425mia. Overexpression of genes (ZAC and HYMAI) at 6q24 locus is the most
common cause of TNDM. Normally, genes at 6q24 locus which are inherited
from the mother undergo imprinting (silencing), whereas paternal alleles
remain active and are responsible for growth and development of β-cell dur-
ing intrauterine life. However, duplication of paternal allele or loss of DNA
methylation of maternal allele results in two copies of genes in active form,
which result in inhibition of β-cell growth and development. Other mutations
responsible for TNDM include hepatocyte nuclear factor-1β (HNF1β),
KCNJ11, and ABCC8. The latter two mutations contribute to approximately
25 % of cases of TNDM. The resolution of diabetes in these children is pos-
sibly attributed to partial defect in metabolic signaling pathway involved in
glucose-mediated insulin secretion and progressive maturation of “glucose-β-
cell axis” with increasing age.- What are the causes of permanent neonatal diabetes mellitus?
Permanent neonatal diabetes mellitus (PNDM) is characterized by onset of
hyperglycemia early in life without an intervening period of remission. PNDM
is due to defect in insulin secretion and/or impaired β-cell growth and develop-
ment. The most common cause of PNDM is heterozygous mutations in ATP-
sensitive K+ channel (K AT P). KCNJ11 gene mutations account for 30 % of
patients with PNDM, whereas ABCC8 and insulin gene mutation contribute
10 % each to PNDM. Further, homozygous mutations in PDX1/IPF- 1 and
glucokinase (GCK) result in PNDM, while heterozygous mutations of these
genes lead to MODY.- How does mutations in ATP-sensitive K+ channel (K ATP) cause neonatal
diabetes?
The ATP-sensitive potassium channel (KAT P) in pancreatic β-cells is formed
by four Kir6.2 subunits and four SUR1 subunits. Kir6.2 is encoded by
KCNJ11 gene and SUR1 by ABCC8 gene. The Kir6.2 subunits form the cen-
tral pore and are surrounded by SUR1 subunits. The KAT P channel is a link
between glucose metabolism and insulin secretion. Entry of glucose into the
β-cell generates ATP through glycolysis and increases ATP/ADP ratio,
which results in closure of KAT P channel (preventing K+ efflux) leading to
depolarization of β-cell membrane. This result in opening up of voltage-
dependent calcium channel and allow the entry of calcium from extracellular
fluid into β-cell, thereby initiating the process of insulin release by exocyto-
sis. Activating mutations of KCNJ11 or ABCC8 reduces the sensitivity of
KAT P channel to ATP. This results in persistently opened up KAT P channel, and
consequent inhibition of downstream cascade of events involved in insulin
secretion, thereby leading to decrease in insulin secretion and neonatal
diabetes.12 Diabetes in the Young