THE DAWN PHENOMENON IN ADOLESCENTS WITH INSULIN-DEPENDENT DIABETES-MELLITUS - POSSIBLE CONTRIBUTION OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-1

OBJECTIVE Insulin resistance increases during adolescence, and is exag gerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-l) may contr ibute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedbac k control, leading to increased insulin resistance and (b) lack of ins ulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the 'dawn phenomenon' is assessed. DESIGN The two possi ble mechanisms were studied during the dawn rise of glucose in puberta l adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen through out.SUBJECTS Twenty-two diabetic adolescent subjects, aged (mean +/- S EM) 14.0 +/- 0.4 years, duration of IDDM 7.9 +/- 0.8 years, were recru ited. Pubertal status was: group 1 (breast stage 1-2; testicular volum e < 4-8 mi) 3 male and 4 female, group 2 (breast stage 3; testicular v olume 10-12ml) 0 male 4 female, group 3 (breast stage 4-5; testicular volume 15-25ml) 4 male and 7 female. Height standard deviation score ( mean +/- SD) (-0.02 +/- 0.99) and daily insulin dose (50.4 +/- 3.1 U/d ay) did not change between studies. There were no differences in HbA1 (study A 11.26 +/- 0.45%, study B 11.09 +/- 0.45%). METHODS The subjec ts were admitted for the two studies 0.3 +/- 0.03 years apart. Blood s amples were taken via an indwelling cannula every 20 minutes between 1 900 and 0700 h. MEASUREMENTS GH was assayed every 20 minutes, IGFBP-1, glucose and free insulin every hour and IGF-I at 0700 h. GH, IGFBP-1, IGF-l and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. T he relations between the dawn rise in glucose and the changes in IGFBP -1, GH and free insulin were examined by multiple linear regression an alysis. RESULTS Serum IGFBP-1 levels rose overnight in the two studies (study A, from 9 +/- 1 at 2200 to 59 +/- 9 mu g/l at 0700 h; study B, from 10 +/- 1 at 2100 to 64 +/- 14 mu g/l at 0700 h) whilst insulin l evels fell from 47 +/- 5 at 2200 to 16 +/- 2 mU/l at 0700h (study A) a nd from 45 +/- 5 at 2000 to 14 +/- 2 mU/l at 0700 h (study B). Glucose levels fell from 16.0 +/- 1.0 to 9.3 +/- 0.9 mmol/l at 0400 h, and th en rose to 11.9 +/- 1.1 mmol/l at 0700h during study A, and from 13.4 +/- 1.3 to 10.1 +/- 1.1 mmol/l at 0400 h and then rose to 13.5 +/- 1.0 mmol/l at 0700h during study B. There were no differences in GH secre tion between studies (mean GH levels (mean+/-SD) (study A, 15.7 +/- 6. 6 mU/l; study B, 16.2 +/- 7.1 mU/l; correlation within subjects betwee n studies r = 0.77, P < 0.001), sum of GH peaks (study A, 189.9 +/- 90 .3 mU/l; study B, 185.8 +/- 100.2 mU/l; r = 0.57, P = 0.006)). Mean GH levels varied with pubertal stage (group 1, 12.1 +/- 1.5 mU/l; group 2, 23.3 +/- 2.1 mU/l; group 3, 15.3 +/- 1.2 mU/l). Serum IGF-I levels were not different (study A, 203 +/- 12 mu g/l; study B, 218 +/- 13 mu g/l). REGRESSION ANALYSIS The change in plasma glucose between 0200 a nd 0700 h in both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose = 7.87 +/- 5.32 log IGFBP-1 (P = 0.0001) - 5.05 log free insulin (P = 0.0001) - 1.44 log GH (P = 0.004); R(2) = 72%). Mean overnight GH levels did not pred ict the morning rise in plasma glucose. CONCLUSION The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subj ects with IDDM and this was a consistent finding in the two studies. T his relation was additive to the effect of insulin deficiency. No posi tive relation was noted between GH secretion and glucose levels. These findings support the hypothesis that the increased GH secretion in ID DM is a marker of IGF-I deficiency rather than a direct causal factor in the increase in insulin resistance. The IGFs may therefore have a d irect role in glucose homeostasis via the 'free' fraction of circulati ng IGFs, the availability of which may be modulated by changes in IGFB P-1 levels.