Original article:
Determinants of growth in diabetic pubertal subjects. Zachrisson I, Brismar K, Hall K et al. Diabetes Care 1997; 20/8: 1261-5.

Summary
The authors examined the relationship between total insulin-like growth factor (IGF)-I concentration, metabolic control and growth in pubertal diabetic subjects in a cross-sectional study comprising a cohort of 72 well-controlled diabetic patients who had been treated for more than 2 years, the majority with four or more daily insulin injections. Blood samples for the measurement of total IGF-I, IGF-binding pro-tein (IGFBP)-1, insulin, HbA 1c and dehydroepi-androsterone sulfate (DHEA-S) were drawn in the afternoon between 1500 and 1600 h.
The authors expressed total IGF-I levels as IGF-I SD score and observed an insufficient increase in IGF-I throughout pubertal development. Poor metabolic control was the most important determinant of this deviation, HbA 1c being inversely correlated to the IGF-I SD score. DHEA-S increased with advancing pubertal stage. IGFBP-1 levels correlated negatively with insulin levels and were not influenced by the other variables. In spite of the blunted increase of total IGF-I concentrations during pubertal development, normal growth and target height were preserved in these children. IGF-I SD score was the only determinant of growth rate, but since IGF-I SD score correlated to HbA 1c , metabolic control was postulated to be an important factor in the attainment of target height.

Comment
In this paper the authors clearly demonstrated that the rise in total IGF-I concentration during puberty is insufficient even in fairly well controlled diabetes. The term IGF-I SD score was introduced to describe for each pubertal stage the deviation in comparison with controls.
Total IGF-I concentration does not seem to be a good determinant of growth in diabetic subjects since normal growth is preserved. This suggests the presence of normal amounts of bio-available free IGF-I to the receptors. Indeed, low free IGF-I values have been observed in diabetic children before treatment, which have tended to normalize during insulin therapy [1]. Since more than 95% of the amount of IGF-I in serum is bound to specific binding proteins (-IGFBPs), the reduction in total IGF-I in diabetic children corroborates a decrease in one or more IGFBPs.
IGFBP-3, which is the major circulating IGFBP, is diminished in diabetic adolescents and does not rise with advancing puberty [2, 3]. One study [4] revealed no differences in IGFBP-3 levels with controls, independent of the degree of metabolic control. The proteolysis of IGFBP-3 is increased during insulinopenia [5] and may also alter the bioavailability of free IGF-I. Finally, IGFBP-1 is shown to be inversely correlated to insulin concentration, as reported in this study and during overnight profiles [6]. All these factors, including growth hormone, may interact in the IGF-I/growth axis during puberty. The authors underline the importance of adequate insulin substitution during puberty, leading to normal IGFBP-1 levels and thus making more free IGF-I available to the tissue receptors.

References
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2. Batch JA, Baxter RC, Werther G. Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes. J Clin Endocrinol Metab 1991; 73: 964-8.
3. Acerini CL, Clayton KL, Hintz R et al. Serum insulin-like growth factor II levels in normal adolescents and those with insulin-dependent diabetes mellitus. Clin Endocrinol 1996; 45: 13-9.
4. Muņoz MT, Barrios V, Pozo J et al. Insulin-like growth factor I, its binding proteins 1 and 3, and growth hormone-binding protein in children and adolescents with insulin-dependent diabetes mellitus: clinical implications. Pediatr Res 1996; 39: 992-8.
5. Bereket A, Lang CH, Blethen SL et al. Insulin-like growth factor binding protein-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity. J Clin Endocrinol Metab 1995; 80: 2282-8.
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