Horm Res Paediatr. 2014;82(1):53-8.

Combined therapy with insulin and growth hormone in 17 patients with type-1 diabetes and growth disorders.

Stefano Zucchinia,  Dario Iafuscob, Silvia Vannellic, Ivana Rabbonec, Giuseppina Salzanod, Gabriella Pozzobone, Mohamad Maghnief, Valentino Cherubinig and Lorenzo Iughettih ,Carla Bizzarrii, Riccardo Bonfantie, Giuseppe D’Annunziof, Lorenzo Lenzij, Maria Cristina Maggiok, Marco Mariglianol, Andrea Scaramuzzam, Stefano Tuminin

 

aDepartment of Pediatrics, S.Orsola-Malpighi Hospital, Bologna, bDepartment of Pediatrics, Second University of Naples, Naples, cCentre of Auxology, University of Turin, Turin, dDepartment of Pediatrics, University of Messina, eDepartment of Pediatrics, Endocrine Unit, Scientific Institute Hospital San Raffaele, Vita-Salute University, Milan,  fPediatric Clinic, IRCCS Giannina Gaslini Institute, Genoa, gDivision of Pediatric Diabetes, Maternal-Infant Department, G. Salesi Hospital, Ancona, hDepartment of Pediatrics, University of Modena and Reggio Emilia, Modena, iBambino Gesù Children’s Hospital, Rome, jMeyer Children’s Hospital, Florence,   kMaternal Infantile Department, University of Palermo, Palermo,  lDepartment of Life and Reproduction Sciences, University of Verona, mLuigi Sacco Hospital, Milan,  nDepartment of Pediatrics, Chieti, Italy

 

ABSTRACT

Background. Combined GH-insulin therapy is rarely prescribed by pediatric endocrinologists. We investigated the attitude of Italian physicians to prescribe that therapy in case of short stature and type-1 diabetes (T1DM).

Materials and Methods. A questionnaire was sent and if a patient was identified, data on growth and diabetes management were collected.

Results. Data from 42 centres (84%) were obtained. 29/42 of the centres reported that the use of combined therapy was  usually avoided. Seventeen patients were treated in 13 centres. In 9 patients GH was started before T1DM onset, in 8 after the onset of T1DM. Height SDS pattern during GH therapy in the 11 patients affected by GH deficiency ranged from -0.3 SDS to +3.1 SDS. In the 8 diabetic patients in whom GH was added subsequently, mean insulin dose increased during the first 6 months of therapy from 0.7±0.2 to 1.0±0.2 U/kg (p=0.004). HbA1c was unchanged during the first 6 months of combined therapy.

Conclusions. Most Italian physicians do not consider the combined GH-insulin therapy in diabetic children with growth problems. However, the 17 patients identified would confirm that the combined therapy was feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth in most patients and did not affect diabetes metabolic control.

PMID: 24925520

 

SUPPLEMENTS

Combined GH and insulin therapy is rarely prescribed in children. So far only one study has been published in German-Austrian patients describing 37 children treated with insulin and GH (1). This is probably due to two main reasons. The first is statistical, since the possibility of the double association type-1 diabetes (T1DM) and GH deficiency (GHD), the leading cause to prescribe GH therapy, is rare: GHD prevalence is between 1:2000 and 1:5000, while T1DM prevalence is 1:800 (2). There are probably concerns among physicians to prescribe a multiple daily injection treatment involving two hormones having opposite effects on glucose metabolism and a further deterrent is the discordant results on the possible increased incidence of T2DM in GH-treated children (3-5).

In 2012 a questionnaire was sent to all Italian Pediatric Endocrinologists to investigate on the attitude to treat simultaneously patients with GH and insulin in the last 20 years and to collect data on the patients possibly identified.  It was considered both the possibility that an already diabetic child required GH for short stature and the opposite in whom T1DM occurred in a child in the course of GH therapy (in both cases for at least 6 months).

The results were that despite 2/3rd of paediatricians declared to not consider the combined therapy, quite surprisingly 17 patients (9 males, 8 females), followed-up in 13 centres and treated with insulin and GH, were identified, demonstrating that in Italy, as well as in Germany and Austria, the presence of T1DM is not an absolute contraindication to prescribe GH. Mean height at GH therapy start was quite low (-2.9±0.7 SDS) and mean age at T1DM onset was 7.6±4.3 years.

There were 2 categories of patients: those in whom GH therapy was started before the diagnosis of T1DM (table 1) and those who had an initial diagnosis of T1DM and the subsequent start of GH therapy (table 2).

 

Table 1 tab1

 

In this group of patients GHD was the main reasons to prescribe GH therapy that was not withdrawn after the onset of T1DM. As shown, duration of GH therapy was highly variable, height SDS was almost always < -2.5 SDS and height SDS pattern from start to stop therapy ranged from -0.3 SDS to +2.3 SDS in the patients with GHD. In the 5 patients who already reached final height, height gain from GH therapy start ranged from +0.4 SDS to +3.9  SDS.

 

Table 2 tab2

 

In this group GH therapy was started after the diagnosis of T1DM and main reason for GH treatment was severe growth deficit, not necessarily due to GHD. Height gain SDS from start to stop therapy ranged from +0.3 SDS to +3.1 SDS in the patients with GHD. Height gain from GH therapy start in the 3 patients who already reached final height ranged from 0 in one patient with Turner syndrome to +1.2 SDS in the patient with isolated short stature. In these patients mean insulin dose increased during the first 6 months after GH start from 0.7±0.2 to 1.0±0.2 U/kg (p=0.004), confirming the GH-induced insulin resistance.  Insulin administered through pump was preferred to the injection regimen in about 1/3rd of cases to better manage the nocturnal insulin resistance consequent to the GH administration. Similarly to the German-Austrian study, HbA1c was unchanged during the first 6 months of combined therapy  (pre-GH values: 7.9±0.8% vs  7.7±0.6%, p=0.91), indicating that with an adequate increase of insulin doses metabolic control can be properly managed.

Height gain was as a whole consistent with the data of the literature (6) and better than that of the German-Austrian study (mean value +0.3 SDS after 2 years of GH therapy) where only already diabetic patients were included, indicating that diabetes itself is not the cause of a poor response to GH therapy (Italian patients were younger and shorter at diagnosis, parameters with a known positive influence on growth response to GH).

The figure below shows in details the growth response (SDS) of the 9 patients with isolated GH deficiency, the patient with multiple hormone pituitary deficiency and the patient with organic GH deficiency (in 4 cases therapy was ongoing). Growth response was positive in all but 2 patients (n° 1 and n° 9).

Fig 1png

 

Our survey demonstrated that, despite many Italian Pediatricians do not consider the combined therapy with GH and insulin in a diabetic child with growth problems, the results obtained in 17 patients would confirm that in diabetic children GH therapy is feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth and did not affect diabetes metabolic control, although GH induced mild insulin resistance.

 

References:

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  3. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet 2000;19;355:610-613.
  4. Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, Blum WF; GeNeSIS International Advisory Board. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab 2011;96:1025-1034.
  5. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab 2010;95:167-177.
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