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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3117-3124
Copyright © 1999 by The Endocrine Society

Original Studies

Suppression of Insulin Oversecretion by Subcutaneous Recombinant Human Insulin-Like Growth Factor I in Children with Congenital Hyperinsulinism Due to Defective ß-Cell Sulfonylurea Receptor1

Lorraine E. Levitt Katz, Robert J. Ferry, Jr., Charles A. Stanley, Paulo F. Collett-Solberg, Lester Baker and Pinchas Cohen

Division of Endocrinology/Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania (L.E.L.K., R.J.F., C.A.S., L.B.), Philadelphia, Pennsylvania 19104-4399; the Division of Pediatric Endocrinology, Department of Pediatrics, Duke University Medical Center (P.F.C.-S.), Durham, North Carolina 27710; and the Division of Pediatric Endocrinology, Department of Pediatrics, University of California (P.C.), Los Angeles, California 90095-1752

Address all correspondence and requests for reprints to: Lorraine E. L. Katz, M.D., Division of Endocrinology/Diabetes, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Room 8416 Main, Philadelphia, Pennsylvania 19104-4399. E-mail: katzl{at}email.chop.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the ß-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 µg/kg, sc, every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 ± 11.1 vs. 6.3 ± 2.2 µIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 ± 0.7 vs. 1.2 ± 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age (1). HI results from heterogeneous defects of glucose-insulin coupling by the pancreatic ß-cell. These defects include autosomal recessive mutations of the ß-cell sulfonylurea receptor gene (SUR1) (2) or the SUR-associated, inward-rectifying, potassium channel (subunit KATPir6.2) (3) as well as autosomal dominant mutations of ß-cell glutamate dehydrogenase (GLUD1) (4, 5) or glucokinase (6). Many cases of HI remain idiopathic. Most HI patients present as newborns who are large for gestational age, with the onset of symptomatic hypoglycemia by the second day of life (7). The SUR1/Kir6.2 defects appear to be the most common cause of HI (8, 9) and to comprise the most clinically severe phenotype (10, 11).

If not diagnosed early and treated aggressively, HI has the potential to result in permanent brain damage from frequent neonatal hypoglycemia (12, 13). Moreover, the hypoglycemia associated with HI is exceedingly difficult to manage. To avoid hypoglycemia, patients typically require glucose infusions in excess of 20 mg/kg·min, reflecting the increased rates of glucose utilization induced by excessive insulin. Furthermore, the elevated insulin level inhibits the production of alternative fuels such as ketones, which can protect the brain during hypoglycemic stress. Unfortunately, current medical and surgical therapies for congenital HI are suboptimal.

Diazoxide treatment for children with SUR1/Kir6.2 defects is ineffective, because diazoxide acts via the SUR. Octreotide and other somatostatin analogs have been used with some success, but typically cannot prevent the need for sub- to near-total (95–99%) pancreatectomy (7, 14). Pancreatectomy carries significant surgical morbidity and mortality, primarily due to the risks of local tissue injury and development of diabetes mellitus (15). Calcium channel antagonists have been used with limited success to suppress insulin secretion (16); however, these agents appear useful only for the less severe (autosomal dominant and focal) forms of HI (17). Other agents, including glucagon, epinephrine, propranolol, phenytoin, glucocorticoids, uncooked corn starch, GH, and streptozotocin, have been attempted for HI, but none has proven effective for long term management (8). The risk of permanent brain damage from persistent hypoglycemia underscores the need for novel, improved therapies (13).

Insulin-like growth factor I (IGF-I) is a 7-kDa peptide hormone belonging to the relaxin/insulin family of peptide hormones. IGF-I binds to the type 1 IGF receptor and, with lesser affinity, to the insulin receptor. The effects of IGFs are modulated by IGF-binding proteins (IGFBPs), which are secreted by various cell types and are found in most biological fluids (18).

Physiological doses of IGF-I potently inhibit insulin secretion in vitro (19, 20, 21). This inhibition also occurs in normal human subjects (22) and patients with GH receptor insensitivity (23) and hyperinsulinemia due to insulin resistance (24, 25). We hypothesized that recombinant human IGF-I (rhIGF-I) would inhibit insulin secretion and ameliorate the fasting hypoglycemia associated with HI. We performed an open label trial of sc rhIGF-I in children with congenital HI due to defective ß-cell SUR.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients’ characteristics and study design

The study group was recruited from children with congenital HI diagnosed and followed at the Endocrine Clinic of Children’s Hospital of Philadelphia. HI was diagnosed by demonstrating evidence of fasting hypoglycemia (serum glucose, <50 mg/dL), with concomitant inadequate suppression of insulin (insulin, >2 µIU/mL) and/or C peptide (>2.2 ng/mL), in the absence of pituitary or adrenal dysfunction. Subjects with HI also had evidence of increased insulin action at the end of a controlled fasting study, such as increased glucose utilization, suppressed lipolysis and/or ketogenesis, or an inappropriate response to glucagon stimulation (i.e., a rise of serum glucose from baseline by 30 mg/dL in response to 0.5–1 mg glucagon, iv/im, administered while the patient was hypoglycemic). The additional entry criterion for this trial was suboptimal glycemic control, defined as inability to fast at least 10 h while maintaining serum glucose above 60 mg/dL. Exclusion criteria included suspected insulinoma, history of malignancy, age under 1 month, renal dysfunction, anemia, evidence of intravascular volume depletion, and fever or other evidence of acute infectious disease. All parents gave written informed consent, and all children above the age of 2 yr gave verbal or written assent. This study was approved by our institutional review board.

The details of the study group are outlined in Table 1Go. Genotyping of subjects 1–5 has been previously reported (2, 26, 27). These five subjects possess at least one of the two known SUR1/Kir6.2 mutations, which together account for about 88% of the HI alleles identified in affected Ashkenasi Jewish patients (2). Subjects 6–8 lack known SUR1/Kir6.2 mutations, but were clinically unresponsive to diazoxide, a medication that acts via the SUR. Subject 9 had HI with hyperammonemia due to a dominant GLUD1 mutation (4, 5). The standard medical regimen for HI patients includes frequent feedings, diazoxide, octreotide, glucagon, and/or sub- to near-total (95–99%) pancreatectomy. Medical treatments were continued during the study.


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  		Table 1. Characteristics of patients

 
Subjects were admitted to the General Clinical Research Center at Children’s Hospital of Philadelphia under an open label protocol in which they served as their own controls. We did not employ a blinded, placebo-controlled methodology in our study because no family consented to the possibility of their child receiving an injected placebo. Subjects underwent baseline 24-h monitoring on their home regimens followed by a supervised fast on day 2 and a controlled Sustacal mixed meal challenge on day 3 (28). The start of each fasting study was defined as 30 min after the last bite of the meal. Fasting studies in older subjects were started after the dinner meal at approximately 2000 h. Infants under 6 months age experienced shorter fasting protocols due to safety concerns (i.e. to avoid unnecessary hypoglycemia), so their fasting studies started after breakfast at approximately 0800 h. The controlled fasting study was terminated when serum glucose dropped below 50 mg/dL or when the child had symptoms consistent with hypoglycemia (even if euglycemic). At 0800 h on the morning after each control fasting study (before rhIGF-I), each subject was given a standard mixed meal Sustacal challenge by mouth or gastrostomy (28). Whole blood glucose, serum insulin, and C peptide levels were determined every 30 min for 3 h. On the evening after the baseline Sustacal protocol, patients received the first dose of rhIGF-I. rhIGF-I was administered as 40 µg/kg·dose, sc, at 2000 h, 20 min before the evening snack, and at 0800 h, 20 min before the second Sustacal administration on day 3. rhIGF-I was continued that evening and the following morning for a total of four doses. The controlled fast was repeated on days 3 and 4.

When not under study patients received their usual meals and snacks. Patients received frequent glucose and safety monitoring at all times.

Source of drugs

Pharmacia Peptide Hormones (Kalamazoo, MI) generously provided rhIGF-I. Sustacal was purchased from Mead Johnson Nutritionals (Evansville, IN).

Assays

Serum glucose was measured by a glucose oxidase method (glucose analyzer, YSI, Inc., Yellow Springs, OH). Serum insulin was determined by microparticle enzyme immunoassay (Abbott IMx MEIA System, North Chicago, IL), which has a sensitivity of 1.0 µIU/mL, cross-reacts 0.005% with proinsulin (at 103 ng/mL), and does not cross-react with either C peptide (at 103 ng/mL) or glucagon (at 106 pg/mL). IGF-I, bilirubin, hemoglobin, and triglycerides do not interfere with this insulin assay. Serum C peptide was assayed by immunochemiluminometry (Endocrine Sciences, Inc., Calabasas Hills, CA) with a sensitivity of 0.1 ng/mL. Serum IGFBP-1 was measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Plasma free (nonesterified) fatty acids (FFA) were determined enzymatically (Half-Micro Test, Roche Molecular Biochemicals, Mannheim Germany). Plasma ß-hydroxybutyrate (BOB) was assayed enzymatically (29). Serum IGF-I and glucagon levels were measured by RIA (Endocrine Sciences, Inc.). This IGF-I RIA has a sensitivity of 20 ng/mL.

Statistical analysis

Main outcome measures included levels of insulin, C peptide, IGFBP-1, FFA, and BOB at the beginning and end of controlled fasting studies. Data were analyzed by paired, two-tailed, Mann-Whitney U tests (InStat for Macintosh, version 2.00, GraphPad Software, Inc., San Diego, CA) comparing values before and during rhIGF-I therapy. Control values were determined before the administration of rhIGF-I to eliminate possible confounding effects of prior exposure to the drug. Serum IGF-I levels before and immediately after rhIGF-I administration were analyzed by paired, two-tailed, Student’s t test. Summative numerical and graphical data are displayed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The individual responses to fasting studies performed before and with rhIGF-I administration are shown in Table 2Go. The mean blood glucose at the start of fasting did not change significantly before rhIGF-I compared to that during rhIGF-I treatment (124 ± 19 mg/dL without vs. 101 ± 14 mg/dL with rhIGF-I; P = 0.46). Nevertheless, at the start of fasting, rhIGF-I significantly lowered the mean serum insulin level by 70% (21.0 ± 11.1 vs. 6.3 ± 2.2 µIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 ± 0.7 vs. 1.2 ± 0.6 ng/mL; P < 0.04; Fig. 1Go). Suppression of C peptide and insulin levels persisted throughout the fast (data not shown).


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  		Table 2. Outcome measures of fasting studies before and during rhIGF-I therapy

 


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  		Figure 1. At the start of fasting, rhIGF-I significantly lowered the mean serum insulin level by 70% (21.0 ± 11.1 vs. 6.3 ± 2.2 µIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 ± 0.7 vs. 1.2 ± 0.6 ng/mL; P < 0.04).

 
Mean blood glucose was lower at the end of fasting compared to that at the start, but did not differ significantly before rhIGF-I compared to that during rhIGF-I treatment (48.1 ± 4.0 mg/dL without vs. 46.3 ± 4.0 mg/dL with rhIGF-I; P = 0.25). At the end of fasting, mean insulin and C peptide levels were not significantly different during rhIGF-I treatment. Specifically, the mean insulin level was 3.5 ± 1.0 µIU/mL without vs. 2.2 ± 0.6 µIU/mL with rhIGF-I (P = 0.11), and the mean C peptide level was 0.67 ± 0.12 ng/mL without vs. 0.54 ± 0.11 ng/mL with rhIGF-I (P = 0.25). Analyzing the fasting studies of the SUR1-/- patients only, by excluding patient 9 with the GLUD1 defect, did not alter the trend or statistical significance of any of the results. The trends observed were not changed by comparing the data from those who had undergone pancreatectomy to those who had not.

Serum IGFBP-1 and plasma FFA and BOB levels did not change significantly during rhIGF-I therapy at the end of fasting (Table 2Go). A representative display of one patient’s response to rhIGF-I therapy during fasting is shown in Fig. 2Go. Although most patients had shorter fasting duration during rhIGF-I treatment, the mean duration of fasting did not change significantly with rhIGF-I (9.4 ± 3.4 h without vs. 8.2 ± 3.0 h with rhIGF-I; P = 0.63). Serum IGF-I levels rose from baseline after the initial rhIGF-I dose by 56% at 30 min (P < 0.01) and by 85% at 120 min (P < 0.02; Table 3Go). Excluding case 5, who was receiving exogenous glucagon, and case 4, for whom levels were not available, we detected no significant differences in serum glucagon levels in the other seven cases at the end of fasting (80 ± 13.1 pg/mL without vs. 86.7 ± 27.8 pg/mL with rhIGF-I; P = 1.0; normal fasting values, 50–150 pg/mL).



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  		Figure 2. A representative display of one child’s responses (Case 1) to rhIGF-I therapy during fasting (A) and after Sustacal challenge (B).

 

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  		Table 3. Serum IGF-I levels after the initial dose of rhIGF-I

 
Table 4Go summarizes the results of a mixed meal Sustacal challenge performed on five patients with SUR1 defects. Outcome variables included the peak and nadir levels of serum insulin, serum C peptide, and whole blood glucose within 3 h of the Sustacal challenge. No significant differences were observed in these variables between control conditions and rhIGF-I treatment, although serum insulin and C peptide levels were suppressed during rhIGF-I treatment. A representative display of one child’s response to rhIGF-I therapy after Sustacal challenge is shown in Fig. 2Go.


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  		Table 4. Outcomes after a mixed meal Sustacal challenge

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
As the most common cause of persistent hypoglycemia in infancy, congenital HI continues to pose therapeutic challenges for the clinician. The majority of children with HI lack effective glucose-insulin coupling via the SUR; therefore, they oversecrete insulin inappropriately while hypoglycemic. Despite modern medical therapy, most of these children require near-total pancreatectomy to ameliorate their hypoglycemia. Several lines of evidence suggested that rhIGF-I could be a new therapy for HI.

Serum glucose elevations during rhIGF-I therapy in normal adults provided indirect evidence of insulin suppression by rhIGF-I and were observed at a dose of 40 µg/kg·day given sc once daily (30, 31), half the total daily dose used in our study. Infusion of rhIGF-I to a child with GH receptor insensitivity (Laron dwarf) resulted in some increases in serum glucose (32). In healthy adult volunteers, Wilton et al. observed that rhIGF-I given once daily (40 µg/kg, sc) lowered postprandial insulin levels, but did not change fasting insulin levels (33). Finally, insulin infusion at a high rate suppressed its own secretion (34, 35), an effect mediated perhaps by insulin binding to the type 1 IGF receptor.

Exogenous IGF-I inhibits insulin secretion by human fetal islets in vitro (20) and clinically in patients (23, 24, 25). In Laron dwarfs and burn patients, continuous infusion of rhIGF-I at 20 µg/kg·h (480 µg/kg·day) suppressed insulin more effectively (36, 37) than intermittent sc administration at 240 µg/kg·day divided twice daily (38), suggesting that the effect depends directly upon the dose and/or method of administration (i.e. rate of absorption). However, the threshold dose or serum level of IGF-I required for this insulin inhibitory effect has not been clearly identified.

We have directly demonstrated that rhIGF-I given at a dose of 40 µg/kg·dose, sc, twice daily inhibits insulin over secretion in children with HI due to defective SUR. These results are intriguing, as most of our patients had less than 5% of the pancreas intact (after pancreatectomy). Our results did not change when we compared surgical to nonsurgical patients in our study. A lower ß-cell load after pancreatectomy may allow greater saturation of type 1 IGF receptors in the remaining islets. Alternatively, with more ß-cells available to respond before surgery, one might expect an even greater reduction of insulin secretion from the baseline, although such differences were not observed in our small groups. Indicators of lipolysis did not change significantly during controlled fasts with rhIGF-I treatment, although the trend was for a slight rise in ketone production, suggesting that rhIGF-I could reverse hyperinsulinemic suppression of lipolysis. rhIGF-I has been shown to inhibit lipolysis in vivo (39).

The mechanism of IGF-I inhibition of insulin secretion is not well understood. ß cells possess the type 1 IGF receptor (40, 41). rhIGF-I appears to have direct effects on ß-cells (19, 42) and inhibits glucose-stimulated insulin secretion without impairing glucose metabolism in normal adults (43). IGF-induced inhibition of insulin secretion may be mediated via somatostatin, as infusion of rhIGF-I at 24 µg/kg·h inhibited both insulin and glucagon secretion in normal adults (44). Moreover, low dose rhIGF-I given as a continuous sc infusion at 5–10 µg/kg·h to adult volunteers decreased plasma insulin, C peptide, and glucagon concentrations without affecting proteolysis or protein anabolism (45). None of the second messenger pathways known to be activated by the type 1 IGF receptor has been shown to directly regulate insulin transcription or expression. However, binding of IGF-I to its receptor does increase glucose uptake by the cell through up-regulation of cell surface glucose transporters (46, 47, 48). One alternative explanation for our results in this study is that rhIGF-I indirectly lowered insulin secretion by decreasing ambient glucose concentrations. However, glucose levels did not differ during the two phases of the study, suggesting a direct effect. This is in keeping with the demonstration in normal adults that rhIGF-I inhibits insulin secretion when glucose levels are kept constant during glucose clamping (43).

The SUR is a key regulator of insulin secretion by the ß-cell. With intact glucose transport, an increase in extracellular glucose results in increased intracellular ATP production. Increased intracellular ATP causes closure of the SUR-associated KATP channel. The resulting membrane depolarization activates voltage-dependent calcium channels, leading to increased intracellular calcium and, in turn, increased insulin secretion. Our data from SUR-defective subjects demonstrate the novel finding that IGF inhibition of insulin secretion is not mediated via SUR, suggesting an endocrine effect of rhIGF-I on the ß-cell, presumably through its type 1 IGF receptor.

A major goal of our study was to improve glycemic control or the duration of fasting tolerance for these brittle patients. Patients’ fasting tolerance varied widely in response to rhIGF-I. The most likely explanation for these observations is that fasting duration can be improved only with more effective suppression of insulin secretion. A higher dose than 80 µg/kg·day or an alternative route of administration (i.e. continuous sc infusion) might be more optimal. Unfortunately, children with defective SUR have dysregulated insulin secretion, not simply insulin oversecretion, so that insulin levels may not be absolutely elevated as in most hyperinsulinemic conditions. Rather, insulin secretion is not appropriately turned off during fasting conditions. Therefore, even with rhIGF-I therapy, insulin levels at the end of fasting remained inappropriately elevated (i.e. >2 µIU/mL). The dysregulation of insulin secretion, which is central to this condition, may account for the minimal response to rhIGF-I that we observed. Alternatively, the minimal improvement in fasting duration that we observed may be due to the insulin-like activity of IGF-I. A lower dose of rhIGF-I might inhibit insulin secretion without additive insulin-like effects (45, 49). It is also possible that rhIGF-I suppressed GH, leading to the lack of improvement in fasting duration (50). Although glucagon suppression by rhIGF-I has been reported (45), our results did not indicate that glucagon was suppressed. Variations in eating habits between the serial fasts could affect fasting duration. A child who ate poorly after several days in the hospital might not be able to fast as long as when in a well-fed state earlier in the admission.

Serum IGFBP-1 is a protein whose secretion is acutely inhibited by insulin and is thought to be the main regulator of free IGF-I levels during daily feeding and fasting cycles (51). IGFBP-1 levels did not change significantly in our patients, although the trends observed were slight rises both at baseline and at the end of the fast during rhIGF-I therapy. This is consistent with our previous data that IGFBP-1 levels are suppressed in children with hyperinsulinism (51). Thus, we cannot attribute the lack of effect on fasting duration to IGF sequestration by rising IGFBP-1 levels (52).

Side-effects commonly reported with short term (<3 months) administration of rhIGF-I include hypoglycemia (53), weight loss (54) or gain (55), hypophosphatemia (56), arthralgias/myalgias (57), protein anabolism (58, 59), and increased bone turnover (60, 61). Other effects noted in adults include fluid retention, headache, tachycardia, and orthostatic hypotension (62, 63, 64). With a mixed meal Sustacal challenge we observed no significant differences in postprandial glucose excursion or insulin action as a result of rhIGF-I. No subject or family in our study reported adverse effects from rhIGF-I therapy apart from transient local discomfort associated with the sc injections.

IGF-I-induced hypoglycemia appears to occur most often during continuous iv infusion of rhIGF-I (65), with the maximal hypoglycemic effect occurring immediately after administration by continuous infusion (66). IGF-I-induced hypoglycemia in children is dose dependent (67) and diminishes after chronic administration at doses of 80–120 µg/kg·day given sc in two divided doses (68), presumably from down-regulation of type 1 IGF receptors. The half-life of exogenous rhIGF-I in healthy adults has been reported to be between 20–30 min (69). As we did not use radiolabeled rhIGF-I, we cannot define the half-life of rhIGF-I in our study. Moreover, as our subjects were mostly children, the limits on phlebotomy volumes prevented us from frequent blood draws, an alternative method for determining drug half-life. In our study, serum IGF-I levels nearly doubled within 2 h of rhIGF-I administration, yet these elevated levels did not cause hypoglycemia, and most patients fasted longer than 2 h during rhIGF-I therapy.

The lack of hypoglycemia in our study is consistent with the results of other investigators (22, 33, 70). Guler et al. demonstrated in two healthy adults that rhIGF-I infused sc at 20 µg/kg·h (480 µg/kg·day) was associated with decreased fasting C peptide levels despite normal blood glucose and fasting insulin levels (22). In children with leprechaunism, in whom postinsulin receptor signaling mechanisms are defective, supraphysiological rhIGF-I (40–110 µg/kg·h, iv, or 1600 µg/kg·day, sc) suppressed insulin secretion without lowering blood glucose, suggesting that rhIGF-I-induced hypoglycemia requires intact postreceptor signaling (71, 72) because the type 1 IGF and insulin receptors share at least one intracellular, second messenger system (73, 74).

Our study is limited by its small number of subjects. Small sample sizes can either overestimate small effects of therapy or underestimate its true effects (by not achieving statistical significance). Three patients (nos. 4, 5, and 8) were receiving octreotide, a long acting somatostatin analog that acts via somatostatin receptors to inhibit insulin secretion. Although octreotide could have compounded or masked IGF-mediated suppression of insulin secretion, we still detected significant inhibition with rhIGF-I at the beginning of fasting. Furthermore, we accounted for the octreotide effect by leaving the octreotide dosing unchanged throughout these studies. As the duration of insulin inhibition by rhIGF-I in these patients was not known at the outset, we elected not to randomize the order in which subjects received rhIGF-I or underwent control conditions (e.g. monitored fast without rhIGF-I). Although such randomization might have reduced the confounding impacts of hospitalization, appetite change during hospitalization, etc., we would have introduced the possibility of unrecognized long term effects of rhIGF-I on glycemic control during control conditions whenever rhIGF-I treatment preceded control conditions.

In conclusion, we have reported the only series of congenital HI patients treated with rhIGF-I as well as one of the larger pediatric trials to date. We have demonstrated that rhIGF-I safely inhibits in vivo insulin secretion via mechanisms independent of ß-cell SUR1 and perhaps GLUD1. The most likely pathway for this inhibition is via the type 1 IGF receptor. rhIGF-I is unlikely to be an effective monotherapy (when given at 40 µg/kg, sc, twice daily) for the severe form of congenital hyperinsulinism due to SUR1 or Kir6.2 mutations. However, at different doses or via continuous infusion, rhIGF-I may provide synergistic inhibition of insulin secretion when combined with agents that inhibit insulin secretion via IGF-independent mechanisms. Elucidating the mechanism(s) by which IGF-I inhibits insulin secretion has importance for further clinical studies of this agent in patients with hyperinsulinism and other conditions, including diabetes mellitus.


   Footnotes
 
1 This work was supported by FDA Grant RO1–01181 (to P.C.), General Clinical Research Center Grant MO1-RR-00240 (to C.A.S., L.B., and P.C.), an NIH Clinical Associate Physician Award (to L.E.L.K.), NIH Grant T32-DK-07314 (to R.F.), and fellowship grants from Eli Lilly & Co. and Pharmacia & Upjohn, Inc. (to R.F. and P.F.C.-S.). Parts of the manuscript were presented in abstract form at Annual Meetings of The Endocrine Society (the 77th Meeting in Washington, D.C., June 1995, and the 81st Meeting in San Diego, CA, June 1999). Back

Received January 22, 1999.

Revised May 6, 1999.

Accepted May 18, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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