does recombinant human insulin-like growth factor-1 have a role in the treatment of diabetes?

REVIEW

Does Recombinant Human Insulin-likeGrowth Factor-1 Have a Role in theTreatment of Diabetes?D.B Dunger, C.L. Acerini

Department of Paediatrics, University of Oxford, Oxford, UK

The structure of IGF-I is similar to that of insulin, having 43 % sequence homology withhuman proinsulin. Both peptides can induce metabolic and mitogenic effects through theirown specific receptors, which also share many structural and functional similarities.Primarily involved in the regulation of growth, IGF-I may have a role in the control ofglucose homeostasis, facilitated by changes in its binding proteins.

RhIGF-I can reduce hyperglycaemia in patients with severe insulin resistance by directeffects mediated via the IGF-I receptor. Improvements in insulin sensitivity, and reductionsin blood glucose levels and HbA1c values have also been seen in subjects with NIDDM.Enhanced insulin sensitivity with low dose rhIGF-I has been observed in adolescents andyoung adults with IDDM. These effects are closely related to reductions in growthhormone levels, but there is also evidence of complex interactions with insulin at thepost receptor level and with IGFBP-1. In recent randomised, double-blind, placebocontrolled trials, rhIGF-I given as an adjunct to insulin therapy reduced to HbA1c values.

Although the ideal dosage to obtain therapeutic efficacy without complications has yetto be determined, rhIGF-I may have an important role in the treatment of hyperglycaemiaand insulin resistance in diabetes. 1997 by John Wiley & Sons, Ltd.

Diabet. Med. 14: 723–731 (1997)

No of Figures: 4. No of Tables: 0. No of Refs: 81

Received 9 May 1997; accepted 12 May 1997

of insulin: IGF-1 having 43 % sequence homology withIntroductionhuman pro-insulin.9 The biological actions of IGF-1 aremediated through a specific cell surface receptor, theInsulin-like growth factor 1 (IGF-1) is a single chain

polypeptide comprising 67 amino acid residues, encoded type 1 IGF receptor, which is structurally and functionallyvery similar to the insulin receptor (Figure 1). Bothby a single gene on human chromosome 12. Following

the isolation of the first human cDNA in 19831 the receptor types are composed of two extracellular alphasubunits, that are primarily concerned with hormonerecombinant human peptide (rhIGF-1) became available

for in vitro and in vivo study. Naturally, early interestfocused on the growth promoting effects of IGF-1 and,once it was shown that the peptide could improve lineargrowth in hypophysectomized and growth hormone (GH)deficient rats,2,3 the first clinical trials were undertakenin patients with the GH insensitivity syndrome.4 However,there was also considerable interest in whether rhIGF-1could have a role in the treatment of patients withdiabetes mellitus.5,6

Structure and Function of IGF-1

The isolation of IGF-1 and IGF-2 arose in part out ofthe work of Froesch and his colleagues on non-suppressible insulin-like activity (NSILA) in humanplasma.7,8 When the peptides were fully characterizedin 1978, their structure proved to be very similar to that

Figure 1. Schematic representation of insulin-like growth factor(IGF) I and II, insulin, the IGF binding proteins 1 to 6, and* Correspondence to: Dr D.B. Dunger, Department of Paediatrics, John

Radcliffe Hospital, Oxford OX3 9DU, UK their cell membrane receptors

723CCC 0742–3071/97/090723–09$17.50 1997 by John Wiley & Sons, Ltd. DIABETIC MEDICINE, 1997; 14: 723–731

REVIEWbinding, and two beta subunits with trans-membrane important determinants of circulating GHBP and IGF-1

concentrations.25 Insulin also has an important roleand tyrosine kinase domains which are involved inintracellular signalling.10 IGF-1 can increase rates of in regulating IGF-bioactivity through the circulating

concentrations of the small molecular weight bindingglucose disposal in skeletal muscle independently ofinsulin.11 However, in contrast to insulin, IGF-1 does protein, IGFBP-1. This IGFBP is produced by the hepato-

cyte and its production is inversely regulated by insulin.26not increase the rate of glucose oxidation and has apreferential effect on the rate of lactate formation.12 Circulating IGFBP-1 concentrations undergo a circadian

variation with peak values being observed overnightThese effects of IGF-1 in skeletal muscle are mediatedthrough the IGF-1 receptor and there has been consider- when insulin levels are at their lowest.27 In most bioassay

systems, IGFBP-1 is an inhibitor of IGF-bioactivity.28able interest in how, under normal physiological con-ditions, insulin regulates intermediary metabolism, Insulin may also affect circulating levels of IGFBP-3

proteases and thus bioavailability of IGF-1.29 Thus insulinwhereas IGF-1 appears to be primarily involved in theregulation of growth and development.13 Initial signalling plays an important role in the regulation of IGF-1

production, bioactivity, and bioavailability. In insulinpathways appear to be common to both peptides andhybrid receptors have been detected in muscle,14 yet deficient states such as malnutrition and diabetes, reduced

IGF-1 bioactivity leads to GH hypersecretion which inreceptors with an IGF-1 intracellular domain are moreeffective at stimulating DNA synthesis.15 As well as turn enhances lipolysis and reduces insulin sensitivity.30

It has been argued that this pivotal role for insulin indifferences in receptor signalling, IGF-1 and insulin differin their site of production and by the presence and the regulation of the GH/IGF-1 axis balances competing

needs for survival and growth (Figure 2).function of the IGF-binding proteins (IGFBPs).

IGF-binding proteins and the Regulation The Role of IGF-1 in the Regulation ofMetabolismof IGF Bioactivity

Unlike insulin, IGF-1 is produced by a wide variety of Guler et al.31 were the first to show that rhIGF-1 couldhave an acute hypoglycaemic effect in healthy humantissues and there are no tissue stores. The liver contributes

the greatest amount to circulating concentrations and volunteers. However, in this respect, IGF-1 proved to be10 times less potent than equivalent doses of insulin.IGF-1 is produced at a relatively constant rate of

around 3–40 mg kg−1 day−1. It circulates at much greater Differential tissue effects of insulin and IGF-1 weresubsequently observed which could largely be explainedconcentrations than those of insulin, as it is bound to a

series of binding proteins of which a total of six (IGFBP1 by differences in receptor distribution. For example, IGF-1 appeared to have more effect on glucose uptake byto 6) have been described to date.16 The largest of these

binding proteins, IGFBP-3, combines with IGF-1 and an muscle than on hepatic glucose production, reflectingthe relative paucity of type 1 IGF receptors on the adultacid labile subunit (ALS) to form a ternary complex of

approximately 150 kDa to provide a circulating reservoir liver. In addition, IGF-1 effects on the adipocyte wereless marked than those of insulin, whereas IGF-1 appearedof IGF-1 which is retained in the circulation.17 Whereas

the half-life of unbound IGF-1 is around 10–12 min, the to be more effective than insulin in stimulating proteinsynthesis.32 Many of these differential effects may alsohalf-life of the ternary complex is approximately 15 h.18

The remainder of the circulating IGF-1 is bound in have resulted from differences in the relative suppressionof endogenous insulin, glucagon and GH production.33binary complexes with IGFBP-3 and the smaller binding

proteins. Detailed discussion of the roles of other IGFBPs The very high doses of rhIGF-1 used in many of thesestudies also led to high free IGF-1 levels and thusis beyond the scope of this article, but it would appear

that they have roles, in different tissues, facilitating the possible interactions with the insulin receptor. It istherefore difficult to extrapolate a physiological rolebioavailability and modulating the bioactivity of IGF-

1.19 Serum proteases have also been identified during for IGF-1 in the control of glucose metabolism fromthese studies.pregnancy and severe illness, and after surgery, which

may alter the affinity with which IGF-1 is bound into It had always been assumed that IGF-1 was unlikelyto have a physiological role in glucose homeostasisthese complexes and hence its bioavailability.20,21

The production of IGF-1, ALS, and indirectly IGFBP- because of the presence of the IGFBPs. However thisposition may need to be re-examined. Lewitt et al.343 is primarily regulated by growth hormone (GH).

However, there is also in vitro evidence that insulin observed that an infusion of IGFBP-1 in experimentalanimals led to a prompt rise of blood glucose whichenhances IGF-1 production by either direct regulation

of the hepatic GH receptor or a permissive effect on could be reversed with rhIGF-1. The implication is thatchanges in IGFBP-1 levels, which are closely related topost-receptor events.22,23 Some in vivo confirmation of

these observations in humans has come from studies of those of ‘free IGF-1’ in the circulation,35 could affectglucose homeostasis. It has also been argued that theGH binding protein (GHBP), which appears to be

identical to the extracellular domain of the GH receptor.24 high IGFBP-1 levels seen in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM)36 could,Both insulin and nutritional status have proved to be

724 D.B. DUNGER, C.L. ACERINI

Diabet. Med. 14: 723–731 (1997) 1997 by John Wiley & Sons, Ltd.

REVIEW

Figure 2. The relationship between insulin and the growth hormone/insulin-like growth factor-1 (IGF-1) axis. ! indicates stimulation;@ indicates inhibition. GHBP—growth hormone binding protein; IGFBP—insulin-like growth factor binding protein

by mopping up ‘free IGF-1’, contribute to the dawn patients where the genetic defect has not been charac-terized.43 The therapeutic value of rhIGF-1 may varyphenomenon.37 Hussain et al.38 were also able to

demonstrate that rhIGF-1 administration leads to depending on whether defects identified in post-receptorinsulin signalling are common to the type 1 IGF receptor.enhanced insulin sensitivity in humans and thus IGF-1

deficiency could theoretically result in insulin resistance. Leprechaunism or Donahue’s syndrome occurs in patientswho are either homozygous for a single mutation, orA role for IGF-1 in normal glucose homeostasis is yet to

be determined, but these observations serve to underpin compound heterozygotes for two distinct mutant allelesof the insulin receptor gene.43 In some of these casesthe subsequent exploration of the use of rhIGF-1 in

patients with diabetes. functional abnormalities of the type 1 IGF receptor havealso been identified44 and investigators have failed toshow any glucose lowering effects of rhIGF-1.45 Rabson-RhIGF-1 and Severe Insulin ResistanceMendenhall’s syndrome is defined by the presenceof several clinical features, including extreme insulinThe potential effectiveness of rhIGF-1 in severe insulin

resistance was first demonstrated by Schoenle et al.39 resistance, acanthosis nigricans, and pineal hyperplasia.43

From a clinical point of view, this syndrome appears toThey observed reductions in serum glucose and plasmainsulin in three patients with type A insulin resistance be intermediate in severity between Leprechaunism and

type A insulin resistance. Again, mutations in both allelessyndrome (see below) after an acute intravenous bolusof rhIGF-1. Subsequently, Morrow et al.40 reported that of the insulin receptor gene have been identified. Quinn

et al.,46 in their study of a child with Rabson-Mendenhall’ssubcutaneous administration of rhIGF-1 in a dose of100 mg kg−1 b.d. for 1 month in two subjects with the syndrome were able to show an acute glucose lowering

effect of rhIGF-1, but sustained clinical benefit wastype A syndrome led to improved glycaemic control,reduced fasting and postprandial serum insulin levels not achieved.

There may be little merit in grouping all patients withand improved insulin sensitivity. Moses et al.41 extendedthese observations to a total of six subjects with various severe insulin resistance together, with respect to their

response to rhIGF-1. As a group they differ, not only informs of severe insulin resistance and Kuzuya et al.42

demonstrated similar findings in seven patients followed their underlying genetic abnormality, but also in theseverity of disease expression as it affects glucose, lipid,up for 1 year while receiving rhIGF-1.

Type A insulin resistance, as defined by the triad of and fat metabolism. Detailed phenotypic characterizationand treatment by standard protocol would inform us asinsulin resistance, acanthosis nigricans, and hyperandrog-

enism (in the absence of obesity or lipoatrophy) probably to which patients are likely to respond to treatment, andprovide insights into mechanisms of action of IGF-1 inrepresents a wide range of disparate genetic conditions.

Although many patients with type A insulin resistance these cases. A joint call for an international registry ofthese patients has recently been made by Professor A.have been reported to have molecular defects in one or

other alleles of the insulin receptor, there are many Moses at Yale, and Professor S. O’Rahilly at Cambridge.

725RECOMBINANT HUMAN IGF-1 AND TREATMENT OF DIABETES

1997 by John Wiley & Sons, Ltd. Diabet. Med. 14: 723–731 (1997)

REVIEWal.50 used a slightly lower dose of rhIGF-1 (100 mgRhIGF-1 and NIDDMkg−1day−1 b.d.) than the earlier studies, significant side-effects were still encountered. These were similar toIn patients with non-insulin dependent (Type 2) diabetes

mellitus (NIDDM), who have failed therapy with diet or those reported by Jabri et al.49 and resulted in threepatients withdrawing from treatment. All of the side-hypoglycaemic agents, insulin is often used as an

alternative therapy. However, insulin may not necessarily effects resolved within 7–31 days of discontinuation ofthe study drug. Subsequent studies reported by thecorrect the underlying insulin resistance and it was

proposed that rhIGF-1 could circumvent insulin resistance RhIGF-1 NIDDM Study Group51 indicate that these side-effects are dose related. In a large prospective study,in these, generally obese, patients by reducing hypergly-

caemia through effects at the IGF-1 receptor.6 The initial 212 subjects with NIDDM were randomized to receiveeither placebo or rhIGF-1 in doses of 10, 20, 40, andstudies of rhIGF-1 in NIDDM were carried out by Zenobi

et al.47 who investigated 8 subjects, during a 5-day 80 mg kg−1; b.d. for 12 weeks. Significant side-effectswere only observed in those subjects taking the largestsubcutaneous infusion of rhIGF-1 (120 mg kg−1 day−1).

They observed reductions in fasting and postprandial dose of rhIGF-1: 80 mg kg−1, b.d.51 The same study groupobserved significant reductions in HbAlc in the subjectsglucose levels together with improvements in lipid

metabolism. Longer-term studies were carried out by given the dose of 40 mg kg, b.d.52 They concluded thatrhIGF-1, at a dose of 40 mg kg−1day−1, b.d. as a soleSchalch et al.48 again using a large subcutaneous dose

of IGF-1 (up to 240 mg kg−1 day−1, b.d.) and these therapy in NIDDM was both efficacious and well-tolerated for 12 weeks.confirmed that rhIGF-1 improved glycaemic control, but

treatment was poorly tolerated. Prolonged administration The mechanism whereby rhIGF-1 in these low dosescould reduce hyperglycaemia and improve insulin sensi-of rhIGF-1 was associated with severe complications

including jaw tenderness, arthralgia, myalgia, hypoten- tivity are unclear. Given the fact that the overall glucoselowering potential of rhIGF-1 is only one-tenth of thatsion, and peripheral oedema.49

Moses et al.50 completed an open label study of rhIGF- of insulin, a dose of 40 mg kg−1, b.d. would representinsulin replacement of the order of around 0.1 unit1 of 6 weeks duration in 12 subjects with NIDDM. All

of the subjects had poor glycaemic control at entry into kg−1day−1. RhIGF-1 therapy could result in decreasedcirculating glucagon and GH levels32 and these couldthe study, and 9 of the 12 completed at least 4 weeks

of rhIGF-1 therapy. In these patients there was a dramatic directly, or indirectly via decreases in levels of free fattyacid, result in improvements in insulin sensitivity. Theimprovement in glycaemic control with reductions in

HbAlc and fructosamine. Fasting insulin levels were dramatic improvements in insulin sensitivity observedby Moses et al.50 might also indicate that NIDDM isreduced but, perhaps most significantly, the authors

observed a substantial increase in the insulin sensitivity characterized by ‘IGF-I insufficiency’. IGF-1 levels declinewith advancing age, and the majority of patients withindex (Si) as measured during a frequently sampled

intravenous glucose tolerance test (after the method of NIDDM are in their later decades when IGF-1 levels aresubstantially lower than in early adulthood.53 WhetherBergman; Figure 3). Although in their study Moses etrhIGF-1 is effective as a ‘replacement therapy’, or as apharmacological agent, remains to be determined inNIDDM. Nevertheless, there is considerable evidence tosupport the proposal that ‘IGF-1 replacement’ may beof therapeutic benefit in patients with IDDM.

RhIGF-1 therapy in IDDM

The proposal that physiological replacement of IGF-1might be of benefit to patients with IDDM resulted fromthe observation that IGF-1 and IGFBP-3 concentrationsare invariably low or in the low-normal range in thesesubjects.54,36 These abnormalities are thought to arise asa result of partial GH insensitivity at the level of thehepatic GH receptor. Growth hormone binding protein(GHBP) levels are low in newly diagnosed patients withFigure 3. Effect of rhIGF-1 on insulin sensitivity in subjectsIDDM.55 Whereas levels tend to rise after the introductionwith Type 2 diabetes mellitus. Insulin sensitivity (Si) was

measured according to the method of Bergman in subjects of insulin therapy, they remain lower than those observedwith NIDDM during a control period and following at least 4 in normal controls.56–58 Concentrations of IGF-1 andweeks of rhIGF-1 (solid bars). These data are compared to Si GHBP in patients with IDDM are closely related to thevalues previously reported by Bergman for different populations

total insulin dose, particularly during puberty.58 Theranging from significantly insulin resistant (lowSi) to normalsubcutaneous administration of insulin dictates that(stippled bars). RhIGF-1 increased Si more than threefold.

(Reproduced with permission by Freund Publishing House Ltd) considerable increases in the insulin dose are required



REVIEWto achieve adequate portal levels of insulin for the double-blind, placebo-controlled studies have been com-

pleted. Quattrin et al,74 have reported similar reductionsnormal production of IGF-1 and the suppression ofIGFBP-1.59 Overall, IGF-bioactivity is also reduced in in insulin requirements and HbAlc in 43 adolescents

with IDDM treated with a single injection of rhIGF-1IDDM,54 reflecting the high circulating concentrationsof the inhibitory insulin dependent IGFBP-1.28 80 mg kg−1day−1 for 28 days in addition to conventional

insulin therapy. More recently Acerini et al.75 have carriedIt could be argued that the reduced circulating IGF-1levels and the reduced IGF-bioactivity in IDDM could out a double-blind placebo-controlled trial examining the

effects of rhIGF-1 in a large cohort of subjects over aresult in direct effects on insulin sensitivity, but they alsoprovide the feedback drive for GH hypersecretion.60 period of 6 months. In this study 53 subjects with IDDM

were randomized to receive either rhIGF-1 at doses ofRaised GH levels in IDDM are closely related to theincreased insulin resistance observed during puberty.61 20 or 40 mg kg−1day−1 or placebo as an adjunct to

multiple injection therapy for 6 months. Forty-fourThe insulin antagonistic effects of GH are well charac-terized62 and increased GH secretion results in the subjects completed the study and significant reductions

in HbAlc were seen with the larger dose after 3 monthschanges in insulin requirements overnight characteristicof the dawn phenomenon63,64 as well as enhanced keto- (median (range) DHbAlc-0.5 % (−2.8 to + 0.5) vs placebo

+0.3 % (−1.0 to + 1.5 %) (Figure 4). These improvementsgenesis.65

The significance of these derangements in the GH/IGF- were achieved without any need to increase the dailyinsulin dose, or at the expense of increased body mass1 axis are of particular importance to the treatment of

adolescents with IDDM.66 Even the highly motivated index, which is often the case during the course ofintensified insulin therapy. Compliance with the 5adolescents participating in the DCCT study had relatively

higher HbAlc levels and a higher prevalence of nocturnal injection a day regimen was however clearly a problemfor some during the later stages of the study, and thehypoglycaemia than adults in that study.67 Thus it was

in this age group that the effects of rhIGF-1 were first improvements seen at 3 months were only sustaineduntil the end in those subjects who maintained elevatedinvestigated. In these subjects, it was argued that

restoration of normal IGF-1 levels might lead to improve- IGF-1 levels throughout the study. Nevertheless, thereductions in HbAlc values were not insignificant givenments in insulin sensitivity, by reducing GH hypersecre-

tion, or by direct effects on glucose homeostasis. that these subjects were already well controlled at thestart of the study (mean (sem) HbAlc7.91 % (±0.4)) andCheetham et al.68 administered rhIGF-1 in a single

subcutaneous dose of 40 mg kg−1 to 9 adolescents with that they were on multiple insulin injection therapy.Ongoing studies in subjects with IDDM have beenIDDM and compared the effects with placebo. Sustained

increases in IGF-1 concentrations were observed which designed with fewer insulin injections and the optimaldose of 40 mg kg−1 b.d. identified in the NIDDM subjectsresulted in consistent reductions in GH secretion. These

reductions in GH hypersecretion were accompanied by has been utilized.improvements in insulin sensitivity. Bach et al.69 observedsimilar changes with a subcutaneous infusion of rhIGF-1 (20 mg kg−1 h−1) in a group of adolescents and youngadults with IDDM. Cheetham et al.70 have recentlyextended their studies to show a direct relationshipbetween reductions in GH levels and improved insulinsensitivity in subjects with IDDM following IGF-1 replace-ment. Nevertheless, the same group have also observedapparent direct effects of rhIGF-1 on insulin sensitivityby repeating their controlled studies in subjects given asomatostatin infusion to suppress all endogenous GHsecretion and replacing GH pulses with the exogenoushormone.71 They also observed interactions with IGFBP-1,72 and it is possible that the effects of rhIGF-1 oninsulin sensitivity in IDDM are mediated, not onlythrough suppression of GH, but also by direct effectsmediated by the IGFBPs.

Prolonged administration of rhIGF-1 was explored ina study where it was given in a daily subcutaneous dose

Figure 4. RhIGF-1 therapy in IDDM study. Mean (±SEM) HbAlcof 40 mg kg−1, in addition to standard multiple injection(%) values during treatment: Wk −4 to 0 multiple insulininsulin therapy, to 6 young adults with IDDM over ainjection therapy only; Wk 0 to 12 multiple insulin injectionperiod of 28 days.73 Sustained effects on GH secretion,therapy plus either placebo (❍, n = 14), or rhIGF-1 at 20 mg

insulin requirements, together with improvement in HbAlc kg−1day−1 (❑, n = 14) or 40 mg kg−1day−1 (▲, n = 17) given aswere observed. This preliminary study was unblinded a single daily subcutaneous injection; p = ,0.05 (ANOVA—

repeated measures)however, and subsequently similar but randomized,



REVIEWComplications of rhIGF-1 Therapy Conclusions

Our understanding of the physiological regulation andThe side-effects observed in the initial studies of rhIGF- biological actions of IGF-1 has moved rapidly over the1 therapy in NIDDM subjects were clearly dose-related last 20 years. First described as a component of NSILAand have not been replicated in more recent studies of in human serum7 IGF-1 may yet have an important role,NIDDM or IDDM using lower doses. Nevertheless, the not only in the regulation of growth, but also in thetherapeutic benefit of rhIGF-1 in diabetes must be control of glucose metabolism. This role may be clarifiedbalanced against any possible adverse effects on diabetic by studies of rhIGF-1 therapy in patients with severemicro-angiopathic complications. Generally, these com- insulin resistance where the phenotype and genotypeplications tend to appear around the time of puberty have been carefully characterized. The mechanismsagainst a background of reduced circulating IGF-1 whereby rhIGF-1 replacement might improve insulinlevels.76 In their analysis of several large studies examining sensitivity in IDDM and NIDDM have not been fullythe relationship between circulating IGF-1 concentrations elucidated. Although indirect effects mediated by changesand the development of complications, Dills et al.77 in glucagon, GH, NEFA, are important, preliminary datawere not able to identify a definite association except also suggest that there may be direct effects of IGF-1,in a subgroup with late onset diabetes.78 In an early mediated by changes in its binding proteins.study, Merimee et al.79 reported an association between Over the next few years we will see the results ofincreased IGF-1 levels and the development of proliferat- further studies of rhIGF-1, given either alone, or as anive retinopathy. Thus it is possible that elevated IGF-1 adjunct to other forms of therapy in subjects withlevels may occur once vascular changes are well NIDDM. The potential of rhIGF-1 therapy in IDDM willadvanced and increased capillary permeability may also be explored using simplified regimens where it ispermit leakage of IGF-1 from the tissues. Although there given as an adjunct to standard insulin therapy in anare no clear data linking circulating IGF-1 levels with attempt to reduce insulin requirements and improvethe risk of complications, there are data suggesting that glycaemic control. All of these studies will have toparacrine production of IGF-1 may have a role in the balance the potential benefits of treatment against anypathogenesis of complications.80 change in the risk for the development of microangi-

GH hypersecretion, on the other hand, has been opathic complications.consistently linked to the pathogenesis of diabetic micro-angiopathic complications.81 In IDDM, the GH insensi-tivity which leads to low circulating IGF-1 levels is Acknowledgementslargely confined to the hepatic GH receptor, and GHhypersecretion continues to exert profound effects on We would like to thank S. O’Rahilly for reading the

manuscript and for his comments, and J. Hilken forinsulin sensitivity. Thus in some tissues, GH hypersecre-tion may lead to enhanced paracrine production of IGF- typing the manuscript.1 without affecting circulating levels of the peptide.Reductions in GH hypersecretion and improvements inHbAlc brought about by rhIGF-1 therapy in diabetes, Referencesshould, on balance, reduce rather than enhance the risk

1. Jansen M, Van Schaik FMA, Recker AT, Bullock B, Woodsof micro-angiopathic complications, but this hypothesisDE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van denneeds to be tested by rigorous long-term placebo-Brande JL. Sequence of cDNA encoding human insulin-like

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human insulin-like growth factor-1 stimulates growth andcarried out by Acerini et al.75 there was no deteriorationhas distinct effects on organ size in hypophysectomisedof standard retinal photographs, GFR, urinary proteinrats. Proc Nat Acad Sci 1988; 85: 4889–4893.excretion or other early markers of diabetic complications. 3. Skottner A, Clark RG, Robinson ICAT, Fryklund L.

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does recombinant human insulin-like growth factor-1 have a role in the treatment of diabetes?

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