ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2020 Nov 1;105(11):dgaa563. doi: 10.1210/clinem/dgaa563. PMID: 32818257.

This manuscript describes an unusual case of a baby born with a homozygous Nkx2.2 mutation who developed severe neonatal diabetes mellitus and then on follow up went onto develop severe obesity characterized by marked hyperphagia.

Nkx2.2 is an important transcription factor involved in the development of the pancreas and the central nervous system. Mice lacking Nkx2.2 develop severe neonatal diabetes mellitus and die shortly after birth. In the pancreas of these mice the islets on gross morphology look normal but there is a loss of beta-cells and a reduction in the number of alpha-cells and pancreatic polypeptide cells (the delta-cells are unaffected). These cells are replaced with an increase in the ghrelin producing cells (called Epsilon cells). Only a few rare cases of human Nkx2.2 neonatal diabetes have been reported so far (1) all without obesity on follow up.

In the case described here, biochemical investigations for obesity showed high baseline and glucose stimulated ghrelin levels which might explain the hyperphagia. In healthy and obese subjects, plasma ghrelin is increased during fasting and is suppressed by the ingestion of glucose, so this case demonstrates an unusual ghrelin profile. It would be interesting to measure glucagon and pancreatic polypeptide in patients with Nkx2.2 mutations as these should also be low/undetectable given the role of this transcription factor in the developmental biology of the pancreas. Patients with Nkx2.2 neonatal diabetes should be followed up and monitored for obesity. If the hyperphagia is due to the high ghrelin levels, then developing treatment options that target ghrelin production should be explored. It is unclear why the absence of Nkx2.2 reprograms the cell fate in the pancreas, especially in favour of ghrelin producing cells. The expansion of ghrelin-producing cells is not specific to Nkx2.2, but has also been observed in Pax4 mutant mice (2).

Reference: 1. Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, de Vries L, Rubio-Cabezas O, Houghton JA, Edghill EL, Patch AM, Ellard S, Hattersley AT. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19(1):146–154.2. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2924–9.