Neonatal Diabetes Melitus

Neonatal diabetes mellitus (NDM) has been defined as insulin-sensitive hyperglycemia that is diagnosed within the first months of life (1). It occurs at a frequency of about 1 in 400,000 births and can be either transient (TNDM) or permanent (PNDM). PNDM has been linked to mutations in several different genes, including KCNJ11 (2-5). GCK (6,7), and IPF1 (8). KCNJ11-related PNDM, which is estimated to account for about 50% of all cases (4,5), appears to be responsive to oral sulfonylurea therapy, while GCK- and IPF1-related PNDM require insulin replacement. Genetic testing for NDM can identify PNDM in newborns and differentiate among different monogenic causes of PNDM, helping the physician to select the most appropriate therapy.

Types and Causes of NDM

All forms of NDM are caused by a failure of the pancreas to release sufficient insulin in response to high blood glucose levels. In TNDM, diabetes develops within days after birth and resolves again within weeks or months, before recurring – in a milder form – in late childhood. In PNDM, diabetes develops within days to months after birth and persists throughout life. PNDM is known to have many different genetic causes, several of which have been identified.

PNDM
KCNJ11-related PNDM

KCNJ11-related PNDM develops during the first three to six months after birth. KCNJ11 codes for the Kir6.2 protein subunit of the ATP-sensitive potassium (KATP) channel in the membrane of pancreatic ß-cells. KATP-channel function represents a crucial element in the complex chain of events that links a rise in blood glucose concentration to insulin release (see Normal Physiology of Insulin Release). Gain-of-function, or activating, mutations in KCNJ11 reduce the sensitivity of the KATP channel to ATP. Consequently, the mutated KATP channels stay open in spite of an increase in intracellular ATP concentration, preventing insulin release in response to high blood glucose levels. Of note, loss-of-function mutations in KCNJ11 do not lead to NDM, but to the “complementary” condition, congenital hyperinsulinsim (9).

GCK-related PNDM

GCK-related PNDM is usually diagnosed within the first week after birth. GCK codes for the glycolytic enzyme glucokinase, which catalyzes the first and rate-limiting step of glycolysis. By determining the rate of ATP production in response to the blood glucose concentration, glucokinase functions as the ß-cells' “glucose sensor” (see Normal Physiology of Insulin Release). Loss-of-function mutations in glucokinase reduce the efficiency with which pancreatic ß-cells use glucose for ATP production, so that higher than normal blood glucose levels are necessary to generate an intracellular ATP concentration sufficient to trigger insulin release. Loss-of-function mutations in both copies of GCK lead to PNDM (6,7), while loss-of-function mutations in only one GCK copy give rise to a milder form of diabetes (MODY2) (10). Of note, gain-of-function mutations in GCK do not lead to diabetes, but to the "complementary" condition, congenital hyperinsulinism (9).

IPF1-related PNDM

IPF1-related PNDM is usually diagnosed within the first week after birth. IPF1 codes for the transcription factor insulin promoter factor 1 (IPF-1), which is required for normal development of the pancreas during embryogenesis. In mature pancreatic ß-cells, IPF-1 stimulates transcription of the insulin gene in response to high blood glucose concentrations. Loss-of-function mutations in both copies of IPF1prevent proper development of the pancreas (8), leading to pancreatic agenesis and thus complete endocrine and exocrine pancreatic insufficiency. If only one of the two IPF1 copies contains a loss-of-function mutation, the pancreas develops normally, but mature ß-cells within the pancreas are progressively less able to increase insulin production in response to high glucose concentrations, leading to a milder form of diabetes (MODY4) (11).

Syndromic PNDM

PNDM can occur as part of the IPEX (Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked) (12) or the Wolcott-Rallison Syndrome (13).

If you want to learn more about Normal Physiology of Insulin Release please click here.

Clinical presentations of PNDM and TNDM are similar in newborns and infants. Both forms of NDM are characterized by insulin-sensitive hyperglycemia that develops during the first few days to months after birth. Infants with NDM generally have low birth weight due to intrauterine growth retardation and may present with lethargy, poor eating, seizures, dehydration, and failure to thrive. Sepsis is sometimes suspected; with NDM, however, the body temperature is usually normal or low, rather than elevated. NDM may be associated with ketoacidosis, but no diabetes antibodies have been detected.

KCNJ11-related PNDM develops somewhat later than other forms of NDM (within weeks or months rather than days or weeks) and, depending on the exact KCNJ11 mutation, can also cause neurological abnormalities such as epilepsy or delayed motor development (2,4). IPF1-related PNDM is associated with complete endocrine and exocrine pancreatic insufficiency.

NDM is indicated by insulin-sensitive hyperglycemia in neonates. PNDM can be differentiated from TNDM by persistence of diabetes into the second and third year of life. IPF1-related PNDM is suggested by pancreatic exocrine as well as endocrine deficiency, and pancreatic agenesis can be confirmed by ultrasound imaging.

Only genetic testing can differentiate PNDM from TNDM in newborns, confirm loss-of-function mutations in IPF1 as the cause of pancreatic agenesis, and distinguish KCNJ11-related and GCK-related PNDM from other forms of PNDM.

All forms of NDM can be treated by insulin replacement therapy. Early studies indicate that KCNJ11-related PNDM may also be managed with oral sulfonylurea therapy (2,3). IPF1-related PNDM requires replacement of both endocrine and exocrine pancreatic functions.

TNDM is associated with defects in an imprinted region of chromosome 6, which only lead to expression of TNDM if both copies of chromosome 6 are paternally derived or if the segment of the paternal chromosome 6 carrying the genetic defect has been duplicated (1, 14).In addition, gain-of-function mutations in KCNJ11 have recently been implicated in TNDM (15).

PNDM has been linked to autosomal recessive loss-of-function mutations in IPF1 or GCK and autosomal dominant gain-of-function mutations in KCNJ11. Gain-of-function mutations in KCNJ11appear to be an especially frequent cause of PNDM, accounting for about 50% of all cases (4,5). At least one case of KCNJ11-related PNDM due to paternal germline mosaicism has been reported (15).

The Neonatal Diabetes Mellitus Evaluation can detect PNDM-linked mutations in KCNJ11, GCK, and IPF1. Identification of PNDM and its exact genetic cause can help the physician to select the most appropriate treatment for the condition and allow family screening for PNDM-linked mutations. Of note, homozygosity for PNDM-linked mutations in GCK or IPF1 leads to PNDM, while heterozygosity gives rise to milder forms of diabetes (MODY2 or MODY4, respectively).

How Is Genetic Testing for NDM Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of KCNJ11, GCK, and IPF1 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a complete, detailed result report is sent to the patient’s physician.

Ordering testing Neonatal Diabetes Mellitus, click here.

Download a printable PDF of this review.