Neonatal diabetes mellitus: current perspective

Figures & data

Table 1 Known genetic mutations causing transient and permanent neonatal diabetes mellitus

Genetic etiology (protein-coded)	Attributable cases	Inheritance	Pancreatic pathology	Associated features
Transient neonatal diabetes mellitus
Chromosome 6q24 abnormalities	70%
Uniparental disomy	40%	Sporadic	Reduced B-cell function	Umbilical hernia, macroglossia, cardiac abnormalities, and delayed maturation
Paternal duplication	40%	AD
Maternal abnormal methylation	20%	Sporadic
Potassium channel (KCNJ11, ABCC8)	25%	Sporadic/AD	Reduced B-cell function	None
HNF-1B mutation	Rare	AD	Reduced B-cell mass	Pancreatic exocrine dysfunction, variable renal involvement

Permanent neonatal diabetes mellitus
Potassium channel (KATP)*
KCNJ11 (KIR6.2 subunit)	30%–50%	Sporadic/AD	Reduced B-cell function	Developmental delay, epilepsy (DEND)
ABCC8 (SUR1 Subunit)	10%–15%	Sporadic/AD/AR
INS (Insulin)	15%–20%	AD	B-cell apoptosis	IUGR
GCK^Table Footnote*,Table Footnote‡ (Glucokinase)	4%	AR	Reduced B-cell function	IUGR
IPF1/PDX1* (insulin promoter factor I)	Rare	AR	Reduced B-cell mass	Pancreatic agenesis, cerebellar hypoplasia, cardiac septal defects or absent gallbladder
GLIS3 (zinc finger protein)	Rare	AR	Reduced B-cell function	Congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys
HNF-1B* (transcription factor)	Rare	AD	Reduced B-cell mass	Pancreatic exocrine dysfunction, variable renal involvement
FOXP3 (transcription factor)	Rare	X-linked	B-cell apoptosis	Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)
EIF2AK3 (eukaryotic translation initiation factor)	Rare	AR	B-cell apoptosis	Wolcott-Rallison syndrome: chondro-osseous dysplasia, recurrent hepatitis and renal dysfunction, growth retardation, learning deficits
SLC19A (high-affinity thiamine transporter)	Rare	AR	Reduced B-cell function	Megaloblastic anemia, sensorineural hearing loss, cardiac defects, visual impairment
SLC2A2 (GLUT2 transporter)	Rare	AR	Reduced B-cell function	Fanconi–Bickel syndrome, renal dysfunction, hypergalactosemia
NEUROD1* and NEUROG3 (transcription factor for pancreatic islets and enteroendocrine cells)	Rare	AR	Reduced B-cell mass	Intractable diarrhea, IUGR
RFX6 (transcription factor-islet cell differentiation)	Rare	AR	Reduced B-cell mass	Hypoplasia of the pancreas and gallbladder, intestinal atresia and intractable diarrhea
PTF1A (transcription factor, early pancreatic development)	Rare	AR	Reduced B-cell mass	Hypoplasia of the pancreas and cerebellum

Notes:

* Implicated in congenital hyperinsulinism

‡ implicated in MODY.

Abbreviations: ABCC8, ATP-binding cassette transporter sub-family C member 8; AD, autosomal dominant; AR, autosomal recessive; ATP, adenosine triphosphate; DEND, developmental delay, epilepsy, neonatal diabetes; EIF2AK3, eukaryotic translation initiation factor 2-alpha kinase; FOXP3, forkhead box P3 protein; GCK, glucokinase; GLIS3, Gli-similar 3 protein (zinc finger protein); GLUT2, glucose transporter 2; HNF-1B, hepatocyte nuclear factor-1-beta; INS, insulin; IPF1, insulin promoter factor; IUGR, intrauterine growth retardation; KCNJ11, potassium inwardly-rectifying channel, subfamily j, member 11; KIR6.2, ATP-sensitive inward rectifier potassium channel; MODY, maturity onset diabetes of the young; NEUROD1, neuronal differentiation 1; NEUROG3, neurogenin-3; PDX1, pancreatic and duodenal homeobox 1 (insulin promoting factor); PTF1A, pancreas transcription factor; RFX6, regulatory factor X 6; SLC, solute carrier protein; SUR1, sulfonylurea receptor.

Figure 1 Pancreatic beta cell depicting the role of genetic defects in neonatal diabetes mellitus.

Notes: Numerous intricate steps are implicated in insulin release by the B-cell, in response to glucose, as shown in the figure. The genes illustrated in the nucleus and boxed elements (such as closure of the K_ATP channel) are necessary for normal function and serve as potential points of defect that can lead to inadequate insulin synthesis and/or release. Although neonatal diabetes is a common outcome, the severity of symptoms and other associated features are dependent on the underlying genetic etiology.
Abbreviations: ADP, adenosine diphosphate; AIP aryl hydrocarbon receptor interacting protein; ATP, adenosine triphosphate; EIF2AK3, eukaryotic translation initiation factor 2-alpha kinase; FOXP3, forkhead box P3 protein; GLIS3, Gli-similar 3 protein (zinc finger protein); GLUT2, glucose transporter 2; HNF-1B, hepatocyte nuclear factor-1-beta; INS, insulin; IPF1, insulin promoter factor; K_ATP, ATP-sensitive potassium channel; NEUROD1, neuronal differentiation 1; NEUROG3, neurogenin-3; PTF1, pancreas transcription factor; RFX6, regulatory factor X 6; SLC19A1, solute carrier (thiamine transporter); SUR1, sulfonylurea receptor; KIR6.2, ATP-sensitive inward rectifier potassium channel.