Long-acting Insulin Analogs Effect on gh/igf Axis of Children with Type 1 Diabetes: a Randomized, Open-label, Two-period, Cross-over Trial

Abstract

Background: Growth hormone (GH) secretion is increased in pre-pubertal children with type 1 diabetes and GH excess produces insulin resistance. Early-morning insulinopenia contributes to lower insulin-like growth factor (IGF-I) levels and to GH hypersecretion.

Objective: To evaluate differences in GH/IGF-I axis of pre-pubertal children with type 1 diabetes treated with glargine or detemir as long-acting insulin analogues, which was the main outcome measure, and to compare insulin effects in obtaining good metabolic control.

Subjects: Children with type 1 diabetes.

Methods: This was a 32-week, randomized, open-label, two-period, cross-over comparison between bedtime glargine and twice-daily detemir insulin, involving pre-pubertal children in care at a diabetes pediatric centre. After a 8-week-run-in period subjects were randomized to bedtime glargine or twice-daily detemir insulin administration. After a 12-week period treatments were inverted and continued for additional 12 weeks.

Results: Overall, 15 pre-pubertal children (53.3% males, mean age 8.6±1.5 years, duration of diabetes 4.2±1.5 years) completed the study. Groups did not differ for GH/IGF axis and HbA1c levels. Treatment with glargine was associated with lower fasting glucose values than treatment with detemir (8.1±1.5 vs. 8.2±1.7 mmol/L, p=0.01). Incidence rate of hypoglycemia was not different between insulin treatments (IRR=1.18, 95%CI 1.00–1.38; p=0.07). Detemir treatment was associated with a higher increase in body weight (p=0.008) and height (p=0.02) when compared with glargine.

Conclusion: Detemir and glargine not show significant differential effects on the GH/IGFI axis. The greater weight gain and height associated with detemir treatment, apparently not related to the level of pubertal growth, deserve further investigation.

Key words

type 1 diabetes - growth hormone - children - insulin analogues

• References

• 1 Yki-Järvinen H, Koivisto VA. Natural course of insulin resistance in type 1 diabetes. N Engl J Med 1986; 315: 224-230
• 2 Amiel SA, Sherwin RS, Simonson DC et al. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 1986; 315: 215-219
• 3 Tamborlane WV, Sherwin RS, Koivisto V et al. Normalization of the growth hormone and catecholamine response to exercise in juvenile-onset diabetic subjects treated with a portable insulin infusion pump. Diabetes 1979; 28: 785-788
• 4 Fowelin J, Attvall S, von Schenck H et al. Characterization of the insulin- antagonistic effect of growth hormone in insulin-dependent diabetes mellitus. Diabet Med 1995; 12: 990-996
• 5 Clemmons DR. Involvment of insuline-like growth factor-I in the control of glucose homeostasis. Curr Opin Pharmacol 2006; 6: 620-625
• 6 Clemmons DR. Role of insulin-like growth factor binding proteins in controlling IGF actions. Mol Cell Endocrinol 1998; 140: 19-24
• 7 Rajaram S, Baylink DJ, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 1997; 18: 801-831
• 8 Edge JA, Dunger DB, Matthews DR et al. Increased overnight growth hormone concentrations in diabetic compared with normal adolescents. J Clin Endocrinol Metab 1990; 71: 1356-1362
• 9 Yde H. The growth hormone-dependent sulfation factor in serum from patients with various types of diabetes. Acta Med Scand 1969; 186: 293-297
• 10 Batch JA, Baxter RC, Werther G. Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes. J ClinEndocrinol Metab 1991; 73: 964-968
• 11 Lundbaek K, Christensen NJ, Jensen VA et al. Diabetes, diabetic angiopathy, and growth hormone. Lancet 1970; 2: 131-133
• 12 Cummings EA, Sochett EB, Dekker MG et al. Contribution of growth hormone and IGF-I to early diabetic nephropathy in type 1 diabetes. Diabetes 1998; 47: 1341-1346
• 13 Amin R, Williams RM, Frystyk J et al. Increasing urine albumin excretion is associated with growth hormone hypersecretion and reduced clearance of insulin in adolescents and young adults with type 1 diabetes: the Oxford Regional Prospective Study. ClinEndocrinol (Oxf) 2005; 62: 137-144
• 14 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF et al. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 1996; 39: 1498-1504
• 15 Ekström K, Salemyr J, Zachrisson I et al. Normalization of the IGF-IGFBP axis by sustained nightly insulinization in type 1 diabetes. Diabetes Care 2007; 30: 1357-1363
• 16 Home P, Bartley P, Russell-Jones D et al. Study to Evaluate the Administration of Detemir Insulin Efficacy, Safety and Suitability (STEADINESS) Study Group. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2004; 27: 1081-1087
• 17 Porcellati F, Rossetti P, Busciantella NR et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogsglargine and detemir at steady state in type 1 diabetes mellitus: a double-blind, randomized, crossover study. Diabetes Care 2007; 30: 2447-2452
• 18 Philotheou A, Arslanian S, Blatniczky L et al. Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. Diabetes Technol Ther 2011; 13: 327-334
• 19 Hills M, Armitage P. The two-period cross-over clinical trial. Br J ClinPharmacol 1979; 8: 7-20
• 20 Diggle PJ, Heagerty P, Liang KY et al. Analysis of longitudinal data. Oxford: Oxford University Press; 1994
• 21 Fontana A, Copetti M, Mazzoccoli G et al. A linear mixed model approach to compare the evolution of multiple biological rhythms. Stat Med 2013; 32: 1125-1135
• 22 Slawik M, Schories M, BusseGrawitz A et al. Treatment with insulin glargine does not suppress serum IGF-1. Diabet Med 2006; 23: 814-817
• 23 Lepore M, Pampanelli S, Fanelli C et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analogglargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000; 49: 2142-2148
• 24 Wurzburger MI, Prelevic GM, Sonksen PH et al. The effects of improved blood glucose on growth hormone and cortisol secretion in insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf) 1990; 32: 787-797
• 25 Campbell PJ, Bolli GB, Cryer PE et al. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Eng J Med 1985; 312: 1473-1479
• 26 Moran A, Jacobs Jr DR, Steinberger J et al. Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis. J Clin Endocrinol Metab 2002; 87: 4817-4820
• 27 Porcellati F, Rossetti P, Candeloro P et al. Short-term effects of the long-acting insulin analogdetemir and human insulin on plasma levels of insulin-like growth factor-I and its binding proteins in humans. J Clin Endocrinol Metab 2009; 94: 3017-3024
• 28 Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998; 19: 717-797
• 29 Robertson KJ, Schoenle E, Gucev Z et al. Insulin detemir compared with NPH insulin in children and adolescents with Type 1 diabetes. Diabet Med 2007; 24: 27-34
• 30 Cherubini V, Iannilli A, Iafusco D et al. Premeal insulin treatment during basal-bolus regimen in young children with type 1 diabetes. Diabetes Care 2006; 29: 2311-2312
• 31 Smyczyńska J, Stawerska R, Hilczer M et al. Secondary IGF-I deficiency as a prognostic factor of growth hormone (GH) therapy effectiveness in children with isolated, non-acquired GH deficiency. Exp Clin Endocrinol Diabetes 2015; 123: 209-214
• 32 Binder E, Lange O, Edlinger M et al. Frequency of dermatological side effects of continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes 2015; 123: 260-264
• 33 Nazim J, Małachowska B, Fendler W et al. Low-grade Albuminuria and Risk Factors of Atherosclerosis in Children with in Type 1 Diabetes. Exp Clin Endocrinol Diabetes 2015; Oct 14. [Epub ahead of print] PubMed PMID: 26465830