond 5 days (7). The questionthus arises as to whether prolonged fasting influences thetissue sensitivity to the protein-sparing effects of so-

The Journal of Clinical Investigation Volume 50 1971 411

TABLE IClinical Data

Sequence of HGHWeight studies

FigureSubject symbol Age Sex Height Initial Final Fed Fasted

yr cm kgG. M. o 50 M 183 145 119 1*M. S. A 23 M 191 214 183 2 1J. C. A 50 F 171 125 102 1 2F. G. * 36 F 155 81 65 1*M. L. 26 F 168 107 it

* Did not receive HGHin fed state.t Not studied in fasted state.

matotropin. In addition, if growth hormone has a regu-latory rather than permissive role in restricting proteincatabolism in starvation, then with an excess of growthhormone it should be possible to reduce further the rateof urinary nitrogen loss. To answer these questions andto evaluate further its role in starvation, we have exam-ined the metabolic response to human growth hormoneduring prolonged fasting. In addition, since very limiteddata are available on the effects of growth hormone innonfasted obese individuals (8), the subjects were alsostudied in the fed state.

METHODSFive obese subjects were admitted to the Clinical ResearchCenter of the Peter Bent Brigham Hospital for study(Table I). Each had volunteered to undergo prolonged

fasting after failure of various dietary regimens. Theywere informed of the nature, purpose, and possible risksinvolved in starvation and growth hormone administration.The screening tests employed to exclude cardiopulmonary,renal, hepatic, or endocrine abnormalities have been reportedpreviously (4).

The subjects were studied both in the fed state (threesubjects) and during prolonged starvation (four subjects).Two subjects were studied in both the fed and fasted statein the sequence demonstrated in Table I. In the fed state,two of the subjects (J.C. and M.L.) received a 2000 kcal,450 g carbohydrate, low residue, synthetic liquid diet (Vi-vonex-100; Vivonex Corp., Mountain View, Calif.) for10-14 days before, during, and for 5 days after administra-tion of growth hormone. Use of this diet eliminated the needfor stool collections and analyses in performing balancestudies, since these patients passed no stools (save forsmall amounts of mucoid material) after the 1st wk onthe liquid diet. The third subject (M.S.) received a 1200kcal conventional diet. During starvation, daily intake was

TABLE I IBlood and Urine Ketone Acid Levels during HGHAdministration in Fed Subjects

HGHtreatment

Experimental period Subject Pre-HGH* Day 3 Day 5 Post-HGH*

Blood j-hydroxybutyrate, M. S. 0.10 0.50 0.38 0.10mmoles/liter J. C. 0.08 0.10 0.13 0.06

M. L. 0.02 0.09 0.24 0.09

Blood acetoacetate, M. S. 0.07 0.44 0.23 0.10mmoles/liter J. C. 0.04 0.08 0.08 0.04

M. L. 0.06 0.08 0.06 0.04

Urine j3-hydroxybutyrate, M. S. 0.17 0.98 0.88 0.14mmoles/24 hr J. C. 0.06 0.41 0.35 0.09

M. L. 0.10 0.53 0.11 0.11

Urine acetoacetate, M. S. 0.13 0.29 0.34 0.10mmoles/24 hr J. C. 0.03 0.10 0.04 0.04

M. L. 0.08 0.17 0.04

* Values for urine fl-hydroxybutyrate and acetoacetate in the pre- and post-HGH periodsrepresent the mean of two to five consecutive daily observations immediately preceding andafter HGHtreatment.

412 P. Felig, E. B. Marliss, and G. F. Cahill, Jr.

restricted to 1500 ml of water, 17 mEq of NaCi (sugar-free tablets), one multivitamin tablet (Theragran; E. R.Squibb & Sons, New York), and intermittently, 17 mEqof KCl (gelatin capsules).

Human g-rowth hormone (H1GH ), prep)aredl (9.) andI)rovicled in generous quantities by Dr. M. S. Raben, wasadministered intramuscularly in a dose of 5 mig every 12 hr.In the studies performed in the fed state, the growth hor-mone was injected for 5 days after a 10-14 day controlperiod. During starvation, growth hormone administrationxvas initiated on the morning of the 35th day of the fastand was continued for 3 days. The fast was extended for4-5 days after injection of the last dose of growth hormone.

Blood samples were obtained betw\een 8:00 and 8:30 a.m.from an antecubital vein after the subjects had been restingin the recumbent position for at least 30 min. In the studiesperformed while the subjects were receiving the 2000 or1200 kcal diet (fed state), specimens were drawn daily for3 days before growth h-ormonie administration, on each day

of injection, and for 3 days thereafter. For collection of allof these specimens the subjects were in the postabsorptivestate (overnight fast). During starvation, samples wereobtainied on the da+ fasting w\ as initiated, after 3, 5, and1(0 dalys of fasting, and daily for 3-6 clays before HGIItreatment (fore-control, days 30-35 of fast ), during HGHtreatment (clays 36-38), and for 5-6 days after completionof grow\th hormone therapy (postcontrol, days 39-43 ofthe fast). In both the fed and fasted states, the morningdose of growth hormone w\-as administered immediatelyafter blood was drawn. Thus the blood specimens obtainedon day 35 of the fast were drawn immediately before in-stitUtion of therapy, while the samples for days 36, 37, and38 represent those obtained 12 hr after the previous or finalclose of grow\-th hormone.

Urine was collected in refrigerated plastic containers for24-hr periods beginning at 7 :30 a.m. The urine specimensfor days 35, 36, and 37 of the fast represent those obtainedduring grow-tlh hormone adm-ninistration.

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FIGURE 1 Influence of human growth hormone (HGH) on nitrogen and potassium balanceand blood glucose and serum immunoreactive insulin levels in fed obese subjects. IRI = im-munoreactive insulin, BG= blood olucose. Unidentified is that component of total nitrogen inurine not accounted for as urea, ammonia, creatinine, and uric acid. In the nitrogen andpotassium balance diagrams, intake is plotted downward from the dashed zero line, and excre-

tion is charted up from this intake line. Positive balance is indicated by a clear area belowthe zero line. Nitrogen and potassium excretion in the subjects on the synthetic diet representsloss in urine only since no stools were passed. In the subject on the 1200 kcal conventional diet,net potassium balance wias not determined because fecal potassium was not measured. For thissubject total urine potassium excretion is shown.

Growth Hormone in Prolonged Starvation 413

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TABLE II IInfluence of HGHAdministration on Circulating Hormone and Substrate Concentrations during Prolonged Fasting*

Precontrolt HGHtreatment PostcontrolExperimental period.Days fasted. 30-35 36 37 38 39 40 41 42

Serum growth hormone, 0.8 4.7 6.5 4.9 1.1 0.8 0.7 0.9m~ug/ml ±0.2 ±0.8 ±2.1 ±1.8 ±0.4 ±0.6 ±0.1 ±0.3

Serum insulin, ;.sU/ml 22.3 53.3 45.8 60.3 50.8 41.3 53.0 46.0±3.6 ±21.6 i3.3 ±7.6 ±6.4 ±6.7 ±7.5 ±7.9

Blood glucose, mg/100 ml 64 ±1 62 ±2 67 ±3 81 ±5 91 ±8 80 ±6 82 ±8 79 ±6Plasma free fatty acids, 1.29 1.83 1.94 2.10 1.63 1.65 1.63 1.70

mmole/liter ±0.06 ±0.08 ±0.23 ±0.15 ±0.09 ±0.17 ±0.11 ±t0.70Blood glycerol, mmole/liter 0.145 0.258 0.240 0.263 0.182 0.168 0.225 0.182

±0.012 ±0.060 ±0.045 ±0.070 ±0.022 ±0.041 ±0.023 i0.043Blood j-hydroxybutyrate, 5.75 7.95 7.98 7.38 4.75 4.31 4.34 4.28

mmole/liter ±0.48 ±0.65 ±-0.83 ±0.90 ±0.52 ±0.28 ±0.57 i0.72Blood acetoacetate, 1.76 2.00 2.13 2.06 1.69 1.52 1.54 1.49

mmole/liter ±0.12 ±0.19 ±0.22 ±0.23 ±0.23 ±0.15 ±0.22 ±0.24* Data presented as mean ASEM.

Precontrol values represent the mean of three to six observations on each subject during the week preceding HGHadmin-istration.

The methods employed for measurement of blood glucose,serum insulin and growth hormone, plasma free fatty acids,total serum CO2, blood glycerol, blood and urinary acetoace-tate and 8-hydroxybutyrate, and total nitrogen, urea nitro-gen, ammonia nitrogen, and potassium in urine have beendescribed (4, 10). The paired t test and calculation of thecoefficient of correlation were employed in the statisticalanalyses (11).

RESULTSFed state. The response to growth hormone in the fed

state is shown in Fig. 1 and Table II. In all subjectspositive nitrogen balance amounting to 2-5 g/day andpositive potassium balance were observed (Fig. 1). Note-worthy is the fact that the decrease in nitrogen loss was

due to a reduction in urea excretion with urine ammoniaremaining unchanged.

In agreement with previous studies in nonobese indi-viduals (12), HGHadministration resulted in an eleva-tion in postabsorptive serum insulin levels in each of theobese subjects. On the other hand, blood glucose levelsfailed to show a consistent increment. The small butmeasurable increases observed in blood and urine ketoneacids (Table II) are consistent with previous reportsin nonfasted subjects (13).

Starvation. The mean concentrations of circulatinghormones and substrates before, during, and after growthhormone administration in prolonged starvation areshown in Table III. Before HGHtreatment each of the

TABLE IVInfluence of HGHAdministration on Urinary Excretion of Ketone Acids, Potassium, and Nitrogen

during Prolonged Starvation*

24 hr urinary excretion

Precontrolt HGHtreatment PostcontrolExperimental period...Days fasted 30-34 35 36 37 38 39 40 41

6-Hydroxybutyrate, mmoks 90 45 155 413 234 ±40 238 ±31 130 410 35 ±12 22 ±i9 18 ±7Acetoacetate, mmoles 12 43 14 ±4 18 ±5 16 A4 10 ±2 6 42 7 ±2 6 ±2Potassium, mEq 16 ±2 19 ±2 37 ±9 52 ±11 27 ±4 16 ±6 15 ±4 14 ±4Total nitrogen, g 4.3 40.5 4.3 40.4 4.4 ±0.3 4.9 ±0.4 4.4 ±0.5 3.5 ±0.6 4.1 ±0.8 4.1 40.8Urea nitrogen, g 1.4 ±0.3 1.5 ±0.2 1.0 ±0.3 0.9 ±0.2 0.6 ±0.1 0.6 ±0.1 1.1 ±0.3 1.5 40.5Ammonia nitrogen, g 1.9 ±0.1 2.0 ±0.2 2.5 A0.2 3.0 A0.3 2.5 ±0.1 1.6 ±0.4 1.8 ±0.4 1.3 ±0.3

* Data presented as mean ±SEM.t Precontrol values represent the mean of five consecutive observations on each subject on the 5 days preceding initiation of HGHtreatment.

414 P. Felig, E. B. Marliss, and G. F. Cahill, Jr.

subjects demonstrated the characteristic metabolic re-sponse to prolonged fasting (4), manifested by lowlevels of growth hormone and a reduction in serum in-sulin and blood glucose (Fig. 2). After initiation oftreatment, circulating HGH levels were 5- to 10-foldabove base line 12 hr after hormone injection. Presum-ably much higher levels would have been observed hadsamples been obtained at shorter intervals after hor-mone injection (14). A significant elevation in seruminsulin (P <0.025) was observed within 24-48 hr ofinitiation of HGH injection and persisted for 4 daysafter cessation of treatment. While blood glucose levelsalso rose to levels significantly above base line (P <0.025), this elevation clearly lagged behind the insulinresponse, becoming apparent only after 72 hr of treat-ment.

Plasma free fatty acids exhibited a progressive riseduring growth hormone administration which reached

its peak after 72 hr of treatment (day 38, P <0.01).That this increase in fatty acid concentration was due toaugmented lipolysis in adipose tissue is supported bythe parallel rise in blood glycerol. Coincident with theincrease in fat mobilization, growth hormone treatmentresulted in a marked augmentation in starvation ketosis.Blood P-hydroxybutyrate levels, which had stabilized be-fore HGH, rose by 40-50% during hormone treatment(P < 0.02), while in three of four subjects, acetoacetatelevels rose by 20-30% (P < 0.05) (Fig. 3). As expected,this increase in organic acids (ketone acids and freefatty acids) was accompanied by a corresponding de-crease in serum [HCO3]- and blood pH (Fig. 4). In-terestingly, after cessation of HGH injection, bloodP-hydroxybutyrate fell significantly below base line (pre-control) levels (P < 0.01).

The components measured in urine are shown inTable IV. P-Hydroxybutyrate excretion increased 2- to

HGH

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FIGURE 2 Individual values for serum growth hormone, serum insulin, andblood glucose before, during, and after human growth hormone (HGH)administration in prolonged starvation. Blood samples were taken at the endof the 12 hr period between injections of HGH.

Growth Hormone in Prolonged Starvation 415

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416 P. Felig, E. B. Marliss, and G. F. Cahill, Jr.

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The contrast with the fed state is also evident from thedata on urinary excretion of total nitrogen. Unlike thefed state in which HGHinduced a marked diminution intotal nitrogen loss in urine (Fig. 1), no significant de-crease in total nitrogen excretion was demonstrable dur-ing HGHtreatment in starvation (Fig. 6). The diminu-tion observed in two patients after cessation of HGHinjection (day 39) was not statistically significant (P >0.2). That exogenous growth hormone was neverthelessnot devoid of effects on protein metabolism during star-vation is apparent from the response of urinary urea andammonia, the primary nitrogenous components of urine.As shown in Fig. 7, before HGHadministration urea

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and ammonia excretion had plateaued at 1.3-1.5 and1.6-2.2 g/day, respectively. Injection of growth hor-mone resulted in a 50% decrease in urea excretion whichwas maximal 24-48 hr after cessation of hormone ad-ministration. In contrast, urine ammonia excretion roseby 50% to a maximal level of 3 g/day and correlated di-rectly with urine 8-hydroxybutyrate excretion (r = 0.728,P < 0.01, Fig. 8). These simultaneous yet oppositely di-rected effects on urea and ammonia excretion thusserved to obliterate any net effect on total nitrogen loss.

Although none of the subjects complained of any un-toward symptoms when receiving growth hormone inthe fed state, all developed nausea, mild vomiting, weak-ness, and myalgias after 24-48 hr of HGHadministra-tion in starvation. The symptoms cleared without specifictherapy within 24 hr of cessation of hormone injection.

30 31 32 33 34 35 36 37 38 39 40 41DAYS OF STARVATI0 N

FIGURE 5 Influence of human growth hormone (HGH) on urinary excre-tion of 8-hydroxybutyrate, acetoacetate, and potassium during starvation.

Growth Hormone in Prolonged Starvation 417

DISCUSSION

Although the metabolic response to exogenous growthhormone has been well characterized in fed subjects (8,15, 16), the present study provides information on theinfluence of prolonged fasting on this response. As inthe fed state, the effects of growth hormone in starva-tion may be considered in terms of alterations in carbo-hydrate and insulin metabolism, fatty acid mobilization,and net protein balance.

Persistence of the insulinotropic effect of growth hor-mone in prolonged fasted man is evident from themarked increment observed in serum insulin levels.Comparable findings have recently been reported infasted dogs (17). Since blood glucose levels did not fallin association with the hyperinsulinemia, a concomitantincrease in peripheral insulin resistance may be in-ferred. With respect to the mechanism whereby somato-tropin elevates insulin levels, the clear lag in the in-crease in blood glucose concentration militates againsthyperglycemia acting as the mediator of the hyperin-sulinemia. Since neither ketones nor free fatty acids

FORE-CONI

61 J.C.5yr

TROL

have been demonstrated to have a consistent insulino-genic effect in man (18) and since, if anything, growthhormone lowers plasma amino acid levels (19), thepossibility of a direct insulinotropic action on the pan-creatic beta cell must be considered. Such an actionwould be consistent with the in vitro stimulating effectsof growth hormone on isolated islets (20).

The elevations demonstrated in free fatty acid andglycerol concentrations indicate that the lipolytic or adi-pokinetic effects of growth hormone are well preservedin starvation. The consequences of this increase in fatmobilization are, however, far different in the fastedthan in the fed state. Whereas only minimal elevationsin blood and urine ketone levels were observed in thefed state, ketonemia amounting to 10-12 mmoles/literwas demonstrated in the fasted subjects. Such elevationsin blood ketone acids are comparable with those ob-served in patients with moderate diabetic ketoacidosis(21). Furthermore, it is likely that the symptoms re-ported by the fasted subjects resulted from the severeketoacidosis and potassium loss induced by somatotropin.

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DAYS OF STARVATIONFIGURE 6 Individual values for total urinary nitrogen excretion in foursubjects treated with human growth hormone (HGH) during prolongedfasting. The dashed horizontal lines represent the mean values in eachsubject for each experimental period.

418 P. Felig, E. B. Marliss, and G. F. Cahill, Jr.

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FIGURE 7 Influence of human growth hormone (HGH) on urinary excretion of ammoniaand urea nitrogen during prolonged starvation. The height of the bars represents the meanvalue for four subjects. I values represent significance of difference from fore-control values(paired t test).

In subjects fasted for prolonged periods, loss of nitro-gen by nonurinarv routes is quantitatively insignificant(22). Urinarv nitrogen excretion in this circumstanceserves as a reliable index of net protein catabolism.The failure to demonstrate a reduction in urinary nitro-gen excretion with growth hormone treatment in starva-tion thus is particularly noteworthy since it is indicativeof the lack of an anticatabolic effect. Obesity per secannot be implicated as interfering wdith the protein-conserving effects of somatotropin since a reduction inurinary nitrogen excretion an(l positive nitrogen balancewere observed in the fed state. A more reasonable ex-planation is provided by the data on the individual com-ponents of urinary nitrogen. The significant reductionin urinary urea suggests that sonmatotropin does havean effect in reducing protein catabolic processes, pri-marily at the liver. As suggested on the basis of data inthe fed state (23). the instilinotropic action of HGHmay be of some importance in mediating this response.A net effect on total protein balance is obliterated, how-ever, by- the concomitant increase in urinary anmnmoniaexcretion. The direct correlation between urinary levelsof 3-lh-droxybutyrate and ammonia (Fig. 8) suggeststhat the heightened ketonemia and ketonuria induced b-gro wth hormone are responsible for the increased lossof nitrogen in urine as ammonia. Thus in starvation, theadipokinetic effect of HGH interferes with its anti-

catabolic action, resulting in no net conservation of bodyprotein stores (Fig. 9). In this respect, the currentfindings support the concept that the dual effects of

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Growth Hormotne in Prolonged Starvation 419

H G HPROFE/N A NSSPARING /ADPO_IES_ S

f IRI t FFA

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TOTAL NITROGENLOSSUNCHANGED

FIGURE 9 Postulated interaction of adipokinetic and proteinsparing effects of human growth hormone (HGH) in pro-longed starvation. The dashed arrow indicates that the in-sulinotropic action of HGHmay be of some importance inmediating the reduction in urea nitrogen excretion. IRI,immunoreactive insulin; FFA, free fatty acids.

growth hormone on fat and protein metabolism are mu-tually antagonistic (24) rather than synergistic (6).

The notion that somatotropin is of physiologic im-portance in reducing protein catabolism in situations ofcaloric deprivation is derived primarily from short-termstudies in hypophysectomized rats (3). The failure toobserve a diminuation in urinary nitrogen loss with anexcess of HGH in the present study, suggests thatgrowth hormone is not the prime regulatory factor re-sponsible for conservation of body protein stores' in manduring prolonged fasting. Supporting this conclusion arethe low levels of circulating HGHand the demonstra-tion that dwarfs with an isolated deficiency of growthhormone have no greater nitrogen loss during starva-tion than normal controls.'

The longstanding interest in growth hormone as adiabetogenic factor (25) raises the question as towhether the observations described in the current studyare manifestations of a transient HGH-induced diabeticstate (idiohyphophyseal diabetes). The latter, however,has been produced in man only' in the case of hypophy-sectomized subjects and is characterized by hypergly-cemia and a reduction in urine nitrogen excretion (26),neither of which was observed in the present study.Furthermore, it has long been recognized that fastingreduces rather than enhances the diabetogenic effectsof growth hormone (25).

Finally, the figures and tables show significant differ-ences in insulin and glucose levels persisting 1 or moredays after cessation of growth hormone administration.Urea nitrogen depression also continues, and thereappears to be a reversal in the severity of the base line

1Merimee, T. J., P. Felig, E. B. Marliss, S. E. Fineberg,and G. F. Cahill, Jr. 1971. Glucose and lipid homeostasis inthe absence of human growth hormone. J. Clin. Invest. Inpress.

ketoacidosis as evidenced by decreased serum and uri-nary levels of P-hydroxybutyrate and acetoacetate. Atpresent only speculation can be given to the meaningof these observations but a physiological basis may bepresent in view of the sporadic nature of growth hor-mone release and its induction of "secondary" factorswhich in turn exert metabolic effects or its initiationof altered enzyme levels with longtime constants.

ACKNOWLEDGMENTSWe wish to express our appreciation to Dzidra Rumba,Adacie Allen, Velta Ramolins, and Anna Karras for theirexpert technical assistance and to the nurses and staff ofthe Clinical Center at the Peter Bent Brigham Hospital.

This work was supported in part by U. S. Public HealthService Grants AM-05077, AM-09584, AM-09748, AM-13,-526, and FR-31, and the John A. Hartford Foundation, Inc.,New York.

REFERENCES

1. Raben, M. S., and C. H. Hollenberg. 1959. Effect ofgrowth hormone on plasma fatty acids. J. Clin. Invest.38: 484.

2. Roth, J., S. M. Glick, R. S. Yalow, and S. A. Berson.1963. Hypoglycemia: a potent stimulus to secretion ofgrowth hormone. Science (Washington). 140: 987.

3. Russell, J. A. 1957. Effects of growth hormone on pro-tein and carbohydrate metabolism. Amer. J. Clin. Nutr.5: 404.

4. Owen, 0. E., P. Felig, A. P. Morgan, J. Wahren, andG. F. Cahill, Jr. 1969. Liver and kidney metabolism dur-ing prolonged starvation. J. Clin. Invest. 48: 574.

5. Owen, 0. E., A. P. Morgan, H. G. Kemp, J. M. Sullivan,M. G. Herrera, and G. F. Cahill, Jr. 1967. Brain metabo-lism during fasting. J. Clin. Invest. 46: 1589.

6. Raben, M. S. 1965. Growth hormone: anabolic and anti-catabolic agent. Diabetes. 14: 374.

7. Lawrence, A. M. 1969. Medical treatment of acromegalywith progestins. Clin. Res. 17: 289.

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