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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 4 1181-1187
Copyright © 1997 by The Endocrine Society

Clinical Studies

Dual Hormonal Replacement Therapy with Insulin and Recombinant Human Insulin-Like Growth Factor (IGF)-I in Insulin-Dependent Diabetes Mellitus: Effects on the Growth Hormone/IGF/IGF-Binding Protein System1

Kathryn Thrailkill, Teresa Quattrin, Lester Baker, Jean Litton, Karen Dwigun, Melissa Rearson, Mary Poppenheimer3, Debbie Kotlovker3, David Giltinan3, Neil Gesundheit2 and Paul Martha, Jr.3

Department of Pediatrics, Duke University Medical Center (K.T., J.L.), Durham, North Carolina 27710; Department of Pediatrics, Children’s Hospital of Buffalo (T.Q., K.D.), Buffalo, New York 14222; and Department of Pediatrics, Children’s Hospital of Philadelphia (L.B., M.R.), Philadelphia, Pennsylvania 19104.

Address all correspondence and requests for reprints to: Kathryn Thrailkill, University of Kentucky, J465 Kentucky Clinic, 740 South Limestone Avenue, Lexington, Kentucky 40536-0284. E-mail: Thrail{at}pop.uky.edu


   Abstract
Top
 Abstract
Introduction
 Study Subjects and Methods
 Results
 Discussion
 References
 
Patients with insulin-dependent diabetes mellitus (IDDM) exhibit abnormalities in the GH/insulin-like growth factor (IGF) axis, including GH hypersecretion, low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels, and elevated IGFBP-1 levels. We recently demonstrated that in IDDM, dual hormonal replacement therapy with insulin plus recombinant human IGF-I (rhIGF-I) improves glycemic control better than insulin alone. To determine whether the addition of rhIGF-I therapy to insulin therapy also corrects GH/IGF/IGFBP abnormalities, we examined the effects of chronic combined rhIGF-I/insulin therapy on key components of the somatotropin axis. Forty-three pediatric IDDM patients were randomly assigned to groups receiving daily, fasting subcutaneous injections of placebo or rhIGF-I (80 µg•kg•day) for 28 days, while continuing to receive split-mix insulin therapy and intensive outpatient management. rhIGF-I therapy corrected IGF-I deficiency, suppressed IGFBP-1 levels (P < 0.01), and induced a trend toward lower circulating GH levels throughout the study. rhIGF-I therapy also induced an approximate 50% decrease in IGF-II levels (P < 0.001) and an approximate 70% increase in IGFBP-2 levels (P < 0.05). Serum IGFBP-3 levels, normal before treatment, remained normal during rhIGF-I administration. All effects were apparent during the first week of rhIGF-I therapy and persisted throughout treatment. Because improvements in the GH/IGF axis abnormalities and in glycemic control were greater in subjects receiving combined rhIGF-I and insulin, these data strongly support the concept that dual hormonal replacement in IDDM may offer distinct therapeutic advantages over insulin monotherapy.


   Introduction
Top
 Abstract
 Introduction
Study Subjects and Methods
 Results
 Discussion
 References
 
INSULIN-dependent diabetes mellitus (IDDM) is associated with perturbations of the GH/insulin-like growth factor (IGF) axis. Twenty four-hour integrated serum GH concentrations are elevated in IDDM, attributable to increases in both the frequency and peak amplitude of GH secretory pulses (1, 2). In addition, in patients with IDDM, GH responses to neurosecretory stimuli are exaggerated (3, 4).

Despite GH hypersecretion, basal levels of IGF-I, the principal mediator of GH activity, are low in IDDM (5, 6). Serum concentrations of IGF-binding proteins (IGFBPs), the carrier proteins that serve to transport IGFs in serum and to modulate their tissue-specific bioactivity, are also altered. Specifically, concentrations of IGFBP-3, the major serum transport protein for IGF-I, are decreased in serum of poorly controlled diabetics (7). In contrast, IGFBP-1, a protein that functions in the autocrine/paracrine modulation of IGF bioavailability, is increased in IDDM serum, and IGFBP-1 levels are inversely correlated with glycemic control (7, 8, 9, 10).

To date, our understanding of the mechanisms responsible for the GH-IGF axis abnormalities in IDDM is incomplete, though recent evidence strongly suggests that portal insulinopenia contributes to dysregulation of this axis. Down-regulation of hepatic GH receptor expression secondary to portal insulin deficiency could explain the apparent GH resistance observed in this disease. Consistent with this hypothesis, others have demonstrated a decrease in circulating concentrations of GH binding protein, a putative index of GH receptor number (11), in children with IDDM (12, 13). Furthermore, results from numerous studies suggest that insulin deficiency in the portal circulation contributes to elevated serum IGFBP-1 concentrations. Hepatic IGFBP-1 gene expression is increased in rat models of IDDM (14), and in vitro studies demonstrate that hepatocyte synthesis of IGFBP-1 is profoundly suppressed by insulin (15). Conversely, portal hyperinsulinemia, as occurs in patients with insulinomas, is associated with subnormal IGFBP-1 levels that correct following tumor excision (9). Peripheral insulin administration (16, 17) and intensification of insulin therapy (18) improve many of the IDDM-induced derangements of the GH/IGF/IGFBP axis. However, numerous studies demonstrate that peripheral insulin alone fails to normalize the abnormalities of the GH/IGF axis (19, 20), and further intensification of insulin replacement is precluded by hypoglycemic complications. In contrast, recent studies by Shishko et al. (21) demonstrated that infusion of insulin directly into the portal system results in normalization of the GH/IGF/IGFBP axis.

We have recently demonstrated that chronic daily administration of rhIGF-I to insulin-dependent diabetics improves glycemic control and reduces daily insulin requirements (22). These findings suggest that rhIGF-I may provide an important therapeutic adjuvant to insulin in the regulation of hyperglycemia. To determine whether rhIGF-I administration also reverses the abnormalities in the GH/IGF axis in IDDM, and to gain insight into the mechanism by which rhIGF-I confers this additional therapeutic benefit, we have now examined the effect of peripheral rhIGF-I supplementation on parameters of the GH/IGF/IGFBP axis in children with IDDM.


   Study Subjects and Methods
Top
 Abstract
 Introduction
 Study Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Forty three children and adolescents with type I diabetes mellitus followed at one of three study sites (Duke University Medical Center, Children’s Hospital of Buffalo, or Children’s Hospital of Philadelphia) were enrolled in this study. Informed consent was obtained from each participant, and the experimental protocol was approved by the investigational review board at each institution.

All patients were between 8 and 17 yr of age, had a medical history consistent with IDDM, and were medically managed with twice daily insulin therapy for at least 6 months before study entry. In addition, despite standard therapy, each patient was considered to have suboptimal glycemic control as evidenced by a glycosylated hemoglobin (HbA1) or hemoglobin A1c (HbA1c) that was greater than the mean for IDDM patients at the respective study site on a minimum of two occasions within 4 months before study entry [Duke: HbA1c >= 8.4% (normal range, 4.1–5.7%); Buffalo: HbA1 >= 10.4% (normal range, 6.8–8.8%); Philadelphia: HbA1c >= 8.2% (normal range, 3.8–6.0%)]. Patients with evidence of diabetic retinopathy, neuropathy, proteinuria, or a history of malignancy or concurrent chronic disease were excluded from participation. Individuals with treated hypothyroidism and normal thyroid function testing were eligible to participate.

Following enrollment, patients were randomly assigned to receive treatment with either rhIGF-I (diluted to a concentration of 5 mg/mL in citrate buffered saline, pH 6.0, supplied by Genentech, Inc., South San Francisco, CA) or placebo (citrate buffered saline). Investigators and patients were both blind about treatment category.

Methods

The study design included a 4-week lead-in period (designated pretreatment), followed by a 4-week treatment period. To collect baseline blood glucose data and assess pretreatment IGF/IGFBP parameters, all patients were evaluated biweekly during the 28-day pretreatment period (22). During the subsequent 28-day treatment period, study subjects received a daily, fasting sc injection (placebo or rhIGF-I) while continuing to receive twice daily split-mix (NPH and regular) insulin therapy and intensive outpatient management. RhIGF-I was administered at a dose of 80 µg/kg for patients with a weight <=120% of ideal body weight for height (IBWH) (as determined from Metropolitan Life tables) and at a dose of 80 µg/(1.2 x kg IBWH) for patients with a weight >=120% IBWH. Study drug injections were administered immediately following morning insulin injections using a separate syringe and a separate injection site.

Throughout both the pretreatment and treatment periods, blood glucose determinations were performed four times daily using a One Touch II home glucose monitor (Lifescan, Inc., Milpitas CA). In both treatment groups, NPH or regular insulin components were adjusted every 3–4 days to maintain fasting blood glucose readings between 80–120 mg/dL for patients older than 12 yr or 80–140 mg/dL for patients less than 12 yr, and 80–180 mg/dL at all other measurement times.

Random, midmorning venous blood samples were obtained on all patients before treatment (designated pretreatment samples). Midmorning, postprandial venous samples were also obtained 2–4 hr after study drug injection at each weekly visit during the 28-day treatment period. These samples were used for measurement of total IGF-I (22), free IGF-I (22), total IGF-II, GH, IGFBP-1, IGFBP-2, IGFBP-3, and the acid-labile subunit of IGFBP-3 (ALS). In addition, on treatment day 1, fasting blood samples were obtained immediately before the initial study drug injection for measurement of IGFBP-1 levels. Following specimen collection, serum was separated and frozen at -20 C pending batch assay.

IGF-II (Endocrine Sciences Laboratory, Calabasas Hills, CA) was measured by RIA, following acid-ethanol extraction to remove IGFs from serum IGFBPs. GH was measured by immunoradiometric assay (Hybritech, La Jolla, CA). IGFBP-1 and -2 were measured by Endocrine Sciences laboratory using a two-site chemiluminescent assay (IGFBP-1) or RIA (IGFBP-2). IGFBP-3 was measured by ELISA (Genentech, Inc.). Serum concentrations of ALS were analyzed in all patients by RIA (kindly performed by Dr. Robert Baxter, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia) and in a subset of 14 patients by immunoblot techniques described by Liu et al. (23), using a rabbit polyclonal antisera generated against a synthetic N-terminal 1–34 amino acid fragment of human ALS (Diagnostics Systems Laboratories, Webster, TX).

Statistical analysis

Between group differences were analyzed using a Student’s t test. Results are expressed as mean ± SEM and a P value <=0.05 was considered to indicate statistical significance.


   Results
Top
 Abstract
 Introduction
 Study Subjects and Methods
 Results
Discussion
 References
 
Thirty nine patients completed the study protocol. Four patients terminated early from the study. Two patients elected to withdraw from the study before completion of treatment. Of these patients, one was in the placebo group and the second was in the rhIGF-I treatment group. One patient in the rhIGF-I treatment group was discontinued because of protocol violation, and one patient in the rhIGF-I treatment group was discontinued because of an adverse event (22).

Demographic characteristics and baseline biochemical parameters of the two study populations are presented in Table 1Go. Patients ranged in age from 8–17 yr with a duration of diabetes ranging from 13–167 months. Study groups were comparable with respect to mean age, duration of disease, baseline weight, percent ideal body weight, and Tanner Stage distribution (Table 1Go). In addition, though randomization created a slight but statistically insignificant skewing of gender distribution between treatment groups, total enrollment of males and females was comparable (21 males/22 females). Pretreatment glycemic control, as evidenced by mean glycosylated hemoglobin and fasting blood glucose results (Table 1Go), was also comparable between groups.


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  		Table 1. Demographic summary statistics and baseline characteristics

 
We have previously demonstrated (22) that pretreatment IGF-I levels in both groups were in the low normal range for age. Daily sc administration of rhIGF-I resulted in a 2- to 3-fold increase in total serum IGF-I levels (22). In contrast, total IGF-I levels among placebo-treated patients remained unchanged from baseline levels. In both placebo and rhIGF-I-treated patients, total IGF-I levels did not correlate with individual HbA1 levels, either before or during treatment (Table 2Go). Free IGF-I levels, which were significantly depressed in diabetic patients, compared with age-matched controls, also increased into the normal range during rhIGF-I treatment (22).


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  		Table 2. Linear regression analyses1

 
Circulating levels of IGF-II, shown in Fig. 1Go, were at the lower limits of age-appropriate reference values before treatment (rhIGF-I = 261 ± 18 ng/mL vs. placebo = 254 ± 19 ng/mL). In contrast to the increase in serum IGF-I concentrations, rhIGF-I treatment induced a more delayed but sustained decrease in serum IGF-II concentrations to 50% of pretreatment values (Fig. 1Go). Because of the reciprocal change in IGF-II levels, the total molar IGF concentration (IGF-I + IGF-II) was not significantly different between groups on treatment day 28 (rhIGF-I, IGF-I + IGF-II = 57.8 ± 3.5 nmol/L vs. placebo = 64.8 ± 5 nmol/L).



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  		Figure 1. Effect of rhIGF-I on serum IGF-II levels. Serum samples obtained on days 1 (before and 180 min after injection), 7, 14, 21, and 28 were assayed for IGF-II, as detailed in Study Subjects and Methods. Placebo-treated patients are shown by open bars and rhIGF-I-treated patients are shown by hatched bars. Results are expressed as mean ± SEM. *, P < 0.05; **, P < 0.001.

 
Although neither fasting nor pharmacologically stimulated GH concentrations were assessed in this study, postprandial serum GH concentrations were measured and are shown in Fig. 2Go. As expected, postprandial GH levels were low in all patients before treatment. Nonetheless, though rhIGF-I-induced changes in GH levels did not reach statistical significance, rhIGF-I treatment was associated with a sustained trend toward suppression of circulating GH levels.



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  		Figure 2. Effect of rhIGF-I on serum GH levels. GH levels were measured before treatment and on days 1, 7, 14, 21, and 28. All treatment samples were obtained 2–4 h after study drug injection. Placebo-treated patients are shown by open bars and rhIGF-I-treated patients are shown by hatched bars. Results are expressed as mean ± SEM.

 
The effect of chronic rhIGF-I administration on serum IGFBP profiles is shown in Figs. 3–5GoGoGo. In both placebo and rhIGF-I treatment groups, mean IGFBP-3 levels (Fig. 3AGo) were in the normal range before treatment and remained constant throughout the study. Similarly, serum ALS concentrations measured either by RIA (Fig. 3BGo) or by immunoblot analysis (data not shown) did not change significantly over time.



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  		Figure 3. Effect of rhIGF-I on IGFBP-3 and ALS levels. IGFBP-3 (A) and ALS (B) levels were measured in placebo-treated (open bars) and rhIGF-I-treated patients (hatched bars) before treatment and on days 1, 7, 14, 21, and 28 of treatment, 2–4 h following daily study drug injection. Results are expressed as mean ± SEM.

 


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  		Figure 4. Effect of rhIGF-I on IGFBP-1 levels. Sequential serum samples were assayed for IGFBP-1 concentration during 28 days of treatment with either placebo (open bars) or rhIGF-I (hatched bars) according to procedures detailed in Study Subjects and Methods. On day 1, samples were obtained before treatment and 180 min following initial study drug injection. Results are expressed as mean ± SEM. *, P < 0.01.

 


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  		Figure 5. Effect of rhIGF-I on IGFBP-2 levels. Serum samples obtained on days 1 (before and 180 min after injection), 7, 14, 21, and 28 were assayed for IGFBP-2, as detailed in Study Subjects and Methods. Placebo-treated patients are shown by open bars and rhIGF-I-treated patients are shown by hatched bars. Results are expressed as mean ± SEM. *, P < 0.05.

 
As demonstrated in Fig. 4Go, mean fasting pretreatment IGFBP-1 levels were 62 ± 11 ng/mL (rhIGF-I) and 67 ± 9 ng/mL (placebo). Throughout the study, nonfasting IGFBP-1 levels in the placebo-treated group were approximately 50% higher than reported age-appropriate normal values [mean nonfasting IGFBP-1 = 19 ng/mL (ages 10–15.5 yr) (24, 25)]. On day 1, 180 min after the initial study drug injection and morning insulin dose, IGFBP-1 levels in placebo-treated patients were 35% of pretreatment values, reflecting an insulin-induced suppression of IGFBP-1. Treatment with rhIGF-I was associated with a more profound suppression of IGFBP-1 to <12% of pretreatment IGFBP-1 levels. In addition, IGFBP-1 levels were significantly lower among rhIGF-I-treated patients at all time points studied. IGFBP-1 levels were not correlated with individual glycosylated hemoglobin values in placebo or rhIGF-I-treated patients before or during treatment (Table 2Go). However, IGFBP-1 levels were inversely correlated with individual IGF-I levels in all patients, both before and during study drug administration (placebo or rhIGF-I) (Table 2Go).

IGFBP-2 levels (Fig. 5Go) were comparable in both groups before treatment (rhIGF-I = 337 ± 30 ng/mL vs. placebo = 347 ± 32 ng/mL). These mean values fall near the mean for age-appropriate serum concentrations of IGFBP-2 in normal children (25, 26). Following rhIGF-I administration, a 70% increase in IGFBP-2 levels was evident by day 7 of treatment. This increase in IGFBP-2 concentrations persisted throughout the treatment period. No correlation between IGFBP-2 and IGF-II was observed in either study group before or during rhIGF-I administration (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Study Subjects and Methods
 Results
 Discussion
References
 
Considerable evidence now exists to suggest that abnormalities in GH secretion and tissue-specific abnormalities in IGF-I bioavailability may contribute to many of the complications of diabetes. Historical studies both in humans and in animal models of diabetes describe the amelioration of biochemical abnormalities following hypophysectomy or the development of hypopituitarism (27, 28). In subsequent studies, the nocturnal increase in GH secretion has been implicated as the mechanism responsible for the dawn phenomenon of fasting hyperglycemia (29), and augmentation of GH production associated with the pubertal growth spurt likely contributes to the increase in insulin requirements of adolescents with IDDM (30). Tissue-specific abnormalities of IGF-I bioavailability caused by specific alterations in local production of IGFBPs have also been linked to the pathogenesis of diabetic nephropathy and diabetic retinopathy (31, 32). Therefore, long-term correction of somatotropin axis abnormalities in IDDM is an important consideration in the development of therapeutic modalities aimed at not only improving metabolic control but in preventing the pathological sequelae associated with IDDM.

Herein we demonstrated that chronic sc rhIGF-I administration to children with IDDM corrects many of the preexisting abnormalities in the GH/IGF/IGFBP axis. Specifically, 28 days of rhIGF-I therapy was associated with correction of IGF-I deficiency (22) and suppression of both IGFBP-1 and GH serum concentrations. In addition, IGFBP-3 and ALS levels, which were normal before therapy, remained unchanged following rhIGF-I therapy. However, concurrent with these trends, rhIGF-I treatment was associated with a reciprocal decrease in IGF-II levels and an increase in IGFBP-2 concentrations toward supraphysiological concentrations.

Our findings substantiate several previous studies examining the effects of short-term rhIGF-I administration in IDDM. Studies by Cheetham et al. (33) demonstrated that a single sc injection of rhIGF-I resulted in increased IGF-I levels, decreased overnight secretion of GH, and decreased insulin requirements in nine adolescent type I diabetics. Similarly, Bach et al. (34) examined the effect of 10-h sc infusions of rhIGF-I, given on 3 successive days to each of four diabetic adolescents. Again, they found that continuous rhIGF-I infusion increased serum IGF-I levels, reduced serum IGF-II levels, and suppressed GH secretion. However, in contrast to our findings, IGFBP-1 levels in their patients increased further following rhIGF-I infusion. The reasons for this discrepancy remain unclear. These investigators attributed the increase in IGFBP-1 to a marked reduction in insulin requirements during the 3 days of rhIGF-I infusion. However, regular insulin requirements in our patients also decreased by approximately 28% (P < 0.05) (22) during the 28-day treatment period, bringing this explanation into question. Differences in IGFBP-1 response may relate to several differences in study design, such as the use of a higher daily rhIGF-I dose (200 mg·kg·day) (34), which resulted in supraphysiological serum IGF-I levels. Furthermore, these authors measured fasting preinfusion IGFBP-1 levels, whereas we report postprandial, postinjection IGFBP-1 levels in the present study.

Our findings are also in keeping with studies of the effects of rhIGF-I replacement therapy in adults with GH receptor deficiency and GH resistance (35, 36) and rhIGF-I treatment in healthy adults (37). In these patients, rhIGF-I therapy resulted in increased serum concentrations of IGF-I and IGFBP-2 and decreased concentrations of IGF-II, without significant change in serum IGFBP-3 or ALS levels. However, in contrast to reports in normal volunteers demonstrating increases in IGFBP-1 following rhIGF-I infusion (38), our results demonstrate independent suppression of IGFBP-1 by rhIGF-I in states of portal insulinopenia. The strong inverse correlation between serum IGF-I and IGFBP-1 levels would support either a direct regulation of IGFBP-1 levels by IGF-I or an indirect suppression of IGFBP-1 by an rhIGF-I-induced restoration of hepatic insulin sensitivity. Indeed, several studies reported that administration of rhIGF-I to patients with disorders of extreme insulin resistance or NIDDM improves insulin sensitivity (39, 40). This relationship between IGF-I and IGFBP-1 appears to have been unmasked in the present study because the confounding suppressive effects of rhIGF-I on endogenous insulin production have been eliminated.

Physiological regulation of IGFBP-2 has been less well characterized. Recent evidence suggests that in vivo IGFBP-2 is regulated both by GH and insulin, with either hormone independently inhibiting IGFBP-2 expression (41, 42). Consistent with this hypothesis, baseline IGFBP-2 levels are elevated among untreated IDDM patients (19), likely reflecting the dual effects of portal insulin deficiency and GH resistance. However, we measured normal baseline IGFBP-2 levels in treated IDDM patients, comparable with previous reports of IGFBP-2 concentrations in insulin-treated IDDM patients (19). During rhIGF-I administration, IGFBP-2 increased significantly. This is similar to the induction of IGFBP-2 following rhIGF-I infusion observed by Zapf et al. (41) in healthy adults; moreover, in these patients, 35% of the infused IGF-I was found in association with the small molecular weight IGFBP fraction, presumably complexed to IGFBP-2. IGFBP-2 levels are also elevated and constitute the major IGFBP in sera from patients with extrapancreatic tumor hypoglycemia (41). In these patients, the majority of total serum IGF was recovered from the small molecular weight IGFBP fraction, suggesting that IGFBP-2 is increased in response to acute or chronic IGF excess, perhaps to buffer the extra hypoglycemic potential. Interestingly, in our patients, the rise in IGFBP-2 was sufficient to complex with an amount of administered rhIGF-I in excess of that necessary to return free IGF-I levels back into the age-appropriate normal range. Because the total molar IGF concentration did not change during rhIGF-I treatment, however, it appears that the reciprocal decline in IGF-II levels observed during rhIGF-I treatment reflects the displacement of IGF-II from binding proteins, with subsequent clearance from the circulation.

Several recent studies demonstrate that the somatotropin axis provides an important complementary pathway for the regulation of glucose homeostasis. Studies by Rajkumar et al. (43), using an IGFBP-1 transgenic mouse model, demonstrate that inhibition of IGF action by constitutive overexpression of IGFBP-1 results in fasting hyperglycemia and growth retardation. Similarly, Lewitt et al. (44) showed that chronic IGFBP-1 infusion increases blood glucose levels in rats and abolishes IGF-I-induced hypoglycemia in these animals. These studies emphasize the important contribution of IGF-I in maintaining euglycemia, a contribution that is lost in states of decreased IGF-I bioavailability caused by excesses of IGFBP-1. We have previously demonstrated that the use of chronic rhIGF-I therapy in insulin-treated type I diabetics is associated with an improvement in glycemic control, as evidenced by decreases in mean daily blood glucose and glycosylated hemoglobin measurements (22). Our current findings suggest that correction of IGF-I deficiency, suppression of high IGFBP-1 levels, and resultant increases in free IGF-I levels can explain the favorable glycemic outcome observed in these patients following rhIGF-I therapy.

Despite the improvement in glycemic control noted in these patients (22), we did not observe a correlation between individual HbA1 levels and individual IGF-I levels or IGFBP-1 levels in these patients (Table 2Go). The reasons for this remain unclear. Unlike HbA1 values, reference ranges for individual IGF-I levels are both age- and sex-dependent. In addition, individual IGF-I and IGFBP-l levels can change rapidly in response to rhIGF-I administration, whereas HbA1 levels are regulated slowly following a change in glycemic control. These differences may account for the lack of direct correlation between these parameters. Alternatively, this lack of correlation may suggest that the effects of rhIGF-I administration on glycemic control are indirect.

At this time, the potential long-term consequences of rhIGF-I therapy remain unknown. Correction of IGF-I deficiency and restoration of normal IGFBP levels in IDDM may be important not only for improving glycemic control but for preventing pathological sequelae associated with IDDM. For instance, diabetic nephropathy is characterized by an increase in kidney size which, in experimental rat models, is preceded by an increase in renal IGF-I levels (45). However, the early accumulation of IGF-I in the kidney is not associated with an increase in IGF-I messenger RNA expression but is associated with increased expression of IGF-I receptor and IGFBP-1 mRNA (29, 46), conditions that would allow for an increase in IGF-I uptake from the circulation. Such studies suggest that changes in IGF-I bioavailability and redistribution of free IGF-I into susceptible tissues may underlie certain microvascular complications of IDDM. Because IGF-I has been shown to down-regulate IGFBP-1 expression in extrahepatic sites, including human decidua and granulosa-luteal cells (47, 48), rhIGF-I treatment may similarly suppress high intrarenal IGFBP-1 levels, diminishing diabetes-associated IGF-I sequestration in the kidney. Furthermore, studies by Ishii et al (49) demonstrate that, despite persistent systemic hyperglycemia, impaired sensory nerve regeneration in diabetic rats can be prevented by local rhIGF-I infusion. Together, these studies suggest that correction of IGF-I deficiency and reestablishing normal IGF bioavailability in IDDM via rhIGF-I supplementation might alter the incidence of diabetic complications over and above the potential benefit of better glycemic control. Abnormalities of GH secretion may also contribute to the pathogenesis of diabetic complications. Thickening of glomerular basement membrane was demonstrated in streptozotocin-induced diabetic rats injected with GH (50), suggesting that overproduction of GH may contribute to diabetic nephropathy. Similarly, early studies demonstrating regression of diabetic retinopathy following hypophysectomy (51, 52) and later studies attributing a lack of severe retinopathy in patients with hemochromatosis-induced diabetes to blunted GH secretion (53), suggest a role for GH hypersecretion in diabetic eye disease. Therefore, suppressive effects of rhIGF-I on GH secretion may also prove beneficial in lessening the incidence of microvascular complications in this disease.

Clearly, establishing the efficacy of rhIGF-I therapy in IDDM will require longer term studies examining the effect of rhIGF-I administration in a more heterogeneous population of patients with IDDM. Moreover, because the role of GH, IGFs, and IGFBPs in the pathogenesis of diabetic complications has yet to be fully defined, there are potentially independent risks of IGF-I exposure that must be monitored carefully in future studies of rhIGF-I therapy in diabetes. Nonetheless, our initial findings, presented both here and in a previous report (22), provide promise that adjunctive rhIGF-I therapy in IDDM may prove more beneficial than insulin monotherapy by simultaneously improving glycemic control, correcting somatotropin axis abnormalities, and possibly lessening the incidence of complications in this disease.


   Acknowledgments
 
We thank Dr. Robert Baxter for measurement of ALS in these patients. We are also grateful to Ms. Delila Serra for technical assistance.


   Footnotes
 
1 This work was supported by Genentech, Inc. Back

2 Current address: Vivus Inc., Menlo Park, California 94025 Back

3 Current address: Genentech, Inc., South San Francisco, California 94080. Back

Received October 18, 1996.

Revised January 3, 1997.

Accepted January 7, 1997.


   References
Top
 Abstract
 Introduction
 Study Subjects and Methods
 Results
 Discussion
 References
 

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