the relationship between insulin, igf-i and weight gain in cystic fibrosis

Clinical Endocrinology (1999) 51, 659–665

659q 1999 Blackwell Science Ltd

The relationship between insulin, IGF-I and weightgain in cystic fibrosis

A. M. Taylor*, A. Thomson*, C. Bruce-Morgan*,M. L. Ahmed*, A. Watts*, D. Harris*, J. M. P. Holly†and D. B. Dunger**University Department of Paediatrics, John RadcliffeHospital, Oxford and †University Department ofMedicine, Bristol Royal Infirmary, Bristol, UK

Summary

OBJECTIVE In cystic fibrosis, reduced body mass isrelated to low levels of IGF-I and changes in the IGFbinding proteins. Our aim was to determine whetherthese abnormalities are linked to pancreatic endo-crine dysfunction.PATIENTS AND DESIGN We measured serum levelsof insulin, IGF-I, IGFBP-I, IGFBP-3 and IGF bioactivityin 77 fasting subjects (43 male) mean age 9·6 years(range 2·99–17·98 years). Data were analysed withrespect of body mass, puberty and stature and com-pared with control data established in the samelaboratory.RESULTS The mean height standard deviationscore (SDS (SD)) was ¹0·54 (0·97) and the bodymass index SDS ¹0·24 (1·09). Both body mass indexSDS (r ¼ ¹0·40, P ¼ 0·0003) and IGF-I SDS (r ¼¹ 0·32,P ¼ 0·009) declined with age. Insulin levels were alsolow and correlated with IGF-I and IGFBP-3 ( r ¼ 0·42,P ¼ 0·0004, and r ¼ 0·45, P ¼ 0·0002, respectively)whereas levels of IGFBP-I were inversely relatedto those of IGF-I and insulin ( r ¼ – 0·43, P ¼ 0·0004,r ¼ ¹ 0·52, P<0·0001). IGF bioactivity was reduced andinversely related to IGFBP-I ( r ¼ ¹ 0·31, P ¼ 0·009). Inmultiple regression analysis, body mass index SDSwas negatively related to age ( P<0·0001) and positivelyrelated to insulin and IGF-I ( P ¼ 0·04, P¼ 0·03, respect-ively). Height SDS was correlated with IGF bioactivity(P¼ 0·003) and negatively with IGFBP-I ( P ¼ 0·01).CONCLUSIONS We conclude that progressive insulindeficiency may result in reduced IGF-I levels andIGF-bioactivity and may determine weight gainand statural growth in cystic fibrosis.

Poor weight gain is often encountered in patients with cysticfibrosis (Schwachman & Kulczycki, 1958; Sprout & Huang,1965; Mitchell Heggset al., 1976) as it can arise as aconsequence of inadequate nutritional intake, malabsorption,and increased energy expenditure (Soutteret al., 1986; Coreyet al., 1988; Shepherdet al., 1988; Buchdahlet al., 1989).Although aggressive nutritional therapy has contributed toimprovements in pulmonary function, growth and survival,weight loss may still occur during intercurrent infection(Levy et al., 1985; Gaskinet al., 1990; Steinkampet al.,1990).

Two recent studies have identified a relationship betweenbody mass index (BMI) and declining IGF-I and IGFBP-3concentrations in patients with cystic fibrosis (Laursenet al.,1995; Tayloret al., 1997). In normal subjects, IGF-I levelsare not usually linked to BMI (Juulet al., 1994), but low IGF-Iconcentrations are observed in cases of severe malnutrition(Grantet al., 1973; Hintzet al., 1978). Generally, IGF-I levelsare closely related to those of growth hormone (GH), but inmalnutrition (Countset al., 1992) and in patients with cysticfibrosis (Culler & Meacham, 1993) this relationship is per-turbed. Since IGF-I could protect against the catabolic effectsof starvation (Douglaset al., 1991) the low levels in cysticfibrosis may be causally related to weight gain and clinicaloutcome (Tayloret al., 1997).

Though primarily regulated by GH, IGF-I production isalso closely related to nutrition (Hochberget al., 1992). Themechanisms whereby nutrition regulates IGF-I are complex,but an important component is insulin levels. The hepatic GHreceptor is partially regulated by insulin (Daughadayet al.,1976; Baxteret al., 1980; Maeset al., 1986; Massaet al., 1993;Clayton et al., 1994). Insulin may also regulate circulatingIGF bioactivity through levels of insulin-like growth factorbinding protein-1 (IGFBP-1) (Hollyet al., 1988; Tayloret al.,1990). The progressive insulin deficiency documented insubjects with cystic fibrosis during childhood (Abdul-Karimet al., 1986; Moranet al., 1991; Hollet al., 1995) could be thelink between abnormalities of IGF-I and its binding proteinsand the decline in body mass index. To investigate thishypothesis, we have examined the relationship betweeninsulin, IGF-I, its binding proteins IGFBP-1 and IGFBP-3and IGF bioactivity in a cross sectional study of childrenand adolescents with cystic fibrosis. We have related ourfindings to changes in body mass index, height, age and pubertyin these subjects.

Correspondence: Dr D. B. Dunger, Department of Paediatrics, JohnRadcliffe Hospital, Headington, Oxford, OX3 9DU, UK. Fax:þ44(0)1865 220479; E-mail: [email protected]

Subjects and methods

Subjects

77 children and adolescents attending the cystic fibrosis clinicwho were not hospitalized or suffering from other endocrinedisorders were studied at their 6 monthly or annual assessments.The mean age of the group was 9·6 years (range of 2·99–17·98 years) and there were 43 males and 34 females (Table 1).All had exocrine pancreatic insufficiency and were takingreplacement pancreatic enzyme therapy. Informed consent forthe study was obtained from the patients and their parents andthe study was approved by the Oxford district ethics committee.

Methods

After an overnight fast, a single blood sample was taken at09 : 00 h. Serum was separated and stored at¹208C until assay.Height and weight were recorded for each subject using aHarpenden Stadiometer and electronic scales, respectively(Cameron, 1984). The body mass index (BMI) was calculatedfrom the formula: weight (kg)/height2 (m2) and BMI standarddeviation scores (SDS) and Height SD scores were calculatedfrom the 1990 British national standards (Coleet al., 1995;Freemanet al., 1995). Pubertal stage was assessed accordingto the method of Tanner (1962) in a subset of 34 subjects withcystic fibrosis who were over 8 years of age (Table 1). Genitalstage (G1-G5) for boys and breast development (B1-B5) forgirls were used in all subsequent analysis.

In this cohort at the time of assessment, nutritional intakewas estimated by the median of a three day diary calorieintake which was 120% of the daily recommended value forage (range 66%–185%) and the median nutritional componentof the Schwachman Score was 22 (range 10–25).

Subcutaneous skinfold measurements were taken at 4 sites(biceps, triceps, subscapular and suprailiac) in 46 subjects using

standard techniques with a Holtain skinfold caliper (Cameron,1984). Body density was calculated using the equations ofBrook (1971) for prepubertal children up to 11 years and thenthose of Durnin & Rahaman (1967) for pubertal childrenbased on the four skinfold measurements. Body fat was thencalculated using the equation of Siri (1956) based on bodydensity.

Annual assessments also included liver ultrasound andmeasures of lung function.

Assays

Free insulin levels were determined by a double antibodyradioimmunoassay (Guildhay Antisera Ltd, Guildford UK)modified from Morgan & Lazarow (1963). The interassaycoefficients of variation were 5·3% and 10·6% at analytelevels of 15·7 mU/l and 61·4 mU/l. The intra-assay coefficientsof variation were 3·6% and 2·9% at analyte levels of 13·3 mU/land 46·4 mU/l, respectively. Age related normal data using thesame assay have been reported previously (Smithet al., 1989)and these were used to calculate age and sex related standarddeviation scores (SDS).

Serum IGF-I was measured by a specific radioimmunoassay,after acid-ethanol extraction of its binding proteins, using apolyclonal antiserum (R557A) raised against purified humanIGF-I (Taylor et al., 1988). The level of detection of this assayis 5mg/l and the interassay coefficients of variation were 9%,4·5% and 6·25% at analyte levels of 654, 231 and 78·4mg/l,respectively, with an intra-assay coefficient of variation of4% at an analyte level of 231mg/l. Age and sex related normaldata using this assay (Tayloret al., 1988; Smithet al., 1989)were used to derive SD scores.

Serum levels of IGFBP-1 were measured by a specific radio-immunoassay (Tayloret al., 1990). Purified human IGFBP-1for labelling and use as a standard was kindly supplied byDr S Drop (Rotterdam, The Netherlands). The minimumdetectable limit of the assay was 10mg/l. Intra-assay variation atan analyte level of 105mg/l was 4%, and the interassay variationwas 5·7% and 6·2% at analyte levels of 60 and 139mg/l,respectively.

Serum IGFBP-3 was measured by a specific radioimmuno-assay (Tayloret al., 1997). Purified recombinant glycosylatedIGFBP-3 and rabbit antihuman IGFBP-3 antibody were kindlysupplied by Drs A Sommers and C Maack (Celltrix Inc, CA,USA). Antigen was iodinated by the chloramine-T method andpurified on a sephadex G-25 column. Separation of boundand free antigens was achieved by the addition of donkeyanti-rabbit Sac-Cel (IDS, Northumberland, Tyne & Wear).There was no crossreactivity with IGFBP-1, IGF-I or IGF-II.The inter- and intra-assay coefficients of variation were 11·4and 4·2%, respectively, at an analyte level of 3·4 mg/l.

660 A. M. Taylor et al.

q 1999 Blackwell Science Ltd,Clinical Endocrinology, 51, 659–665

Table 1 Details of subjects with cystic fibrosis.

Male Female

n 43 34Age (Mean6 1SD) 9·3064·1 9·996 4·37

Range 2·99–17·98 3·8–17·98

BMI SDS (Mean6 SD) ¹0·236 1·12 ¹0·306 1·22Height SDS (Mean6 SD) ¹0·476 1·3 ¹0·416 1·04

Pubertal status<8 years of age 21 22>8 years Prepubertal 12 5(G1, B1)>8 years Pubertal 10 7(G2–G5, B2–B5)

Serum IGF bioactivity was determined by using a cartilagebioassay, previously described (Spencer & Taylor, 1978;Taylor et al., 1988). IGF bioactivity was measured by theuptake of35S sulphate into small uniform discs of preadolescentporcine costal cartilage. All samples were assayed against anormal adult reference serum pool, assigned a value of 1 unitof IGF bioactivity per ml of serum by definition, over a doserange of 6·25–25·0% of serum diluted in Ham’s F12 culturemedium (v/v). Dose response curves of the results were plottedand linear sections were selected by eye for statistical analysis.A regression analysis was performed and an index of precisioncalculated froms/b where s2 is the residual mean square ofvariation andb is the slope. Selected linear sections of the doseresponse curve were analysed with respect to linearity,regression, preparation differences, parallelism and heterosce-dasticity. Fieller’s theorem was used to calculate the potencyratio and fiducial limits about the potency at 95% confidencelimits (Finney, 1952). The statistical parameters for thecartilage bioassay are on average: index of precision (Fieller’sg, 0.06, and index of variation, lambda,l, 0.18).

Liver enzymes, aspartate aminotransferase and alkalinephosphatase were measured by standard methods.

Statistical analysis

Results are given as the mean (1SD) unless otherwise stated.Standard deviation scores (SDS) were calculated from age,puberty and sex matched control data using the formula;([observed value—population mean]/population SD). Correla-tion coefficients were performed in order to assess associationsbetween variables by simple regression analysis, with theprobability of significance derived from analysis of varianceand theF-test. P-values #0·05 were considered significant.Multiple stepwise regression analysis was used to clarify themost important determinants of the variance in BMI SD andheight SD scores.

Results

Body mass index and height

The overall mean body mass index for subjects with cysticfibrosis was 16·76 (2·15) kg/m2 (range; 13·17–24·99). Whenexpressed as a BMI standard deviation score, the mean overallvalue was,¹0·24 (1·09) with a range,¹2·88 toþ 2·15 and wassignificantly different from normal controls (P<0·001). Therewere no significant differences between the sexes but BMISD scores decreased significantly with age (r ¼ ¹ 0·40,P¼ 0·0003).

The mean height SDS,¹0·54 (0·97) (range¹3·50 toþ1·5)was also significantly different from normal controls (P<0·01),but there was no significant relationship with age.

IGF-I, IGFBP-1 and IGFBP-3 levels

IGF-I levels increased with age (r ¼ 0·47, P<0·001) andcorrelated positively with IGFBP-3 (r ¼ 0·47, P<0·0001).However when expressed as an IGF-I SD score, the overallmean value for the cystic fibrosis population was¹0·36 (1·43)(range ¹2·75 to þ4·56) and IGF-I SD scores decreasedwith age; the trend being particularly marked during puberty(r ¼ ¹ 0·32,P¼ 0·009).

Five (6·5%) children were found to have raised liverenzymes and ultrasound findings indicative of liver dysfunc-tion and their mean IGF-I SDS was lower (¹1·14 (0·27)) thanthe whole group. However as their exclusion had little impacton the overall mean IGF-I SDS (¹0·30 (1·48), compared to¹0·36 (1·43)) they were included in subsequent analyses.

The overall mean concentration of IGFBP-1 in subjectswith cystic fibrosis was 70·15 (49·7)mg/l and was inverselyrelated to IGF-I (r ¼¹ 0·43,P¼ 0·0004). Levels of IGFBP-1also declined with age (r ¼ ¹ 0·31,P¼ 0·01).

Insulin

Overall, mean fasting insulin levels were significantly reducedwhen compared to normal controls (6·9 (4·27) mu/lvs. 11·06(4·86) mu/l, respectively,P<0·0001). The lowest insulinlevels were observed in the youngest children with cysticfibrosis and levels were higher in the older children (Fig. 1).When expressed as an insulin SD score, the overall mean valuefor the cystic fibrosis population was¹ 1·37 (2·2) and whilstinsulin levels tended to increase with age, they remained lowduring mid-puberty, only increasing by stage 4/5 (Fig. 2).

Insulin levels were positively correlated with IGF-I andIGFBP-3 (r ¼ 0·42,P¼ 0·0004 (Fig. 3a);r ¼ 0·45,P¼ 0·0002

Cystic fibrosis, IGF-I and insulin deficiency 661


Fig. 1 Fasting insulin levels in subjects with cystic fibrosis (o)plotted on a log scale against age. The solid line represent the normalmean6 2SD (dotted lines) for the normal reference population.

Fig. 3(b) respectively, yet they were inversely related toIGFBP-1 (r ¼ ¹ 0·5,P<0·0001) (Fig. 3c).

IGF bioactivity

IGF bioactivity was reduced in subjects with cystic fibrosis andthe mean value was 0·47 (0·21) u/ml, which was significantlydifferent from normal controls, 0·93 (0·23) u/ml (P<0·0001).There was no increase in IGF bioactivity during puberty, unlikethat observed in normal controls. A significant negative corre-lation between IGF bioactivity and IGFBP-1 was observedin the cystic fibrosis population (r ¼ – 0·31,P¼ 0·009) (Fig. 4)but there were no significant correlations with other variables.

Relationships with BMI and height

Using multiple regression analysis with BMI SDS held as thedependent variable, there was a negative relationship with age(P<0·0001) and positive relationships with both insulin andIGF-I (P¼ 0·04,P¼ 0·03, respectively). When height SDS washeld as the dependent variable, the only significant associationswere with IGFBP-1 and IGF bioactivity (P¼ 0·01 andP¼ 0·003, respectively). Finally when fat mass (derived fromskinfolds, n¼ 46) was held as the dependent variable; asignificant positive association with insulin (P<0·001) anda negative association with age (P¼ 0·007) were noted.

Discussion

Early reports of IGF-I levels in cystic fibrosis producedconflicting results (Leeet al., 1980; Rosenfeldet al., 1981)



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mu

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n=24

Pubertal stage G/B (Tanner)

n=171

ns

n=14 n=6 n=18 n=11

**

*

2 & 3 4 & 5

Fig. 2 Insulin levels plotted against pubertal stage in patients withcystic fibrosis (A) and normal controls (B). Pubertal stages (2 & 3)and (4 & 5) were pooled due to the low numbers of subjects inpubertal stages G/B 2–5. *P¼ 0·03; **P<0·0001.

Fig. 3 Relationship in patients with cystic fibrosis between insulinand (a) IGF-I concentrations (r ¼ 0·42;P¼ 0·0004), (b) IGFBP-3concentrations (r ¼ 0·42;P¼ 0·0002) and (c) IGFBP-1 concentrations(r ¼¹ 0·5;P<0·0001).

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but two recent studies have demonstrated reduced IGF-I andIGFBP-3 levels (Laursenet al., 1995; Tayloret al., 1997). Inboth studies the age related decline in IGF-I levels was closelyrelated to reduced body mass index, however, as blood sampleswere not always taken in the fasting state no data regardinginsulin levels were presented.

In 77 of the subjects that we studied (Tayloret al., 1997),blood samples were taken fasting and concomitant insulin,IGF-I, IGFBP-1, IGFBP-3 and IGF bioactivity data are nowpresented. Predictably we observed reduced levels of IGF-I andIGFBP-3 and close correlation between serum levels of thesetwo peptides. Insulin levels were generally low in the subjectsyet their nutritional intake was reasonably good, and pubertynot delayed. Thus we could speculate that low levels reflectedprogressive beta-cell impairment (Arrigoet al., 1993) and lossof first phase insulin responses that have been consistentlydocumented in patients with cystic fibrosis (Hamdiet al., 1993;Austinet al., 1994; Rakotoambininaet al., 1994). Insulin levelswere positively related to those of IGF-I and IGFBP-3 whereasan inverse relationship was noted with IGFBP-1. Thus relativeinsulin deficiency during childhood and early puberty couldbe the major determinant of the abnormalities of IGF-I andits binding proteins in cystic fibrosis.

In addition to poor nutrition and evolving insulin deficiency,other factors could contribute to the abnormal IGF-I concentra-tions (Hanaire-Broutinet al., 1996). Reduced IGF-I levelshad been observed in cystic fibrosis during the developmentof liver impairment (De Schepperet al., 1992). In a recent studyLaursenet al. (1995) were not able to identify any relationshipbetween liver function and IGF-I SD scores. Five of ourchildren had raised liver enzymes and ultrasound findingsindicative of liver dysfunction and their mean IGF-I SDSwas lower than other subjects in the study. However, they only

constituted 6·5% of our population and their inclusion hadlittle impact on the overall IGF-I SD scores and the relation-ships between IGF-I and other hormones. The IGF-I axis couldalso be perturbed by recurrent infection (Cwyfan Hugheset al.,1992; Miell et al., 1992) as cytokines such as TNF can affectIGFBP production and therefore IGF-I actions at the cellularlevel (Yatemanet al., 1993). However our patients were notacutely unwell at the time of study.

Body mass index SDS (BMI SDS) declines with age incystic fibrosis (Laursenet al., 1995; Tayloret al., 1997) andin multiple regression analysis it was independently relatedto both insulin and IGF-I. In a subset of patients where skin-folds were available; calculated fat mass was significantlyrelated to insulin levels and inversely correlated with age. Weconclude that the progressive insulin loss is the majordeterminant of the reduced fat mass in cystic fibrosis. Theindependent relationship between IGF-I levels and BMI isunexplained, but it could relate to the putative role of IGF-Iin the prevention of catabolism during poor nutrition or insulindeficiency and thus maintenance of lean body mass (Douglaset al., 1991).

In contrast to the relationship between insulin and BMISDS, height SDS was related, in multiple regression analysis,to IGF bioactivity and IGFBP-1 levels. Serum IGFBP-1 levelswere inversely related to IGF bioactivity and it has beenshown that IGFBP-1 is an inhibitor of IGF bioactivity in thein vitro cartilage bioassay system that we used (Tayloret al.,1990). Interestingly height SDS did not decline with age in oursubjects, despite decreasing IGF-I levels. Similar preservationof height SDS despite low IGF-1 levels has been noted duringpuberty in subjects with type 1 diabetes (Zachrissonet al.,1997; Ahmedet al., 1998). It has been argued that this could beexplained by decreasing IGFBP-I levels with increasing age.

IGFBP-1 levels are inversely related to those of insulin,particularly during puberty and it has been postulated that thismay provide one mechanism whereby nutrition regulates thetempo of growth (Hollyet al., 1988). Although insulin levelswere generally lower in the younger subjects that we studied,insulin SDS improved with increasing age particularly duringthe latter stages of puberty. However, insulin levels stillremained significantly lower at puberty stages 3–5 comparedto normal controls. Insulin resistance and fasting hyper-insulinaemia are an established feature of normal puberty(Smith et al., 1989) resulting in reduced IGFBP1, increasedIGF bioactivity and conserved statural growth. In the subjectswith cystic fibrosis insulin levels increased during late puberty,perhaps reflecting the development of insulin resistance, butlevels were still lower than in controls. In these subjectsthe decreased IGF bioactivity was similar to that observedin subjects with insulin dependent diabetes (Tayloret al.,1990). Although height SDS did not change with age it was



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Fig. 4 Relationship between IGF bioactivity and IGFBP-1 inpatients with cystic fibrosis (r ¼¹ 0·31;P¼ 0·009).

significantly lower than normal and was closely related tolevels of IGF bioactivity and IGFBP1.

From these studies we conclude that there is a closerelationship between the decline of body mass index andinsulin levels in cystic fibrosis, but it is yet to be determinedwhether reduced IGF-1 levels are independently related tobody mass index. Reduced IGF bioactivity is directly asso-ciated with levels of IGFBP1 and although height SDS in ourpatients remained unchanged with age, it was closely relatedto levels of IGFBP1 and IGF bioactivity. These conclusionswere drawn from cross-sectional data and whilst providingevidence supporting the idea that pancreatic endocrine dys-function is linked to reduced body mass index related to lowlevels of IGF-1 and changes in the IGF binding proteins, alongitudinal study is required to confirm these findings.

Acknowledgements

This study has in part been presented at the ninth annual NorthAmerican cystic fibrosis conference in Dallas, Texas, inOctober 1995 (abstract published in Paediatric Pulmonology1995, suppl 12: 292 (abstract 293) and at the 16th Joint Meetingof the British Endocrine Societies in Harrogate, Yorkshire inApril 1997 (abstract published in the Journal of Endocrinology,March 1997; volume 152, supplement, P73).

We thank the cystic fibrosis trust UK for its financial supportof this study. The manuscript was typed by Joanna Hiken.

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the relationship between insulin, igf-i and weight gain in cystic fibrosis

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