NEONATAL DIABETES MELLITUS

Dr Nahim
DM Neo Resident , ICH & HC

– Dr Kamalarathnam, Professor & HOD

Dept of Neonatology, ICH, Egmore
CASE HISTORY
 Late pre term 36 weeks /SGA / IUGR 1.7 kg /female

 Delivered by LSCS in view of previous LSCS

 21 years G2 P1 L1 , NCM ,spontaneous conception

 Referred on day 16 of life in view of hyperglycemia

ANTENATAL HISTORY

 1ST Trimester uneventful

 Antenatal scans - features of IUGR (8th month)
 Had anemia – iron sucrose
 Had GHTN on labetalol since 8th month
 Hypothyroidism on 25 mcg Thyroxine
NATAL HISTORY
 Born by LSCS in view of previous LSCS
 Dob – 20/9/21 @ 5 :10 pm at cuddolore gh

 Cried after birth

 APGAR 7 , 8 at 1 & 5 min

 Weight 1.7 kg , length 42 cm hc 29 cm

POST NATAL EVENTS – REFFERAL
HOSPITAL
 Had respiratory distress soon after birth , settled at 16
HOL
 Baby handed over to mother , on DBF

 CBG was checked in view IUGR & LBW

 It was found to be more than 160 but < 250 mg/dl

 Evaluated for sepsis – all screen came negative

 No antibiotics were given
 Investigations

 Hb 10.6 , PCV 31.6 , TLC 6600 , DLC P67L22 ,

PLATELET 2.15l , NA 136 , K 5.7 , CRP 0.6
 CBG was high – referred to ICH on day 16 of life , baby
was on DBF through out the hospital stay , before
shifting
AT ADMISSION – DAY 16 OF LIFE
 O/E HR 134 DOA – 06/10/21
 RR 46 WEIGHT 1.5 KG
 CRT < 3 SEC

 SPO2 99% AT ROOM AIR ,

 NIBP 64/48 ( 52)

 CBG – HIGH
HEAD TO EXAMINATION
 Head normal shape

 No dysmorphic features

 Normal tongue

 Normal umbilicus
DIFFERENTIAL DIAGNOSIS
 HYPERGLYCEMIA OF NEW BORN

 TRANSTIONAL NEONATAL DM

 PERMANAENT NEONATAL DM

 SYNDROMIC DM ( ? ROGERS )
 Repeat CBG was done – high

 Plan – to do s/s , electrolytes , serum RBS , urine sugar ,

urine ketone , ABG

 Stepped up -insulin , c-peptide , abdomen & brain

imaging, Genetic testing

 Started on first line A/B

INITIAL INVESTIGATIONS
DATE 6/10/21
HB 9.2
PCV 22
TLC 8500
DLC 47/47/4
Platelet 3.4 lakh
QCRP 0.6
MCV / MCH / MCHC 84.3 / 35 / 42
RBS 746
Urea /CREAT 48/1.1
S. CA 11
NA/K 112/4.8
SGOT/PT 8/17
URINE GLUCOSE +VE
URINE KETONE -VE
BLOOD GAS

Metabolic acidosis (adequately compensated)

D1-D4 OF ADMISSION
 In view of persistent hyperglycemia .High CBG and
polyuria ( 5 ml/kg/hr )
 Insulin infusion was started @ 0.05 u/kg/hr, CBG was
monitored hourly
 Gradually insulin infusion was tapered to 0.02 u/kg/hr at
which CBG was stabilized between 200-250 mg/dl
 So planned to shift to SC
 So total dose required per day
 0.02 x body weight x 24

 0.02x 1.5 x 24 = 0.7 u ( approx )

 So long acting insulin GLARGINE was planned to

give ,once daily
 CBG monitoring was done as per protocol
 Pediatric endocrinology opinion was sought  advised
for genetic study and GAD levels ( autoimmune )

 CT abdomen ( to rule out agenesis of pancreas )

SUBSEQUENT DAYS ……
 Baby developed seizures – evaluated for the same
 Serum sodium falls to 114

 Correction was given

 CT BRAIN was obtained  normal

 Baby sensorium improved

 Total dose was 0.7 u  was planned to give od in the
morning
 CBG monitoring was done half an hourly at change of
dose , otherwise 6th hourly
INSULIN GLARGINE
DIFFICULTIES ….
 As GLARGINE 0.7 u were plan to give , however , due
to technical difficulty , we were not able to give 0.7 units
,
 Baby started developing hypoglycemia as low as
requiring GIR
 GIR infusion went upto 8 also

 Gradually GIR were tapered and then again insulin was

given
PLAN
 It was planned , once CBG gets stabilized
 Switch over to oral glyburide ( SUR )

 However , plain oral glyburide was not available

( glyburide + metformin )
 So GLIBENCLIMIDE was started
 As baby was going recurrent hypoglycemia , it was
planed to quit GLARGINE pen

 And exact 0.7 u dose was planned to give via insulin

syringe
 SERUM INSULIN – 0.9 microU/ml (29-80)

 C-PEPTIDE 0.2 ng/ml (2.7-5.6)

 Blood ketones – 0.3

 So . 0.7 u was given sc once daily , but baby was again
going into hypoglycemia requiring GIR
 So dose was tapered to 0.5 then 0.4

 Still baby was going into hypoglycemia but time

duration has increased for baby to go into hypoglycemia
 Dose was reduced to 0.1 u , then baby CBG was
fluctuating above 300 mg /dl
 So dose was increased to 0.3

 However , again episodes of hypoglycemia ,warranting

seizures in baby
 Baby also had electrolytes imbalance
( pseudohyponatemia )
 CBG chart
800
700
600
500
CBG chart
400
300
200
100
0
 Gradually baby sensorium was deteriorating
 Repeated sepsis screen was sent which came positive

 And baby developed septic shock

 And unfortunately , baby then succumbed on 1/11/21 on

day 45 of life .
FREE PPT TEMPLATES: ALLPPT.COM
TIMELINE OF EVENTS

Day 21-
Day 1 - 14 30 Day 30-
Day 15 – 40 Day 45
day 20
£€

.
IV INSULIN
CUDDALORE INFUSION
SC Death
GH
0.05 GLARGINE GLIBENCLA .
U/KG/HR MIDE
+/-
. +
GLARGINE.
DBF . GIR

www.free-powerpoint-templates-design.c
DISCUSSION
 Background
 Genetics basis

 Clinical course

 Diagnostic approach

 Management
BACKGROUND
 Congenital diabetes / diabetes of infancy
 Monogenic defects , under 6 months

 1 in 90,000-160,000 live births

 Categorizes into
TRANSIENT/PERMANAENT/SYNDROMIC

Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W.

(2017). Neonatal Diabetes Mellitus. Clinics in Perinatology, (),
S0095510817301070–. doi:10.1016/j.clp.2017.10.00
NEONATAL HYPERGLYCEMIA VS DM
  Neonatal hyperglycemia is more common to develop in
the firs 3–5 days of life and resolve within 2–3 days of
onset but can persist up to 10 days

 prevalence of hyperglycemia in preterm infants can vary

from 25% to 75%.

Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W. (2017). Neonatal

Diabetes Mellitus. Clinics in Perinatology, (),
S0095510817301070–. doi:10.1016/j.clp.2017.10.00
Aldoretta PW, Carver TD, Hay WW Jr. Maturation of glucosestimulated
insulin secretion in fetal sheep. Biol Neonate. 1998;73:
375–386
GENETIC BASIS
 There are over 20 known genetic causes for neonatal
diabetes mellitus.
 80 % had a known genetic diagnosis

 Mutations in KCNJ11 and ABCC8 (affecting the

pancreatic beta-cell K-ATP channel) and account for
about 40 percent of these patients.

Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W.

(2017). Neonatal Diabetes Mellitus. Clinics in Perinatology, (),
S0095510817301070–. doi:10.1016/j.clp.2017.10.00
MECHANISM
 Alteration in beta cell function affecting synthesis or
secretion of insulin-KCNJ11 ,ABCC8,INS

 Pancreatic hypoplasia or aplasia –PAX6 , NEUROD

1,PDX 1

 Damage to pancreatic beta cells-INS , FOXP3,WFS1

Dahl, Amanda; Kumar, Seema (2020). <p>Recent Advances in Neonatal Diabetes</p>.

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Volume 13(), 355–
364. doi:10.2147/DMSO.S198932 
TRANSIENT DM
 TNDM resolves at a median age of 12 weeks; however,
approximately 50% of cases will ultimately relapse
 insulin dose requirement is often lower than that needed
in PNDM
 always associated with IUGR

 umbilical hernia and macroglossia, which were present

in 9 and 30% of subjects
 Overexpression of genes on the 6q24 locus is the
most,common cause of transient neonatal diabetes
 second most common cause of transient neonatal DM is
mutations in the two genes encoding the subunits of the
voltage-dependent potassium channels

Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W. (2017). Neonatal

Diabetes Mellitus. Clinics in Perinatology, (), S0095510817301070–. doi:10.1016/j.clp.2017.10.00
 TNDM caused by either KCNJ11 or ABCC8 mutations
cause a clinical picture that can be indistinguishable
from 6q24-related
 Birthweight is typically lower in 6q24 TNDM

 and diabetes onset occurs at an earlier age, as does

remission
PERMANENT DM
 most common cause of permanent neonatal diabetes is
activating heterozygous mutations in KCNJ11 or ABCC8
 account for more than 50% of all cases

 KATP channels are expressed in the brain, patients with

KCNJ11 mutations may have a wide range of
neurocognitive
 second most common- INS

Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W. (2017). Neonatal

Diabetes Mellitus. Clinics in Perinatology, (),
S0095510817301070–. doi:10.1016/j.clp.2017.10.00
 KCNJ11 mutations result in decreased sensitivity of the
Kir6.2 subunits to ATP, with failure of channel closure
and
 consequently insufficient or absent insulin release from
the b-cell
 neurological features in their most severe form comprise
a syndrome known as DEND
 Facial dysmorphisms- prominence of the metopic suture,
bilateral ptosis and down-turned mouth
SYNDROMIC FORMS
 beta-cell destruction, pancreatic hypoplasia or aplasia,
impaired beta-cell function or severe insulin resistance.
 Wolcott-Rallison syndrome which is an autosomal
recessive disorder caused by a mutation in EIF2A,
 IPEX syndrome-FOXP3

 Fanconi Bickel syndrome-SLC2A2

 Rogers syndrome-SLC19A2

 Wolfram syndrome-WFS1
CLINICAL PRESENTATION
 asymptomatic hyperglycemia to severe dehydration and
diabetic ketoacidosis (DKA)
 Common clinical manifestations-SGA/IUGR

  poor postnatal growth or failure to thrive 

 DKA may have few nonspecific symptoms such as tachypnea,

lethargy, irritability, and sunken fontanels and eyes.

Karges B, Meissner T, Icks A, Kapellen T, Holl RW. Management of diabetes

mellitus in infants. Nat Rev Endocrinol. 2011;8(4):201–211.
doi:10.1038/nrendo.2011.204
DIAGNOSTIC WORK UP
 Laboratory evaluation

 Genetic testing
LABORATORY EVALUATION
 Serum glucose,
 C-peptide,

 insulin,

 urine ketones

 Pancreatic USG

 ? Hb1Ac
GENETIC TESTING
 prognosis and treatment options for monogenic forms of
neonatal DM are influenced to a major extent by the
specific gene that is mutated.
 Targeted gene panels are available in various laboratories
for genes associated with neonatal diabetes
 molecular genetic testing to define their subtype of
monogenic neonatal diabetes mellitus (NDM)
 mutations in KCNJ11 and ABCC8 are responsive to
sulfonylurea therapy

 Can be transitioned from insulin to sulfonylurea therapy

after the genetic basis for their diabetes has been
identified
RECOMMENDATIONS
 Less than 6 months -molecular genetic testing to define
their subtype of monogenic neonatal diabetes mellitus
(NDM), as type 1 diabetes is extremely rare in this
subgroup

 6-12 months –testing for NDM is recommended in those

without islet antibodies as the majority of patients in this
age group have type 1 diabetes

Hattersley AT, Greeley SAW, Polak M, et al. ISPAD clinical practice consensus guidelines 2018:
the diagnosis and management of monogenic diabetes in children and adolescents. Pediatr
Diabetes. 2018
TREATMENT
 Infusion insulin / SC Insulin

 Continous SC insulin infusion

 Oral SUR

 Transtion from Insulin to oral SUR

INSULIN
 Infusion dose - an initial dose of 0.05 units/kg/hour was
commonly used

 insulin infusion rates should be titrated by small

increments of 0.01 units/kg/h

 Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K,

vanWeissenbruch M, Midgley P, Thompson M, Thio M, et al. Prevalence and Determinants of
Hyperglycemia in Very Low Birth Weight Infants: Cohort Analyses of the NIRTURE Study. J
Pediatr. 2010; 157:715–719.e3. [cited 2017 Jul 16] Internet.
SUBCUTANEOUS INSULIN
 Recommend starting dose with pre-prandial short acting
( lispro, aspart ) doses in the amount of 0.1-0.15 units per
kg/ dose, or doses guided by the response to intravenous
insulin.
 blood glucose levels are at least above 200-250 mg/dL.

 glargine at a dose of 0.2–0.4 unit/kg/day in 1 or 2

injections per day
CONTNIOUS SC INSULIN INFUSION
 dosing can be difficult due to frequent intake and
variability in quantity
 infants with neonatal diabetes are susceptible to
hypoglycemia
 allow for very small accurate doses to be given in a
physiologic way, with a continuous basal dose (as low as
0.025 units/hr) that may be adjusted hourly
THINGS TO CONSIDERED ..
 To know the infusion pump settings
 Types of infusion set and tubings

 Method of insertion

 Alarm features

 Water proof casing

SULFONYLUREAS
 Sulfonylurea-responsive mutations are the most common cause
of neonatal diabetes.
 90-95% of patients with NDM caused by KCNJ11 may be
successfully transitioned
 sulfonylurea (SU) therapy may also lead to beneficial effects on
neurocognitive development

Fujimura N, Tanaka E, Yamamoto S, Shigemori M, Higashi H. Contribution of ATP-sensitive

potassium channels to hypoxic hyperpolarization in rat hippocampal CA1 neurons in vitro. J
Neurophysiol
 A trial of glyburide may be considered in newly
diagnosed neonatal diabetes because of the relatively
high chance of having a mutation responsive to treatment
 trial of sulfonylurea therapy can be considered even
before a genetic diagnosis is made, although genetic
testing must be done in all cases
APPROACH TO TRANSITION INSULIN TO
ORAL SUR
 the basal rate should be reduced by 50 percent prior to
glyburide administration.
 Glyburide tablets can be crushed and readily prepared in
aqueous suspension
 An initial dose of 0.1 mg per kilogram per dose twice
daily before meals is most often used.
 the dose can be increased by 0.1 mg per kilogram per
dose.
 The dose may thus be increased each day, progressing up
to a dose of at least 1 mg/kg/day (usually achieved
within 5-7 days) if pre-meal capillary blood sugars
continue to be greater than 200 mg
RESPONSE TO ORAL SUR
 glucose and c-peptide levels may be drawn before a meal
and again 90-120 minutes after meal is eaten (and
glyburide is given).
 with appropriate response to glyburide should have an
appreciable increase in c-peptide level following
glyburide dosing and a meal
LEARNING LESSON ……
 Long acting Glargine PEN , to be avoided if dose is less
 SUR to be started as early as possible

 CSII better option

 CBGM better than conventional checking

………..
 THANK YOU