DIABETES TECHNOLOGY & THERAPEUTICSVolume 2, Number 1, 2000Mary Ann Liebert, Inc.

Insulin-Like Growth Factor-I in Diabetes Mellitus: Its Physiology, Metabolic Effects, and

Potential Clinical Utility

KATHRYN M. THRAILKILL, M.D.

ABSTRACT

Type 1 diabetes mellitus (DM) is a disease of insulin deficiency, resulting from the autoim-mune-mediated destruction of pancreatic beta cells. However, as a likely consequence of in-traportal insulin deficiency, patients with type 1 DM also exhibit abnormalities of the growthhormone (GH)/IGF/IGF-binding protein (IGFBP) axis, including GH hypersecretion, reducedcirculating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels ofIGFBP-1. These abnormalities not only exacerbate hyperglycemia in patients with type 1 DM,but may contribute to the pathogenesis of diabetes-specific complications, including diabeticneuropathy, nephropathy, and retinopathy. Therefore, therapeutic modalities aimed at restor-ing the GH-IGF-IGFBP axis are being considered. Herein, we review the efficacy of one suchtherapy, specifically IGF-I replacement therapy. To date, short-term beneficial metabolic ef-fects of recombinant human IGF (rhIGF)-I therapy have been demonstrated in numerous di-abetic conditions, including type 1 DM, type 2 DM, and type A insulin resistance. However,the long- term safety and metabolic efficacy of rhIGF-I therapy remains to be established.Moreover, the potential impact of rhIGF-I on the natural history of diabetic complicationshas yet to be explored.

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INTRODUCTION

OVER THE PAST 10–15 YEARS, our under-standing of the hormonal abnormalities

characteristic of type I diabetes mellitus (DM)has evolved from the concept of a single hor-mone deficiency to one of multiple hormoneabnormalities. Specifically , we have come tounderstand that type 1 DM is characterized notonly by a primary deficiency of insulin, but alsoby an equally important secondary disruptionof the growth hormone-insulin-like growth fac-tor-insulin-like growth factor binding protein(GH-IGF-IGFBP) axis. This article first reviewsour current understanding of the status of the

GH-IGF-IGFBP axis in type 1 DM. Second, wediscuss the potential role of the somatotropinaxis in the pathogenesis of diabetes-relatedcomplications. Finally, this review updates thereader on the existing clinical experience in theuse of IGF in the treatment of type 1 DM, aswell as in type 2 DM and various syndromesof insulin resistance.

DYSREGULATION OF THE GH-IGF-IGFBP AXIS IN DIABETES

Several lines of evidence suggest that re-gional deficiency of insulin in the portal circu-

Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky.

lation, a condition that persists in all conven-tionally treated patients with type 1 diabetes,produces dysregulation of the GH-IGF-IGFBPaxis. Downregulation of hepatic GH receptorexpression secondary to portal insulin defi-ciency has been proposed as an explanation forthis phenomenon. Growth hormone bindingprotein (GHBP) corresponds to the extracellu-lar domain of the liver GH receptor, and hasbeen accepted as a putative index of GH re-ceptor number.1 In Type 1 DM, circulating lev-els of GHBP are decreased,2,3 while circulatinglevels of GH are increased, suggesting that type1 DM is characterized by a state of hepatic GHresistance. As a consequence of GH resistance,circulating levels of IGF-I are low,4–6 as are lev-els of IGFBP-3 in several studies.7,8 Consistentwith these findings in type 1 DM, Mercado etal,9 demonstrated that as a group, patients withtype 2 DM have normal GHBP levels, althoughinsulin-requiring type 2 diabetics have lowerGHBP levels than those patients not requiringinsulin therapy. These results again suggestthat the magnitude of GH-IGF-IGFBP axis ab-normalities in diabetes correlates with the de-gree of endogenous beta cell secretion.

Results from numerous studies suggest thatinsulin deficiency in the portal circulation alsocontributes to elevated serum IGFBP-1 concen-trations. Hepatic IGFBP-1 gene expression is in-creased in rat models of IDDM,10 and in vitrostudies demonstrate that hepatocyte synthesisof IGFBP-1 is profoundly suppressed by in-sulin.11 In type 1 DM, circulating IGFBP-1 lev-els are increased,12 whereas in type 2 DM,IGFBP-1 levels are inversely correlated withresidual endogenous insulin secretion.13 Fi-nally, portal hyperinsulinemia, as occurs in pa-tients with insulinomas, is associated with sub-normal IGFBP-1 levels that correct after tumorexcision.14

Studies examining the effects of differingmodes of diabetes treatment on the GH-IGF-IGFBP axis further emphasize the negative con-sequences of portal insulinopenia. For exam-ple, peripheral insulin administration15,16 andintensification of insulin therapy5 improvemany of the diabetes-induced derangements ofthe GH-IGF-IGFBP axis. However, numerousstudies demonstrate that peripheral insulinalone fails to normalize the abnormalities of the

GH-IGF-IGFBP axis,17,18 and further intensifi-cation of insulin replacement is precluded byhypoglycemic complications. Intraperitonealinsulin delivery is somewhat more effective inrestoring the somatotropin axis.8 However, asshown by Shishko et al.,19 only infusion of in-sulin directly into the portal system results innormalization of the GH-IGF-IGFBP axis.

In summary, patients with type 1 DM expe-rience a primary deficiency of insulin, and asecondary disruption of the GH-IGF-IGFBPsystem, likely resulting from deficiency of in-sulin in the portal circulation. Some patientswith type 2 DM and diminished endogenousinsulin secretion demonstrate similar abnor-malities. As is reviewed in the following para-graphs, these GH-IGF-IGFBP axis abnormali-ties may not only disrupt glucose homeostasisin their own right, but may also contributemechanistically to many of the organ-specificcomplications associated with diabetes.

METABOLIC CONSEQUENCES OF GH-IGF-IGFBP AXIS DYSREGULATION

Several preclinical studies imply that themetabolic derangements characteristic of typeI DM are due not only to insulin deficiency, butalso to the concomitant disruption of the GH-IGF-IGFBP system. Studies by Rajkumar et al.20

using an IGFBP-1 transgenic mouse model,demonstrate that inhibition of IGF action byconstitutive overexpression of IGFBP-1 resultsin fasting hyperglycemia and growth retarda-tion. Moreover, long-term IGFBP-1 infusion21

increases blood glucose levels in rats, and abol-ishes IGF- I–induced hypoglycemia in these an-imals. These studies emphasize the importantcontribution of IGF-I in maintaining eugly-cemia, a contribution that is lost in states of de-creased IGF-I bioavailability caused by ex-cesses of IGFBP-1. Several groups have shownthat administration of IGF-I to rats with dia-betes22,23 and depancreatized dogs24 lowerstheir blood glucose levels, demonstrating a rolefor IGF-I in the maintenance of euglycemia. Fi-nally, studies in humans using the euglycemic,hyperinsulinemic clamp technique have shownthat subcutaneous IGF-I administration tohealthy volunteers leads to increased insulin

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sensitivity,25 inferring that IGF-I deficiency intype 1 DM may further diminish the metaboliceffectiveness of insulin in this disease.

GH-IGF-IGFBP AXIS DYSREGULATIONAS IT RELATES TO DIABETES

COMPLICATIONS

Tissues-specific abnormalities of IGF-I bio-availability caused by specific alterations in thelocal production of IGFs and IGFBPs have alsobeen linked to the pathogenesis of diabetes-re-lated complications, as reviewed below.

Neuropathy

IGFs are neurotrophic growth factors thathave demonstrated effects on sensory, motor,and sympathetic neurons. Specifically , IGFshave been shown to stimulate motor neuronproliferation and differentiation, enhance mo-tor neuron sprouting, increase myelination andinhibit demyelination, reduce neuron apopto-sis during normal development, enhance ax-onal regeneration after injury and protect neu-rons from toxicity induced by chemicals,cytokines, and cancer chemotherapy.26 Asnoted above, type I DM is characterized bothby a reduction in total IGF-I concentration, aswell as increased sequestration of IGFs byhigher concentrations of IGFBP-1, resulting ina further decrease in bioavailable (or free) IGFs.Because hyperglycemia alone cannot accountfor the natural history of diabetic neuropathy,a role for IGFs in the pathophysiology of dia-betic neuropathy has been explored.

Several nerve-specific abnormalities in theGH-IGF axis have been demonstrated in ani-mal models of diabetes. Wuarin et al.27 demon-strated a reduction in IGF-I and IGF-II mRNAcontent in peripheral nerves of streptozotocin(STZ)-induced diabetic rats; moreover, theseabnormalities were partially reversible by in-sulin treatment. In subsequent studies they alsodemonstrated a decrease in IGF-II mRNA (thepredominant IGF in adult brain) in central ner-vous system (CNS) tissues of both STZ-diabeticrats (a model of insulin-deficient DM), andspontaneously obese Zucker rats (a model of type 2 DM).28 Among poorly controlled

STZ-induced diabetic rats, Busiguiana et al.29

demonstrated lower levels of IGF-I protein,IGFBP-2 protein, and IGFBP-2 mRNA in cere-bellar tissues.29 And, recently Bitar et al.30

found a decrease in mRNA transcripts for bothIGF-I and the IGF-I receptor in the spinal cordof STZ-diabetic rats, which, again, could bepartially restored following insulin replace-ment therapy.30

Consistent with these animal studies, pa-tients with type 2 diabetes with peripheral neu-ropathy have lower serum levels of IGF-I andred cell IGF-I receptors when compared withnonneuropathic patients with diabetes andcontrols without diabetes.31 In addition, ad-vancing age, acute weight loss, and shortstature among children are all risk factors forthe development of diabetic neuropathy andare conditions that independently cause a fur-ther reduction in circulating levels of IGF-I.32

On the basis of these findings, several animalstudies have examined the therapeutic utilityof IGFs in diabetic neuropathy. Studies byZhuang et al.33 demonstrated that IGF-I treat-ment halted the progression of hyperalgesiaand partially reversed the impaired sensorynerve regeneration characteristic of STZ-dia-betic rats. Similarly, Ishii et al.34 found that,both locally and systemically administeredIGF-I ameliorated the impairment of sensorynerve regeneration after a sciatic nerve crushinjury in STZ-diabetic rats. Subcutaneous infu-sion of IGF-II has been shown to improve hy-peralgesia present in Zucker rats with dia-betes.35 Furthermore, in an in vitro rat cervicalganglion model of diabetic neuropathy, IGF-Iprevented apoptosis of ganglion neurons andameliorated the pathologic neurite changes in-duced by a high-glucose milieu.36 Together,these studies suggest that dysregulation of theGH-IGF axis, and in particular, low systemicand neuronal levels of IGF-I contribute to thedevelopment of diabetic neuropathy.

Nephropathy

The kidney is a source of significant synthe-sis of IGF-I, some of which is released into thecirculation. In addition, the kidney is a targetof IGF action. In vitro, IGF-I has been shown tobe mitogenic for renal cells, promote nephron

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hypertrophy, and stimulate tubular phosphatetransport.37 Furthermore, states of GH excess(i.e., acromegaly) as well as systemic adminis-tration of IGF-I cause increases in renal bloodflow and glomerular filtration rate whereasthese same parameters are reduced in states ofGH deficiency.37 Clearly, the GH-IGF axis is animportant constituent of normal renal function.Consequently, a role for the GH-IGF axis in thepathophysiology of various renal diseases hasbeen hypothesized.

Streptozotocin-induced diabetes in the ratcauses early renal hypertrophy with eventualincrease in urinary albumin excretion (UAE)rates. Several investigators have demonstratedthat these changes are preceded by a robust in-crease in IGFBP-1 mRNA expression, primar-ily in renal cortex, leading to intrarenal accu-mulation of IGF-I protein, despite generallyreduced IGF-I mRNA expression.38,39 Thesechanges appear to be partially reversible withinsulin therapy.38 In contrast, when dwarf ratsdeficient in GH and IGF- I are made diabeticwith STZ, they experience a lesser degree of re-nal/glomerular hypertrophy and a smaller in-crease in UAE,40 again suggesting that theseDM-induced changes are dependent on contri-butions of the GH-IGF axis. Segev et al.41 havedemonstrated similar findings in the NODmouse model of autoimmune diabetes. And,among a large cohort of children and adoles-cents with type 1 DM, Cummings et al.42 foundthat subjects with microalbuminuria hadhigher 24-hour urinary IGF-I and GH concen-trations and higher urinary IGF-I levels wereassociated with increased kidney volume.Taken together, these studies suggest that dia-betes-induced changes in IGF-I bioavailabilityand redistribution of free IGF-I into suscepti-ble tissues may underlie the development of di-abetic kidney disease.

Retinopathy

A role for the GH-IGF-I axis in the develop-ment and progression of diabetic retinopathyhas been inferred for decades, ever since hy-pophysectomy was first introduced as a treat-ment for diabetic retinopathy.43 Furthermore,it is clear that while rapid improvements inglycemic control can promote clinical regres-

sion of proteinuria and symptomatic neuropa-thy, such changes can also be accompanied bya significant worsening of retinal disease. Be-cause improvements in glycemic control are ac-companied by increases in serum IGF-I con-centrations, and because IGF-I has been shownto act as an angiogenic agent in animal corneaand retina,44 a deleterious link between IGF-Iand diabetic retinopathy has been proposed. Infact, Chantelau et al.45 recently reported thatamong a group of four patients, marked re-duction in glycosylated hemoglobin (HbA1c)over a 5-month period was associated bothwith a 70%–220% increase in serum IGF-I lev-els and a significant progression of retinopa-thy. However, as the following paragraphsdemonstrate, the precise role of the GH-IGF- Iaxis in diabetic retinopathy remains controver-sial.

Recent studies by Janssen et al.46 demon-strated that while circulating concentrations oftotal and free IGF-I are low in patients withtype 1 DM (n 5 54) compared with age and sex-matched controls, age-adjusted free IGF-I lev-els were significantly higher among those dia-betics with retinopathy, than in diabeticswithout retinopathy. Boulton et al.47 measuredgrowth factor levels in vitrectomy samplesfrom patients with diabetes with prolifera-tive diabetic retinopathy (PDR) (both insulin-treated and noninsulin treated) and control pa-tients without diabetes, and found that IGF-Ilevels in vitreous were also significantly greaterin diabetics than in controls. In addition, in-jecting the vitreous cavity of animals withrhIGF-I produces a retinal microangiopathywith certain features resembling diabeticretinopathy.48 Studies such as these suggestthat the development of diabetic retinopathymay result from associated changes in intraoc-ular IGF bioavailability.

However, numerous other studies appear tochallenge the concept that IGF-I may play acausal role in diabetic retinopathy. Lowe et al.49

found that in STZ-induced diabetic rats, levelsof IGF-I mRNA in retinal tissues were, in fact, decreased.49 Pfeiffer et al.50 and Meyer-Schwickerath et al.51 studied the vitreous frompatients with PDR, as well as from patientswith nonproliferative eye disease and pati-ents with ischemia-induced neovascularization

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from a variety of other causes. Their studiesdemonstrated that growth factor changeswithin the vitreous were not specific for dia-betes. Rather, greater elevations in IGFs andIGFBPs were seen in nondiabetic retinal isch-emia,50 suggesting that abnormalities of in-travitreous growth factor concentration were aconsequence more of retinal ischemia than ofdiabetes. Finally, studies by Giannini et al.52 ofbovine retinal endothelial cells in culturedemonstrated that while insulin was a potentmitogen for these cells, IGF-I, inhibited by thepresence of endogenous IGFBPs failed to be mi-togenic. They have suggested that the effects ofhyperinsulinemia, rather than high IGF-I lev-els, may be more important in regulating reti-nal cell growth.

Several clinical studies have also failed toprovide a causal link between IGF-I and dia-betic retinopathy. In a large population-basedstudy of diabetics, Wang et al.53 examined therelationship between serum IGF-I levels andthe incidence and progression of diabeticretinopathy over a 6-year period. They foundno association between serum IGF-I levels andthe incidence or progression of retinopathyamong over 1,200 adult-onset and childhood-onset diabetes patients. Similar findings werereported in a smaller study of young patientswith type I DM and rapidly progressive severeretinopathy.54 Moreover, other studies havefailed to demonstrate differences in vitreousIGF-I concentrations in patients with diabeteswith PDR compared with controls without di-abetes.55

Concern about the role of IGF-I in diabeticretinopathy has also arisen from clinical stud-ies demonstrating an increased incidence of op-tic disc swelling and early worsening ofretinopathy among patients with diabetestreated with subcutaneous IGF-I (ref. 56, studydetailed below). However, such changes wereobserved in the face of simultaneous rapid improvements in glycemic control, and were not associated with retinal neovascularization.Studies by Smith et al.57 examined the role ofthe GH-IGF-I axis in ischemia-induced retinaldamage by experimentally manipulating GH levels in transgenic mice. Animals over-expressing a GH antagonist or systemicallytreated with an inhibitor of GH release devel-

oped less retinal neovascularization than con-trols and treatment with exogenous IGF-I alonedid not promote neovascularization. These re-sults suggest that treatments designed to sup-press the elevated GH levels seen in type 1 DM(i.e., IGF-I treatment, or the historical use of hy-pophysectomy) might actually lessen the inci-dence of proliferative diabetic retinopathy.

THE ROLE OF THE GH-IGF-IGFBP AXIS IN BETA-CELL FUNCTION

AND SURVIVAL

Regulated functioning of the IGF system hasbeen shown to be an important component ofnumerous biologic systems, including repro-ductive physiology, gastrointestinal physiol-ogy, bone growth and development, and renalgrowth and hemodynamics, among others.Several lines of evidence now also demonstratethat the IGF system is involved in early pan-creatic development, and specifically in betacell functioning and beta cell survival. Thesefindings suggest that while autoimmune-me-diated insulin deficiency might promote GH-IGF-IGFBP axis dysregulation, the resultingIGF-I deficiency could serve to further perpet-uate the autoimmune-mediated destruction ofpancreatic beta cells.

First, IGFs are important for maintainingbeta cell viability. Studies by Rawdon et al.,58

demonstrated that when culturing dorsal pan-creatic buds from chick embryos, supplemen-tation of serum-free medium with IGF-I in-creased the proportion of insulin-producingcells considerably more than supplementationwith insulin. Furthermore, localized delivery ofIGF-I to fetal pancreas transplants has beenshown to aid engraftment of the pancreatic tis-sue.59

IGFs may also function to inhibit physiologicbeta cell apoptosis. Although rates of beta cellreplication in the adult pancreas are typicallylow (approximately 3% of beta cells per day),60

neonatal beta cells transiently maintain their re-generative capacity. For example, replenish-ment of beta cells occurs after treatment of theyoung rabbit with alloxan (a beta cell toxin).61

However, Hill et al.60 have demonstrated thatin the neonatal rat, “proliferative”-type neona-

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tal beta cells are partially replaced by a cohortof nonproliferative adult-type beta cells asthese animals mature, due to the apoptoticelimination of fetal-type cells. Several lines ofevidence suggest that the IGFs have the po-tential to interrupt this process of physiologicapoptosis. First, IGFs have been shown to bepotent antiapoptotic factors in numerous celltypes including cerebellar neurons,62 preovu-latory follicles,63 and hematopoietic cells.64 Inthe pancreas, Petrik et al.65 have shown thatamong young Wistar rats, islet cell apoptosispeaks at postnatal day 14, temporally associ-ated with a decline in islet cell expression ofIGF-II. However, in these animals, treatmentof isolated islets with IGF-I or IGF-II pro-longed islet cell survival. In addition to thesephysiologic studies, several pathophysiologicconditions provide insight into the role ofIGFs in beta cell proliferation and growth. Forinstance, overexpression of IGF-II has beenshown to promote the development ofnesideoblastosis66 while increased IGF-ImRNA expression has been demonstrated innumerous pancreatic tumors,67 comparedwith the low IGF- I mRNA levels typical of thenormal adult pancreas.

IGF-I may also function to inhibit patholog-ical beta cell apoptosis, as suggested by stud-ies in the nonobese diabetic (NOD) mouse. TheNOD mouse develops an autoimmune form ofinsulin-dependent diabetes mellitus that isvery similar to type 1 DM in humans. In theseanimals, the destruction of insulin-producing,pancreatic cells is mediated through antigen-reactive CD4 1 T cells that produce proinflam-matory cytokines. Nevertheless, only recentlyit has been shown that the death of beta cellsoccurs by programmed cell death (i.e., apopto-sis), and not necrosis. In two independent stud-ies using different NOD models, researchershave shown that autoimmune-mediated betacell death is due to progressive apoptosis.68,69

These observations can be coupled with stud-ies showing that the pretreatment of isolatedrat islets70,71 or prediabetic NOD mouse islets60

with IGF-I or IGF-II protected them from cy-tokine-mediated apoptotic cell death. Thesestudies suggest a role for IGF-I in preventingthe pathologic, cytokine-mediated beta celldeath associated with autoimmune diabetes in

rodent models of diabetes and support a rolefor IGFs in preserving pancreatic function.

IGF-I TREATMENT IN DIABETES

A role for rhIGF-I in inhibiting cytokine-me-diated beta cell apoptosis while simultaneouslyrestoring the GH-IGF-IGFBP axis, thereby im-proving systemic glucose homeostasis, andnormalizing IGF bioavailability in vulnerabletissues suggests that IGF-I might represent amultifaceted therapeutic option for the treat-ment of type 1 DM. Results of numerous ani-mal studies examining the effects of IGF-I ad-ministration in diabetes motivated subsequenthuman trials of recombinant human IGF-I(rhIGF-I) therapy in type 1 DM, type 2 DM, andsyndromes of insulin resistance, as describedbelow.

Type 1 DM

Several human studies have examined the ef-fects of short-term administration of rhIGF-I onglycemic control and on regulation of the GH-IGF-IGFBP axis in patients with type 1 DM.Studies by Cheetham et al.72 demonstrated thata single subcutaneous injection of rhIGF-I (40m g/kg) given at 1,800 hours resulted in in-creased IGF-I levels, decreased overnight se-cretion of GH, and decreased insulin require-ments in nine pubertal adolescents with type 1DM. Bach et al.73 examined the effect of 10-hoursubcutaneous infusions of rhIGF-I, given on 3successive days to each of four diabetic ado-lescents and six pubertal-stage matched con-trols. Again, they found that such treatment in-duced a marked increase in serum IGF-I levels,suppression of overnight GH secretion and areduction in insulin requirements. Later stud-ies by Cheetham and colleagues74 examinedthe effect of a 40 m g/kg rhIGF-I injection givenonce daily for 28 days to six adolescents withtype 1 DM. In this study, IGF-I administrationled to a sustained increase in serum IGF-I lev-els, with a concomitant fall in HbA1c despite areduction in daily insulin requirements. Carrollet al.75 in studies examining the effects ofrhIGF-I administration to adults with type 1 di-abetes corroborated these adolescent studies. Intheir study, patients received either placebo or

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rhIGF-I at a dose of 50 m g/kg twice daily for19 days. rhIGF-I administration decreased in-sulin requirements and improved the plasmalipid profile in adult patients while maintain-ing glycemic control.

To examine if dual replacement with insulinand rhIGF-I might result in improved meta-bolic control and reduced insulin usage, weconducted a 4-week, randomized, placebo-con-trolled double-blind study comparing the ef-fects of rhIGF- I plus insulin compared with in-sulin monotherapy in children and adolescentswith type 1 DM.76,77 Forty-three pediatric pa-tients with type 1 DM were randomly assignedto groups receiving a single daily fasting, sub-cutaneous injection of placebo or rhIGF-I (80m g/kg per day) for 28 days, while continuingto receive split-mix insulin therapy and inten-sive outpatient management. The mean bloodglucose levels during the last 10 days of treat-ment was lower in the rhIGF-I group (174 6 37vs. 194 6 32 mg/dl). A greater improvement inmean HbA1c was also apparent in the rhIGF-Igroup ( 2 1.85% vs. 2 1.3%). Moreover, 28 daysof rhIGF-I therapy was associated with correc-tion of IGF-I deficiency, and suppression ofIGFBP-1 levels and a trend toward lower cir-culating GH levels throughout the study.

Having demonstrated that patients treatedwith a combination of subcutaneous IGF-I andinsulin given for only 4 weeks experienced im-proved glycemic control, we then undertook astudy designed to extend these earlier obser-vations and to identify a safe and effective mul-tidose regimen of rhIGF-I, that when used incombination with insulin, would improveglycemic control better than insulin alone.56

Two hundred twenty-three patients, ranging inage from 11–66 years, were randomly assigned(double-blind) to receive 12 weeks of treatmentwith twice daily subcutaneous injections ofplacebo, or rhIGF-I at a dose of 40/40 m g/kg(AM/PM ), 80/40, or 80/60, while continuing toreceive standard insulin therapy. Cotherapywith rhIGF-I/insulin produced a mean de-crease in HbA1c of 1.2 %, compared with a 0.7% decrease in HbA1c for patients receiving in-tensified insulin therapy alone (p # 0.01). Dailyinsulin requirements among subjects receivingrhIGF-I/insulin cotherapy also decreased by11%–19%, compared with a 7% increase in in-

sulin usage reported by the placebo group. Adverse events related to rhIGF-I treatment inthis study included peripheral edema, jawpain, and tachycardia. Some patients, primar-ily those receiving the highest rhIGF-I treat-ment doses, also experienced early worseningof diabetic retinopathy (approximately 8%) andoptic disc swelling (approximately 12%). Together, these phase 2/3 studies clearlydemonstrated that rhIGF-I/insulin cotherapycould improve glycemic control in patientswith type 1 DM better than optimized insulinmanagement alone. Moreover, improved gly-cemic control was accomplished without con-comitant weight gain or the occurrence of morefrequent hypoglycemia,56 although ophthal-mologic consequences were noted with higherdose therapy.

Several mechanisms may contribute to theability of IGF-I to improve blood glucose con-trol. Certainly, a direct hypoglycemic effect isexpected, and can be explained by the observedincrease in serum free IGF-I levels among dia-betics treated with rhIGF-I. However, studiesby Asada et al.78 have demonstrated thatrhIGF-I administration in rats with diabetes isalso associated with normalization in the ex-pression of GLUT-1, GLUT-2 and GLUT-5 inthe kidney, suggesting that IGF-I therapy mayhave indirect effects on peripheral glucose uti-lization. In addition, Hussain et al.25 havedemonstrated that treatment of healthy sub-jects with 5 days of rhIGF-I resulted in en-hanced insulin-stimulated oxidative and non-oxidative glucose disposal. Together thesestudies suggest that rhIGF-I administrationmay induce a secondary increase in insulin sen-sitivity in these patients.

Several lines of evidence suggest that IGF-Itreatment early in the course of diabetes mayalso function to interrupt the ongoing autoim-mune destruction of beta cells. Prophylacticadministration of IGF-I to NOD mice prior toage 9 weeks was shown to significantly delaythe onset of diabetes and decrease the severityof insulinitis in these animals.79 In studies byBergerot et al.80 comparing protective effects ofIGF-I and insulin on autoimmune beta cell de-struction, recipient mice were adoptively trans-ferred with autoreactive T-cells from diabeticNOD mice, and then treated with subcuta-

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neous IGF-I or insulin. IGF-I significantly re-duced the successful transfer of diabetes tothese animals, concomitant with a marked re-duction in histologically identifiable insulinitiscompared with either the control or insulin-treated mice. These authors further hypothe-size that IGF-I may protect against the devel-opment of pancreatic autoimmunity in mice byinducing selective effects on T-cell traffickingto lymphoid organs.

In summary, in type 1 DM, a primary defi-ciency of pancreatic insulin secretion appears toinduce a secondary disruption in the GH-IGF-IGFBP axis. The combined abnormalities in bothof these hormonal systems are jointly responsi-ble for disrupted glucose homeostasis. Studiesto date suggest that replacement of both hor-monal systems is metabolically superior to in-sulin therapy alone. Studies by Hugl et al.81 haveshown that in the pancreatic beta cell line INS-1, IGF-I–mediated cell proliferation was glucose-dependent within a physiologic glucose con-centration range. Such studies would suggestthat in the pancreas, the mitogenic effects of IGFsare also uniquely linked to normal glucose me-tabolism. Consequently, in type 1 DM, portal in-sulin deficiency, by producing both chronic hy-perglycemia and IGF-I deficiency, might furtheraccelerate ongoing beta cell destruction by elim-inating the normal contribution of IGFs to betacell recovery and survival.

Insulin resistance and type 2 DM

Genetic syndromes of insulin resistance arecharacterized either by mutations effecting theinsulin receptor or defects in postreceptor sites.Similarly, type 2 DM, characterized by insulinresistance, is associated with downregulationof peripheral insulin binding sites, but upreg-ulation of tissue- specific IGF binding. Conse-quently, the use of rhIGF-I in these clinical en-tities has been investigated as a means ofmetabolically circumventing the ill-functioninginsulin system in these disorders.

In the early 1990s, Schoenle et al.82 reportedon the effectiveness of isolated intravenousdoses of rhIGF-I in lowering blood glucose lev-els in patients with type A insulin resistance.In subsequent years, a series of studies83–86

demonstrated that relatively short-term daily

subcutaneous administration of rhIGF-I in pa-tients with type A insulin resistance was effec-tive in reducing fasting and postprandial glu-cose levels, in addition to lowering insulin andC-peptide levels. The effectiveness of rhIGF-Iin this setting was confirmed in longer term tri-als completed in Japan. Ishihama et al.87 treateda girl with type A insulin resistance for 2 years,demonstrating that IGF-I treatment was effec-tive in ameliorating hyperglycemia, althoughtherapy was complicated by worsening hyper-androgenism. Moses et al.88 then studied sixsubjects with severe insulin resistance of vary-ing etiologies, but without insulin receptor mu-tations. Among these patients, subcutaneousrhIGF-I therapy normalized fasting and post-prandial glucose levels among the subset ofsubjects (4/6) with overt diabetes, and signifi-cantly lowered circulating insulin and triglyc-eride levels among the two subjects with base-line normal glucose tolerance. Finally, IGF-Ihas been shown to be metabolically therapeu-tic in patients with Rabson-Mendenhall syn-drome,89 congenital lipodystrophy and lep-rechaunism,90 and in a patient with high titersof anti-insulin autoantibodies.91

The effectiveness of rhIGF-I in improvingglucose control in patients with type 2 DM hasalso been studied. Schalch et al.92 treated 12 pa-tients with type 2 DM with twice daily subcu-taneous rhIGF-I for 5 days. Once again, ad-ministration of rhIGF-I significantly loweredfasting blood glucose, insulin, and C-peptidelevels and induced significant but lesser re-ductions in serum lipids. In a later study of 12patients with type 2 DM, Moses et al.93 demon-strated that the subcutaneous administration ofrhIGF-I for 6 weeks significantly lowered bloodglucose and serum insulin levels and improvedHbA1c by more than 2.0%. These changes wereaccompanied by clinical evidence of improvedinsulin sensitivity and body composition. Un-fortunately, only approximately 50% of sub-jects completed the 6 weeks of therapy due tounacceptable side effects.

SUMMARY

It has been shown that diminished endoge-nous insulin secretion, universally present in

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type 1 DM and less commonly characteristic ofdecompensated type 2 DM, leads to a decreasein bioavailable IGF-I. Recombinant DNA tech-nology has increased the therapeutic availabil-ity of IGF-I for a variety of clinical uses. Con-sequently, use of rhIGF-I in several diabeticconditions has now been explored, and hasbeen shown to result in improved glucose control, decreased exogenous insulin require-ments, and increased insulin sensitivity. Suchstudies would suggest that use of rhIGF-I as anadjuvant therapy in diabetes management re-mains promising. Clearly, long-term studiesare still needed to establish both the safety andlong-term efficacy of IGF-I therapy in diabetes,as well as to determine the impact of IGF-I ad-ministration on the natural history of diabeticcomplications.

REFERENCES

1. Daughaday WH, Trivedi B, Andrews BA: The on-togeny of serum GH binding in man: A possible in-dicator of hepatic GH receptor development. J ClinEndocrinol Metab 1987;65:1072– 1074.

2. Menon RK, Arslanian S, May B, Cutfield WS, Sper-ling MA: Diminished growth hormone-binding pro-tein in children with insulin-dependent diabetes mel-litus. J Clin Endocrinol Metab 1992;74:934– 938.

3. Holl RW, Siegler B, Scherbaum WA, Heinze E: Theserum growth hormone-binding protein is reduced inyoung patients with insulin-dependent diabetes mel-litus. J Clin Endocrinol Metab 1993;76:165– 167.

4. Taylor AM, Dunger DB, Grant DB, Preece MA: So-matomedin-C/IGF-I measured by radioimmunoas-say and somatomedin bioactivity in adolescents withinsulin-dependent diabetes compared with pubertymatched controls. Diabetes Res 1988;9:177–181.

5. Amiel SA, Sherwin RS, Hintz RL, Gertner JM, PressCM, Tamborlane WF: Effect of diabetes and its con-trol on insulin-like growth factors in the young sub-ject with type 1 diabetes. Diabetes 1984;3:1175– 1179.

6. Tan K, Baxter RC: Serum insulin-like growth factor Ilevels in adult diabetic patients: the effect of age. JClin Endocrinol Metab 1986;63:651– 655.

7. Batch JA, Baxter RC, Werther G: Abnormal regulationof insulin-like growth factor binding proteins in ado-lescents with insulin-dependent diabetes. J Clin En-docrinol Metab 1991;73:964– 968.

8. Hanaire-Broutin H, Sallerin-Caute B, Poncet MF,Tauber M, Bastide R, Rosenfeld R, Tauber JP: Insulintherapy and GH-IGF-I axis disorders in diabetes: Im-pact of glycaemic control and hepatic insulinization.Diabetes Metab 1996;22:245– 250.

9. Mercado M, Molitch ME, Baumann G: Low plasma

growth hormone binding protein in IDDM. Diabetes1992;41:605– 609.

10. Ooi GT, Orlowski CC, Brown AL, Becher RE, Unter-man TG, Rechler MM: Different tissue distributionand hormonal regulation of messenger RNAs encod-ing rat insulin-like growth factor-binding proteins-1and 2. Mol Endocrinol 1990;4:321– 328.

11. Villafuerte BC, Goldstein S, Robertson DG, Pao C-I,Murphy LJ, Phillips LS: Molecular regulation ofIGFBP-1 in hepatocyte primary culture. Diabetes1992;41:835– 842.

12. Brismar K, Gutniak M, Povoa G, Werner S, Hall K:Insulin regulates the 35 kD IGF binding protein in pa-tients with diabetes mellitus. J Endocrinol Invest1988;11:599– 602.

13. Hall K, Brismar K, Grissom F, Lindgen B, Povoa G:IGFBP-1 production and control mechanisms. ActaEndocrinol (Copenhagen) 1991;124:48– 54.

14. Suikkari AM, Koivisto VA, Rutanen EM, Yki-JärvinenH, Karonen SL, Seppälä M: Insulin regulates theserum levels of low molecular weight insulin-likegrowth factor-binding protein. J Clin EndocrinolMetab 1988;66:266– 272.

15. Bereket A, Lang CH, Blethen SL, Gelato MC, Fan J,Frost RA, Wilson TA: Effect of insulin on the insulin-like growth factor system in children with new-onsetinsulin-dependent diabetes mellitus. J Clin En-docrinol Metab 1995;80:1312– 1317.

16. Rieu M, Binoux M: Serum levels of insulin-likegrowth factor (IGF) and IGF binding protein in in-sulin-dependent diabetics during an episode of severemetabolic decompensation and the recovery phase. JClin Endocrinol Metab 1985;60:781– 785.

17. Strasser-Vogel B, Blum WF, Past R, Kessler U, Hoe-flich A, Meiler B, Kiess W: Insulin-like growth factor(IGF)-I and -II and IGF-binding proteins-1, -2, and -3in children and adolescents with diabetes mellitus:correlation with metabolic control and height attain-ment. J Clin Endocrinol Metab 1995;80:1207– 1213.

18. Clayton KL, Holly JMP, Carlsson LM, Jones J,Cheetham TD, Taylor AM, Dunger DB: Loss of thenormal relationships between growth hormone,growth hormone-binding protein and insulin-likegrowth factor-I in adolescents with insulin-dependentdiabetes mellitus. Clin Endocrinol (Oxf) 1994;41:517–524.

19. Shishko PI, Dreval AV, Abugova IA, Zarjarny IU,Goncharov VC: Insulin- like growth factors and bind-ing proteins in patients with recent-onset type 1 (in-sulin dependent) diabetes mellitus: Influence of dia-betes control and intraportal insulin infusion.Diabetes Res Clin Pract 1994;25:1– 12.

20. Rajkumar K, Barron D, Lewitt MS, Murphy LJ:Growth retardation and hyperglycemia in insulin-likegrowth factor binding protein-1 transgenic mice. En-docrinology 1995;136:4029– 4034.

21. Lewitt MS, Denyer GS, Cooney GJ, Baxter RC: Insulin-like growth factor-binding protein-1 modulates bloodglucose levels. Endocrinology 1991;129:2254– 2264.

22. Jacob RJ, Sherwin RS, Bowen L, Fryburg D., Fagin KD,

IGF-I IN DIABETES 77

Tamborlane WV, Shulman GI: Metabolic effects ofIGF-I and insulin in spontaneously diabetic BB/wrats. Am J Physiol 1991;260:E262– 268.

23. Levin N, Brunet C, Won WB, Oster MH, MortensenD, Ma Y-H, Clark R: Serum glucose lowering effectsof insulin-like growth factor-I (IGF-I) in a rodentmodel of NIDDM [Abstract]. Endocr Soc 1995;P1–272.

24. Giacca A, Gupta R, Efendic S, Hall K, Skottner A, Lick-ley L, Vranic M: Differential effects of IGF-I and in-sulin on glucoregulation and fat metabolism in de-pancreatized dogs. Diabetes 1990;39:340– 347.

25. Hussain MA, Schmitz O, Mengel A, Keller A, Chris-tiansen JS, Zapf J, Froesch ER: Insulin-like growth fac-tor I stimulates lipid oxidation, reduces protein oxi-dation, and enhances insulin sensitivity in humans. JClin Invest 1993;92:2249– 2256.

26. Dore S, Kar S, Quirion R: Rediscovering an old friend,IGF-I: Potential use in the treatment of neurodegen-erative diseases. Trends Neurosci 1997;20:326– 331.

27. Wuarin L, Guertin DM, Ishii DN: Early reduction ininsulin-like growth factor gene expression in diabeticnerve. Exp Neurol 1994;130:106– 114.

28. Wuarin L, Namdev R, Burns JG, Fei ZJ, Ishii DN:Brain insulin-like growth factor-II mRNA content isreduced in insulin-dependent and non-insulin de-pendent diabetes mellitus. J Neurochem 1996;67:742–751.

29. Busiguina S, Chowen JA, Argente J, Torres-Aleman I:Specific alterations of the insulin-like growth factor Isystem in the cerebellum of diabetic rats. En-docrinology 1996;137:4980– 4987.

30. Bitar MS, Pilcher CW: Attenuation of IGF-I antinoci-ceptive action and a reduction in spinal cord gene ex-pression of its receptor in experimental diabetes. Pain1998;75:69– 74.

31. Migdalis IN, Kalageropoulou K, Kalantzis L, Nouno-poulos C, Bouloukos A, Samartzis M: Insulin-likegrowth factor-I and IGF-I receptors in diabetic pa-tients with neuropathy. Diabetes Med 1995;12:823–827.

32. Ishii DN: Implication of insulin-like growth factors inthe pathogenesis of diabetic neuropathy. Brain ResBrain Res Rev 1995;20:47– 67.

33. Zhuang HX;Snyder CK, Pu SF, Ishii DN: Insulin-likegrowth factors reverse or arrest diabetic neuropathy:effects on hyperalgesia and impaired nerve regener-ation in rats. Exp Neurol 1996;140:198– 205.

34. Ishii DN, Lupien SB: Insulin-like growth factors pro-tect against diabetic neuropathy: effects on sensorynerve regeneration in rats. J Neurosci Res 1995;40:138–144.

35. Zhuang HX, Wuarin L, Fei ZJ, Ishii DN: Insulin-likegrowth factor (IGF) gene expression is reduced inneural tissues and liver from rats with non- insulin-dependent diabetes mellitus, and IGF treatment ame-liorates diabetic neuropathy. J Pharmacol Exp Ther1997;283:366– 374.

36. Russell JW, Feldman EL: Insulin-like growth factor-Iprevents apoptosis in sympathetic neurons exposedto high glucose. Horm Metab Res 1999;31: 90–96.

37. Hirschberg R, Kopple JD: Insulin-like growth factor Iand renal function. Diabetes Rev 1995;3:177–195.

38. Fervenza FC, Tsao T, Hoffman AR, Rabkin R: Re-gional changes in the intrarenal insulin-like growthfactor-I axis in diabetes. Kidney Int 1997;51:811– 818.

39. Price GJ, Berka JL, Werther GA, Bach LA: Cell-spe-cific regulation of mRNAs for IGF-I and IGF-bindingproteins-4 and 5 in streptozotocin-diabetic rat kidney.J Mol Endocrinol 1997;18:5– 14.

40. Gronbaek H, Vomers P, Bjorn SF, Osterby R, OrskovH, Flyvbjerg A: Effect of GH/IGF-I deficiency onlong-term renal changes and urinary albumin excre-tion in diabetic dwarf rats. Am J Physiol 1997;272:E918–924.

41. Segev Y, Landau D, Marbach M, Shehadeh N, Flyvb-jerg A, Phillip M: Renal hypertrophy in hyper-glycemic non-obese diabetic mice is associated withpersistent renal accumulation of insulin-like growthfactor I. J Am Soc Nephrol 1997;8:436– 444.

42. Cummings EA, Sochett EB, Dekker MG, Lawson ML,Daneman D: Contribution of growth hormone andIGF-I to early diabetic nephropathy in type 1 diabetes.Diabetes 1998;47:1341– 1346.

43. Luft R, Olivecrona H, Sjögren: Hypophysectomy inman. Nord Med 1952;47:351.

44. Grant MB, Mames RN, Fitzgerald C, Ellis EA,Aboufriekha M, Guy J: Insulin-like growth factor Iacts as an angiogenic agent in rabbit cornea andretina: comparative studies with basic fibroblastgrowth factor. Diabetologia 1993;36:282– 291.

45. Chantelau E: Evidence that upregulation of serumIGF-1 concentrations can trigger acceleration of dia-betic retinopathy. Br J Ophthalmol 1998;82:725– 730.

46. Janssen JA, Jacobs ML, Derkx FH, Weber RF, van derLely AJ, Lamberts SW: Free and total insulin-likegrowth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the pres-ence of diabetic retinopathy and glomerular hyperfil-tration in insulin-dependent diabetes mellitus. J ClinEndocrinol Metab 1997;82:2809– 2815.

47. Boulton M, Gregor Z, McLeod D, Charteris D, Jarvis-Evans J, Moriarty P, Khaliq A, Foreman D, AllambyD, Bardsley B: Intravitreal growth factors in prolifer-ative diabetic retinopathy: Correlation with neovas-cular activity and glycaemic management. Br. J Oph-thalmol 1997;81:228– 233.

48. Danis RP, Bingaman DP: Insulin-like growth factor-1retinal microangiopathy in the pig eye. Ophthalmol-ogy 1997;104:1661– 1669.

49. Lowe WL Jr., Florkiewicz RZ, Yorek MA, SpanheimerRG, Albrecht BN: Regulation of growth factor mRNAlevels in the eyes of diabetic rats. Metabolism1995;44:1038.

50. Pfeiffer A, Spranger J, Meyer-Schwickerath R, SchatzH: Growth factor alterations in advanced diabeticretinopathy: a possible role of blood retina barrierbreakdown. Diabetes 1997;46:S26– 30.

51. Meyer-Schwickerath R, Pfeiffer A, Blum WF, Frey-berger H, Klein M, Losche C, Rollmann R, Schatz H:Vitreous levels of the insulin-like growth factors I and

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II and the insulin-like growth factor binding proteins2 and 3, increase in neovascular eye disease. Studiesin nondiabetic and diabetic subjects. J Clin Invest1993;92:2620– 2625.

52. Giannini S, Cresci B, Manuelli C, Fujita-Yamaguchi Y,Romagnani P, Mohan S, Rotella CM: Insulin-like growth factor binding protein production inbovine retinal endothelial cells. Metabolism 1997;46:1367–1379.

53. Wang Q, Dills DG, Klein R, Klein BE, Moss SE: Doesinsulin-like growth factor I predict incidence and pro-gression of diabetic retinopathy? Diabetes 1995;44:161–164.

54. Agardh CD, Agardh E, Eckert B, Sjoberg U: Growthhormone levels in the basal state and after thy-rotropin-releasing hormone stimulation in youngtype 1 (insulin-dependent) diabetic patients with se-vere retinopathy. Diabetes Res 1992;19:81– 85.

55. Lee HC, Lee KW, Chung CH, Chung YS, Lee EJ, LimSK, Kim KR, Huh KB, Lee SC, Kwon OW: IGF-I ofserum and vitreous fluid in patients with diabetic pro-liferative retinopathy. Diabetes Res Clin Pract 1994;24:85–88.

56. Thrailkill KM, Quattrin T, Baker L, Kuntze JE, Comp-ton PG, Martha PM Jr. for the rhIGF-I in IDDM StudyGroup: Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemiccontrol in Type 1 diabetes. Diabetes Care 1999;22:585–592.

57. Smith LE, Kopchick JJ, Chen W, Knapp J, Kinose F,Daley D, Foley E, Smith RG, Schaeffer JM: Essentialrole of growth hormone in ischemia-induced retinalneovascularization. Science 1997;276:1706– 1709.

58. Rawdon BB, Andrew A: Effects of tri-iodothyronine(T3), insulin, insulin-like growth factor I (IGF-I) andtransforming growth factor beta1 (TGFbeta1) on theproportion of insulin cells in cultured embryonicchick pancreas. Anat Embryol (Berl) 1998;198:245–254.

59. Adams GA, Squiers EC, Maestri M, Lee L, Alfrey EJ,Dafoe DC: Regimens of IGF-I treatment in fetal pan-creas transplantation. J Surg Res 1997;68:73–78.

60. Hill DJ, Petrik J, Arany E: Growth factors and the reg-ulation of fetal growth. Diabetes Care 1998;21(Supp l.2):B60–B69.

61. Bencosme SA: Cytology of the islet cells in alloxan di-abetic rabbits. Am J Pathol 1955;31:1149– 1164.

62. Galli C, Meucci O, Scorziello A, Werge TM, CalissanoP, Schettini G: Apoptosis in cerebellar granule cells isblocked by high KCL, forskolin, and IGF- I throughdistinct mechanisms of action: the involvement of in-tracellular calcium and RNA synthesis. J Neurosci1995;15:1172– 1179.

63. Chun SY, Billig H, Tilly JL, Furuta I, Tsafriri A, HsuehAJW: Gonadotropin suppression of apoptosis in cul-tured preovulatory follicles: mediatory role of en-dogenous insulin-like growth factor I. Endocrinology1994;135:1845– 1853.

64. Rodrigueztarduchy G, Collins MKL, Garcia I, Lo-pezrivas A: Insulin-like growth factor-I inhibits apop-

tosis in IL-3–dependent hemopoietic cells. J Immunol1992;149:535– 539.

65. Petrik J, Arany E, McDonald TJ, Hill DJ: Apoptosis inthe pancreatic islet cells of the neonatal rat is associ-ated with a reduced expression of insulin-like growthfactor II that may act as a survival factor. Endo-crinology 1998;139:2994– 3004.

66. Sun FL, Dean WL, Kelsey G, Allen ND, Reik W: Trans-activation of IGF2 in a mouse model of the Beckwith-Wiedemann syndrome. Nature 1997;389:809– 815.

67. Bergmann U, Funatomi H, Yokoyama M, Beger HG,Kore M: Insulin-like growth factor I overexpressionin human pancreatic cancer: Evidence for autocrineand paracrine roles. Cancer Res 1995;55:2007– 2011.

68. Kurrer MO, Pakala SV, Hanson HL, Katz JD: b cellapoptosis in T cell-mediated autoimmune diabetes.Proc Natl Acad Sci 1997;94:213– 218.

69. Augstein P, Stephens LA, Allison J, Elefanty AG, Ek-berg M, Kay TW, Harrison LC: Beta-cell apoptosis inan accelerated model of autoimmune diabetes. MolMed 1998;4:495– 501.

70. Hill DJ, Delovitch TL: Insulin-like growth factors pro-tect isolated islets of Langerhans from the cytotoxiceffects of cytokines. J Endocrinol 1997;147(supp l):O39.

71. Mabley JG, Belin V, John N, Green IC: Insulin-likegrowth factor I reverses interleukin-1beta inhibitionof insulin secretion, induction of nitric oxide synthaseand cytokine-mediated apoptosis in rat islets ofLangerhans. FEBS Lett 1997;417:235– 238.

72. Cheetham TD, Jones J, Taylor AM, Holly J, MathewsDR, Dunger DB: The effects of recombinant insulin-like growth factor I administration on growth hor-mone levels and insulin requirements in adolescentswith type 1 (insulin-dependent) diabetes mellitus. Di-abetologia 1993;36:678– 681.

73. Bach MA, Chin E, Bondy CA: The effects of subcuta-neous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab1994;79:1040– 1045.

74. Cheetham TD, Holly JM, Clayton K, Cwyfam-HughesS, Dunger DB: The effects of repeated daily recombi-nant human insulin-like growth factor I administra-tion in adolescents with type 1 diabetes. Diabet Med1995;12:885– 892.

75. Carroll PV, Umpleby M, Ward GS, Imuere S, Alexan-der E, Dunger D, Sonksen PH, Russell-Jones DL:rhIGF-I administration reduces insulin requirements,decreases growth hormone secretion, and improvesthe lipid profile in adults with IDDM. Diabetes1997;46:1453– 1458.

76. Thrailkill K, Quattrin T, Baker L, Litton J, Dwigun K,Rearson M, Poppenheimer M, Kotlovker D, GiltinanD, Gesundheit N, Martha P: Dual hormonal replace-ment therapy with insulin and recombinant humaninsulin-like growth factor (IGF)-I in insulin-depen-dent diabetes mellitus: Effects on the growth hor-mone/IGF/IGF-binding protein system. J Clin En-docrinol Metab 1997;82:1181– 1187.

77. Quattrin T, Thrailkill K, Baker L, Litton J, Dwigun K,Rearson M, Poppenheimer M, Giltinan D, Gesundheit

IGF-I IN DIABETES 79

N, Martha P: Dual hormonal replacement with insulinand recombinant human insulin-like growth factor inIDDM: Effects on glycemic control, IGF-I levels andsafety profile. Diabetes Care 1997;20:374– 380.

78. Asada T, Ogawa T, Iwai M, Shimomura K, KobayashiM: Recombinant insulin-like growth factor I normal-izes expression of renal glucose transporters in dia-betic rats. Am J Physiol 1997;273:F27– 37.

79. Kaino Y, Hirai H, Ito T, Kida K: Insulin-like growthfactor I (IGF-I) delays the onset of diabetes in non-obese diabetic (NOD) mice. Diabetes Res Clin Pract1996;34:7–11.

80. Bergerot I, Fabien N, Maguer V and Thivolet C: In-sulin-like growth factor I (IGF-I) protects NOD micefrom insulinitis and diabetes. Clin Exp Immunol1995;102:335– 340.

81. Hugl SR, White MF, Rhodes CJ: Insulin-like growthfactor I (IGF-I)- stimulated pancreatic beta-cell growthis glucose-dependent. Synergistic activation of insulinreceptor substrate-mediated signal transduction path-ways by glucose and IGF-I in INS-1 cells. J Biol Chem1998;273:17771– 17779.

82. Schoenle EJ, Zenobi PD, Torresani I, Werder EA,Zachmann M, Froesch ER: Recombinant human in-sulin-like growth factor I (rhIGF-I) reduces hypergly-caemia in patients with extreme insulin resistance. Di-abetologia 1999;34:675– 679.

83. Morrow LA, O’Brien MB, Moller DE, Flier JS, MosesAC: Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin ac-tion in the type A syndrome of severe insulin resis-tance. J Clin Endocrinol Metab 1994;79:205– 210.

84. Zenobi PD, Glatz Y, Keller A, Graf S, Jaeggi-Grois-man SE, Riesen WF, Schoenle EJ, Froesch ER: Benefi-cial metabolic effects of insulin-like growth factor I inpatients with severe insulin-resistant diabetes type A.Eur J Endocrinol 1994;131:251– 257.

85. Usula AL, Madigan T, Burguera B, Cefalu W, SinhaMK, Powell JG, Usula SJ: High dose intravenous, butnot low dose subcutaneous, insulin-like growth fac-tor-I therapy induces sustained insulin sensitivity inseverely resistant type I diabetes mellitus. J Clin En-docrinol Metab 1994;79:435– 440.

86. Vestergaard H, Rossen M, Urhammer SA, Muller J,Pedersen O: Short- and long-term metabolic effects ofrecombinant human IGF-I treatment in patients withsevere insulin resistance and diabetes mellitus. Eur JEndocrinol 1997;136:475– 482.

87. Ishihama H, Suzuki Y, Muramatsu K, Nagai M,Kokubo M, Shiraya H, Kawakita A, Nishimura Y,Imamura T, Kobayashi M: Long-term follow-up intype A insulin resistant syndrome treated by insulin-like growth factor I. Arch Dis Child 1994;71:144– 146.

88. Moses AC, Morrow LA, O’Brien M, Moller DE, FlierJS: Insulin-like growth factor I (rhIGF-I) as a thera-peutic agent for hyperinsulinemic insulin-resistant diabetes mellitus. Diabetes Res Clin Pract 1995;28:S185–194.

89. Quin JD, Smith K, Beastall GH, Miell JP, MacCuishAC: The effect of recombinant insulin-like growth fac-tor I on ketone body ketoacidosis in severe insulin re-sistance. Diabet Med 1994;11:590– 592.

90. Kuzuya H, Matsuura N, Sakamoto M, Makino H,Sakamoto Y, Kadowaki T, Suzuki Y, Kobayashi M,Akazawa Y, Nomura M, Yoshimasa Y, Kasuga M,Goji K, Nagataki S, Oyasu H, Imura H: Trial of in-sulinlike growth factor I therapy for patients with ex-treme insulin resistance syndromes. Diabetes 1993;42:696–705.

91. Kajimoto Y, Kawamori R, Fujitani Y, Kishimoto M,Kubota M, Yamasaki Y, Morishima T, Kamada T: Acase of non-insulin dependent diabetes with antiin-sulin antibody: effect of subcutaneous injection of hu-man recombinant insulin-like growth factor I. EndocrJ 1995;42:101– 105.

92. Schalch DS, Turman NJ, Marcsisin VS, Heffernan M,Guler HP: Short-term effects of recombinant humaninsulin-like growth factor I on metabolic control of pa-tients with type II diabetes mellitus. J Clin EndocrinolMetab 1993;77:1563– 1568.

93. Moses AC, Young SC, Morrow LA, O’Brien M, Clem-mons DR: Recombinant human insulin-like growthfactor I increases insulin sensitivity and improvesglycemic control in type II diabetes. Diabetes 1996;45:91–100.

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J465 Kentucky Clinic740 S. Limestone

Lexington, KY 40536–0284

E-mail: thrail@pop.uky.edu

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