Neonatal Hyperglycaemia

Question 1

What is the Definition of Neonatal Hyperglycaemia?

Answer 1

• Definition uncertain – often defined as blood glucose >6.9 mmol/L or plasma glucose >8.3mmo/L1
• Typically occurs when a newborn cannot adapt to parenteral glucose infusion by decreasing endogenous glucose production or increasing peripheral glucose uptake

Question 2

What are the causes of Neonatal Hyperglycaemia?

Answer 2

• High rates of glucose infusion: >10 – 12 mg/kg/min (in babies who don’t have CHI) may result in hyperglycaemia, particularly in extremely low birth weight infants.
• Prematurity: Hyperglycaemia is common in premature infants, especially very low birth weight infants (<1500g). Proposed mechanisms include reduced insulin secretion, incomplete suppression of hepatic glucose production, and stress response resulting in counter hormone regulation
• Stress: The stress response (adrenaline and cortisol) may result in hyperglycaemia
• Sepsis: Potential mechanisms in sepsis include the stress response, decreased insulin release and reduced peripheral utilisation of glucose.
• Drugs: common complication of glucocorticoid therapy, also noted following phenytoin administration
• Neonatal diabetes mellitus

Question 3

What is Neonatal Diabetes Mellitus?

Answer 3

• Defined as uncontrolled diabetes presenting in the first 6 months of life1
• Rare: 1:300,000 – 400,000 live births.
• Affects all races and ethnic groups.
• Majority of cases present with intrauterine growth retardation (IUGR), failure to thrive, decreased sc fat and low or undetectable C-peptide levels.
• Genetically heterogeneous, multiple underlying mechanisms.
• Approx 50% cases are transient, 50% are permanent

Question 4

What causes Transient Neonatal Diabetes Mellitus?

Answer 4

Caused by overexpression of imprinted genes at 6q24PLAGL1 (ZAC) and HYMAI.

• Normally expression of the maternal alleles of PLAGL1 and HYMAI are silenced by methylation and only the paternal alleles are expressed.
• In 6q24 TNDM, PLAGL1 and HYMAI are overexpressed due to one of three mechanisms.

Diabetes commences in first 6 weeks of life and resolves by 18 months.

Question 5

What are clinical features of TNDM due to 6q24 abnormalities?

Answer 5

• Severe IUGR
• Hyperglycaemia
• Dehydration
• Absence of ketoacidosis.

Question 6

What are biochemical/immunological investigations of TNDM due to 6q24 abnormalities?

Answer 6

• Plasma insulin levels are low in the presence of high serum glucose.
• Ketones are not usually present in the urine.
• Islet cell antibodies are absent.
• Small minority have cytogenetically visible duplication of 6q24. FISH or chromosomal microarray analysis can be used to confirm duplication.

Question 7

What are molecular mechanisms of 6q24 TNDM ?

Answer 7

UDP6 (paternal uniparental disomy of chromosome 6)

• Two chromosome 6q24 regions, each with an expressed copy of PLAGL1 and HYMAI are inherited from the father and none from the mother (41% cases)

Paternal duplication of 6q24.

• Usually a submicroscopic duplication results in the presence of 2 copies of PLAGL1 and HYMAI on one paternal chromosome 6 (29% cases)

Hypomethylation of the maternal PLAG1/HYMAI DMR (differentially methylated region).

• Loss of normal methylation results in inappropriate expression of the maternal PLAGL1 and HYMAI alleles (30% cases).

Question 8

How does KCNJ11 and ABCC8 cause neonatal diabetes mellitus?

Answer 8

• Activating mutations of KCNJ11 and ABCC8 genes can cause transient and permanent neonatal diabetes.
• KCNJ11 and ABCC8 code for the Kir 6.2 and SUR1 subunits respectively of the ATP-sensitive potassium channel of pancreatic b-cells.
• Activating mutations increase the number of open KATP channels at the plasma membrane, hyperpolarizing the beta calls and preventing the release of insulin.
• Together heterozygous mutations in these two genes account for 33-50% of permanent neonatal diabetes and 26% of transient neonatal diabetes.

Question 9

What are clinical features of KCNJ11 and ABCC8 related neonatal diabetes mellitus?

Answer 9

• Affected infants present with low birth weight and hyperglycaemia.
• Compared with 6q24 DM, usually presents slightly later, birth weight is higher, remission usually takes longer, and ketoacidosis is often present at diagnosis.
• Some of the children have epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus (DEND syndrome). DEND syndrome has been associated with both KCNJ11 and ABCC8 mutations.

Phenotype correlates with genotype depending on the impact of the mutation on ATP binding.

Question 10

What are features of Permanent Neonatal Diabetes Mellitus?

Answer 10

• Mean age at presentation 7 weeks: range birth to 26 weeks. Does not resolve over time.
• Five genes in which mutations currently known to cause non-syndromic PNDM.
• Also rare syndromic forms of PNDM.
• Course of PNDM varies with genotype.
• TNDM and PNDM cannot be distinguished clinically – genetic analysis is crucial as the identification of the molecular defect will determine the clinical prognosis, treatment and genetic counselling.

Question 11

What are Genes causing non syndromic permanent neonatal diabetes mellitus?

Answer 11

• KCNJ11: Autosomal dominant
• ABCC8: Autosomal dominant1 or autosomal recessive
• INS: Autosomal dominant or autosomal recessive
• GCK: Autosomal recessive
• PDX12: Autosomal recessive

Question 12

What are the molecular genetics of Nonsyndromic PNDM?

Answer 12

• Individuals with autosomal dominant PNDM may have an affected parent or may have de novo pathogenic variant. Each child of an individual with autosomal dominant PNDM has a 50% chance of inheriting the pathogenic variant.
• The transcription factor insulin promoter factor 1 (PDX1) is a master regulator of pancreatic development as well as the differentiation of progenitor cells into the beta-cell phenotype.
• At least four PDX1mutations have been described in association with pancreatic agenesis and PNDM.

Question 13

What are features of KCNJ11 and ABCC8 associated PNDM?

Answer 13

• Most diagnosed by 3 months but a few present in childhood or early adult life.
• Majority have low birthweight.
• Typical presentation symptomatic hyperglycaemia and in many cases ketoacidosis.
• 20% have neurological features (DEND: developmental delay, epilepsy, neonatal diabetes)

Question 14

What are features of INS associated PNDM?

Answer 14

• Diabetic ketoacidosis/marked hyperglycaemia.
• Most newborns small for gestational age.
• Median age at diagnosis 9 weeks, but some present after 6 months.

Question 15

What are features of GCK associated PNDM?

Answer 15

• Severe form.
• Permanent insulin-requiring diabetes from the first day of life.

Question 16

What are features of PDX1 associated PNDM?

Answer 16

• More severe insulin deficiency than in K_ATP PNDM.
• Lower birth weight and younger age at diagnosis.
• Also, pancreatic exocrine insufficiency.

Question 17

Describe Glucose Regulation of Insulin

Answer 17

• Normal resting beta cell membrane is maintained in a hyperpolarised state by the Na-K-ATPase pump and open, ATP sensitive potassium channels
• When plasma glucose increases, it enters the beta cell through a specific membrane-bound glucose transporter GLUT 2
• It is then phosphorylated by glucokinase and metabolised, resulting in phosphorylation of ADP to ATP, increasing ATP/ADP ratio.
• Increased ATP/ADP ratio causes K_ATP channels to close.
• This leads to depolarisation of the cell membrane, opening of voltage dependant Ca channels and a rise in intracellular calcium concentration.
• This activates insulin-containing secretory granules.
• Granules are translocated to the plasma membrane where fusion and exocytosis occurs.

Question 18

What are come syndromic causes of PNDM?

Answer 18

• PTF1A-related PNDM1
• Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome
• Wolcott-Rallison syndrome
• A syndrome of neonatal diabetes mellitus with congenital hypothyroidism
• A syndrome of neonatal diabetes mellitus with pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia
• A syndrome of neonatal diabetes, cerebellar hypoplasia, sensineural deafness and visual impairment
• A syndrome of congenital malabsorptive diarrhoea and neonatal diabetes

Question 19

How does diagnosis of TNDM differ from PNDM?

Answer 19

• Patients with TNDM are more likely to have IUGR and less likely to develop ketoacidosis than patients with PNDM.
• TNDM patients are younger at the age of diagnosis of diabetes and have lower initial insulin requirements.
• Considerable overlap occurs between the two groups so that TNDM cannot be distinguished from PNDM based on clinical features.
• Recurrent diabetes is common in patients with “transient” neonatal DM and prolonged follow up is essential.
• Molecular analysis of chromosome 6 anomalies, the KCNJ11 and ABCC8 genes (encoding Kir6.2 and SUR1 respectively) provide a tool for identifying transient from permanent DM in the neonatal period.

Question 20

How is Neonatal Diabetes mellitus treated?

Answer 20

• Rehydration and intravenous insulin infusion should be started promptly after diagnosis, particularly in infants with ketoacidosis.
• In general, rapid-acting (lispro and aspart) and short-acting preparations should be avoided as they may cause severe hypoglycaemic events.1
• The newer, longer acting preparations such as glargine may work better in small infants. Intermediate-acting insulins tend to have a shorter duration of action in infants, possibly because of smaller dose or higher subcutaneous blood flow.
• Continuous insulin pump therapy has been used successfully in a number of cases.
• Identification of a KCNJ11 or ABCC8 mutation is important since most individuals with these mutations can be treated with oral sulfonylureas.
• High calorie intake should be maintained to achieve weight gain.