ESPE Abstracts

Background: NKX2-2 gene mutation (reported in 3 cases worldwide) cause severe IUGR and neonatal diabetes. Beta-cells of the mice Nkx2-2 ^(−/−) model were recently shown to convert into cells producing the appetite-promoting peptide ghrelin. Classically, ghrelin secretion is stimulated during fast and suppressed by nutrients or glucose ingestion in all age groups. In obese children this ghrelin suppression reaches a minimum of 60% of baseline at the 60 minutes time point following glucose ingestion.

Objective: To examine the ghrelin secretion in response to OGTT in a severely obese hyperphagic child with neonatal diabetes due to NKX2-2 mutation in order to test the hypothesis that beta to ghrelin producing cell conversion is responsible to her rapid weight gain.

Methods: A 3.5 years old girl with neonatal diabetes due to NKX2-2 mutation (c.356delG, p.P119fs64*64*) and severe obesity performed OGGT (1.75 gr/kg). Glucose, insulin and total ghrelin levels were measured at 0, 30, 60 minutes time points. The ghrelin levels were assessed in comparison to reported data of age matched healthy obese and non- obese children.

Results: Our patients gained weight dramatically since one year of age and her weigh at the age of 3.5 years old weights 19.5 kg (BMI SDS +4.32). During the OGTT-while glucose increased from 19.4 mmol/l at baseline to 30.8 mmol /l after 60 minutes insulin levels dropped from 101.36 pmol/l to 31.11 pmol/l with constantly undetectable C- peptide levels. Interestingly, total ghrelin levels paradoxically increased from 1011 pg/ml at baseline (similar to baseline values in obese children) to 1349 pg/ml after glucose ingestion.

Conclusion: NKX2-2 mutation phenotype includes severe early childhood obesity in addition to neonatal diabetes. During OGTT, our obese (neonatal diabetic) patient showed paradoxical increase in ghrelin levels concomitantly with decrease in insulin levels. This results suggest that in patients with NKX2-2 mutation- human beta cell mimic Nkx2-2 ^(−/−) mice’s beta cells conversion to ghrelin producing cells and elevated ghrelin levels are the pathophysiologic mechanism for hyperphagia and obesity.