Effects of combined recombinant insulin-like growth factor (IGF)-I and IGF binding protein-3 in type 2 diabetic patients on glycemic control and distribution of IGF-I and IGF-II among serum binding protein complexes.
BACKGROUND
Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined.


OBJECTIVE
The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment.


METHODS
A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125-2.0 mg/kg.d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets.


RESULTS
Fasting glucose was reduced in the groups that received either 1 (32 +/- 5% reduction) or 2 mg/kg.d (40 +/- 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 +/- 4% in the 1 mg/kg group and by 33 +/- 5% in the 2 mg/kg group compared with 18 +/- 4% in the placebo group. Total serum IGF-I increased between 2.0 +/- 0.3- and 5.7 +/- 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 +/- 4% and 64 +/- 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment.


CONCLUSIONS
Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.
Clemmons
D R
DR
Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7170, USA. endo@med.unc.edu
Sleevi
M
M
Allan
G
G
Sommer
A
A
D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II