Unit IV – lweendo nchimba hamuyuni

Common clinical finding in NICUs Hyperglycaemia in neonates is a significant risk factor for increased morbidity and mortality. Most of the neonates are under significant physiological stress in addition to their co- morbidities, increasing the likelihood of developing hyperglycaemia

 Infants frequently get hyperglycaemic when faced with stressful situations such as sepsis, necrotizing enterocolitis, acute intracerebral bleeding, and also during or after surgery  The administration of excess IV glucose  Factitious hyperglycaemia  Hyperglycaemia may be also associated with medications, especially high-dose postnatal steroids and theophylline

 Usually insulin is not needed for transient increases in glucose  Identify and treat underlying cause  Monitor dextrose delivery rate and adjust if > 10mg/kg/hr  Monitor glucosuria  Treatment with insulin infusion is necessary if  If blood glucose > 12mmol/l AND glucosuria 3+; blood glucose > 15mmol/l  DOSE: 0.02 to i.u./kg/hr (clinical guidelines North Trent Network NHS)

 NDM is a monogenic form of diabetes that occurs in the first 6 months of life.  It is a rare condition occurring in only one in 300,000 to 400,000 live births.  Infants with NDM do not produce enough insulin, leading to an increase in blood glucose

 In about half of those with NDM, the condition is transient and disappears during infancy but can reappear later in life; this type of NDM is called transient neonatal diabetes mellitus (TNDM)  In the rest of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM).

 Resolves at median age of 12 weeks (although relapse in 50%)  Common clinical features are hyperglycaemia, IUGR, small for age, glycosuria, severe dehydration, minimal or no ketonaemia/ ketonuria. Macroglossia.  Majority of patients have an abnormality of genetic inprinting (uniparental disomy) of the ZAC and HYMA1 genes located on Chromosome 6q24

 May require high doses of insulin initially and the dose rapidly reduces (suggesting an underlying anomaly causing a functional delay in the maturation of the cells)  Response to sulphonylureas or metformin poor /uncertain

 Requires continual treatment from diagnosis  Commonest known causes are mutations in the KCNJ11 encoding the Kir6.2 subunit of the K ATP channel and the ABCC8 gene encoding the SUR1 subunit of the K ATP channel  these mutations lead to permanent opening of the potassium channel, therefore preventing any action of the voltage-gated Ca channels and any glucose induced insulin secretion.

 MODY 2 or mutations in the glucokinase gene (autosomal recesssive) can also result in PNDM  Common in consanguinity (heterozygous parents of a homozygous individual)  In gestational diabetes or parents with mild intolerance; screening for this mutation warranted

 IPEX syndrome and FOXP3 gene: x linked syndrome with a combination of exfoliative dermatitis, intractable diarrhea, hemolytic anemia, autoimmune thyroiditis and NDM.  Wolcott-Rallison syndrome – autosomal recessive assoc with spondyloepiphyseal dysplasia, hepatomegaly, renal failure, mental retardation and early death. consanguinity

 Pancreas agenesis and IPF1 gene  Severe hypoplasia of the pancreas and congenital cyanotic heart disease (AD)  (consanguinous family) NDM and cerebellar hypoplasia  X-linked phosphoribosyl-ATP pyrophosphatase hyperactivity and NDM  Maternal enterovirus infection and autoimmune NDM

 Insulin therapy crucial to obtain satisfactory weight gain and growth  Paediatricians face numerous difficulties in managing insulin therapy in the newborn (indications, doses, delivery, hypoglycaemia)  One study (Mitamura 1996) recommended the use of ultralente SC in TNDM to avoid hypogycaemia rather than lente or soluble insulin

 Another paper (Polak 2007) recommends that multiple injections of short acting insulin be better avoided; except initially when continuous infusions of soluble can be used to initially stabilize the patient  Use of Isophane on a once-daily basis in UK hospitals has afforded reasonable control  Some centres in France use continuous SC insulin infusion with good response

 The advances in the comprehension of NDM caused by mutations causing abnormal KATP channel function (mutations in KCNJ11 or ABCC8) has found major clinical application.  The transfer from insulin therapy to oral glibenclamide seems highly effective and safe for most such patients  This is a spectacular example of how pharmacogenomic approach improves in a tremendous way the QOL of young diabetic patients

NOTE: Sulfonylureas are not licensed to be used in young children so there are legal implications to be considered

Prognosis in the neonatal period is linked to the severity of the disease, the degree of dehydration and acidosis as well as the rapidity with which the disease is recognised and treated. Later prognosis is determined by the associated malformations and lesions

 NDM is rare  Brings out the importance of how understanding of molecular mechanisms can aid in the better management of diabetes as a whole