DI

DM DKA
Basic Science Lecture
Ma. Giselle G. Genovata, MD
3rd Year Pedia Resident
Medical Center Paranaque

Gist Definitions
Diabetes Mellitus

a. the passage of large volumes

(>4ml/kg/hr) of dilute urine (< 300
mOsm/kg).

Diabetes Insipidus

b. A combination of hyperglycemia,

Diabetic Ketoacidosis

c. A common chronic metabolic syndrome

acidosis and ketones

characterized as hyperglycemia as a
cardinal biochemical feature

DI

DM DKA
Diabetes Insipidus

Diabetes Insipidus (DI)

a heterogeneous clinical syndrome of disturbance in water balance,
characterized by polyuria (urine output > 4 ml/kg/hr), polydypsia (water
intake > 2 L/m2/d) and failure to thrive.

CENTRAL
DIABETES
INSIPIDUS
Vassopresin
deficiency

NEPHROGENIC
DIABETES
INSIPIDUS

Vassopresin
insensitivity at
both central and nephrogenic DI can be hereditary,
or secondary
the level
of to
variety of causes
the kidney
Source: Nelsons Textbook of Pediatrics 19

th

Ed.

Regulation of VP secretion and

Serum Osmolality

Causes of Diabetes Insipidus

Central DI
10% idiopathic
Genetic
Trauma
Congenital
Neoplasms
Infiltrative,
autoimmune and
infectious
diseases
Increased VP
metabolism

Nephrogenic
DI
Genetic
Acquired
Hypercalcemia
Hypokalemia
Drug induced
Chronic renal
failure
PCKD
Medullary cystic
dse
Sjogren
syndrome
Sickle cell
disease
Excessive water

Clinical Presentation of DI
Establishment of pathologic polyuria or
polydipsia (exceeding 2L/m2/24hr)
Careful history must be obtained

Non specific features

Poor suck, failure to thrive, irritability

Earliest signs include vigorous suck w/ vomiting,

fever w/o apparent cause, constipation,
excessively wet diapers
In older infants and children, they can be irritable
Nocturia
Signs of dehydration on PE

Complications of DI

Growth failure
Nocturia and enuresis
Hypernatremic dehydration
Seizures
Mental retardation

Approach to Patient with Suspected DI

Seru
m

Urine

Osmolalit
y
Sodium

Osmolalit
y

Potassium
BUN

Specific
Gravity

Creatinine
Glucose
Calcium

Glucose

The
Thediagnosis
diagnosisof
ofDI
DIisis
established
establishedif:
if:
1.
1. the
theserum
serum
osmolality
osmolalityisisgreater
greater
than
300
mOsm/kg
than 300 mOsm/kg
(if
(if<270,
<270,ititisisunlikely)
unlikely)
(if
(if270-300,
270-300,do
dowater
water
deprivation
test)
deprivation test)

2.
2.and
andthe
theurine
urine
osmolality
osmolalityisisless
lessthan
than
300
300mOsm/kg.
mOsm/kg.
(if
(if>600,
>600,ititisisunlikely)
unlikely)

Water Deprivation Test: How it is done?

(Step 1)

Should be done in the morning under

observation
8 hours fasting enough for children
Weigh the child hourly and measure
plasma and urine osmolality q2 hours

Water Deprivation Test: Initial Interpretation

(Step 2)

NORMA
L
plasma
osmolality
hardly rises
(<300) but the
urine output is
reduced and
urine osmolality
rises (800-1200)

PRIMAR
Y
POLYDIP
SIAlow
Start with

normal serum
osmolality (280)
but urine/plasma
osmolality ratio
rises to >2 after
dehydration

DIABET
ES
INSIPID
US
The plasma

osmolality rises
and
urine/plasma
osmolality ratio
remains <1.5

Water Deprivation Test: The VP challenge test

(Step 3)

At the end of the test, ADH is given (20mg DDAVP

intranasally or 2mg IM) then fluid intake was
allowed
Concentration of dilute urine confirms central DI
and failure suggest nephrogenic causes

Treatment of Central DI
Fluid Therapy
Vasopressin Analogs
Desmopressin
In tablet and intranasal spray forms
Dose is determined based on the desired length of
antidiuresis

Vasopressin Aqueous

Treatment of Nephrogenic DI

Provision of adequate fluids and calorie

Low Sodium Diet
High dose of DDAVP
Correction of underlying cause
Drugs (thiazides, indomethacin
carbamazepine)

Main treatment of NDI focuses on elimination of underlying

disorder
Congenital NDI is difficult to treat

Case 1: History
A 6-month old boy is referred because of
failure-to-thrive and vomiting
No other significant past or family history,
born at 37 weeks gestation, normal
pregnancy

Case 1: examination
Unremarkable examination: weight: 5.54
kg (<0.4th 5ile), height: 62.5 cm (>0.4th),
OCF: 42.5 cm (<9th %ile)
BP: 94 mmHg systolic
Normal renal US
biochemistri Plasma
es

Urine

unit

Sodium

157

<5

mmol/l

creatinine

0.03

1.1

mmol/l

osmolality

319

83

mosmol/kg

Approach to Patient with Suspected DI

Seru
m

Urine

Osmolalit
y
Sodium

Osmolalit
y

Potassium
BUN

Specific
Gravity

Creatinine
Glucose
Calcium

Glucose

The
Thediagnosis
diagnosisof
ofDI
DIisis
established
establishedif:
if:
1.
1. the
theserum
serum
osmolality
osmolalityisisgreater
greater
than
300
mOsm/kg
than 300 mOsm/kg
(if
(if<270,
<270,ititisisunlikely)
unlikely)
(if
(if270-300,
270-300,do
dowater
water
deprivation
test)
deprivation test)

2.
2.and
andthe
theurine
urine
osmolality
osmolalityisisless
lessthan
than
300
300mOsm/kg.
mOsm/kg.
(if
(if>600,
>600,ititisisunlikely)
unlikely)

Diagnosis?
Diabetes insipidus (central or
nephrogenic)

Further investigations
Admission for iv DDAVP test
Max urine osm: 83 mosm/kg

Diagnosis:
Nephrogenic diabetes insipidus

NDI: management
Dietetic advice: restricting solute load to 15
mosm/kg/d but providing appropriate calories
and RDA for protein
Each gram protein is metabolised to appr. 4
mmol of urea
Each gram of salt constitutes appr. 18 mosm
(9 each for sodium and chloride)
Lipids and carbohydrates do not generate
solute load (hence maxijul fortified milk)

NDI: medications
Indometacin: enhances (?) proximal tubular
sodium uptake. NOT by chemical
nephrectomy
Thiazide: enhances proximal tubular
sodium uptake
As PT is permeable for water, enhanced
sodium uptake results in enhanced water
reabsoprtion, thus less water is transported
to CD, where it cannot be reabsorbed.
Medications can often be discontinued with
increasing age

DI

DM DKA
Diabetes Mellitus

Source: Nelsons Textbook of Pediatrics 19th Ed.

Diabetes Mellitus (DM)

a common, chronic, metabolic syndrome characterized by

hyperglycemia as a cardinal biochemical feature

Classification
TYPE 1
DIABETES
MELLITUS
Insulin deficiency
due to pancreatic
beta cell damage
More common

TYPE 2
DIABETES
MELLITUS

Insulin resistance
of skeletal muscle,
liver and adipose
tissue

More toxic way of

Morbidity
and mortality stem for acute metabolic derangements and from
living

long term complications

Pathophysiology of Diabetes Mellitus

Type I DM

Formerly called insulin dependent DM (IDDM) or Juvenile

Diabetes
Low or absent levels of endogenously produced insulin
More prone to develop DKA
May be present on any age but ofen on on childhood (7-15
years old)
Can be associated with other illnesses like thyroiditis, celiac
disease, multiple sclerosis and addison dse
More common on African-Asian origin (dont look at me please )

Causes T1
ENVIRONMENTAL
TRIGGERS
CELLULAR (T CELL) AUTOIMMUNITY
HUMORAL AUTOANTIBODIES

BETA CELL MASS

(ICA, IAA, GAD65A, ICA512A)

LOSS OF INSULIN
GLUCOSE STARTS TO INCREASE

Honeymoon

GENETICS

BETA CELL INJURY

TIME

PRE
DIABETES

DIABETES

NEWLY DIAGNOSED DIABETES

Causes of Type 1 DM: Genes and Antibodies

4 antibodies: glutamic acid decarboxylase (GADA), islet
tyrosine phosphatase (IA2), zinc transporter 8 A
(ZnT8A), insulin autoantibodies (IAA)
>90% newly diagnosed +Abs; 3.54% of unaffected first-degree
relatives

4050% of genetic predisposition on short arm of

chromosome 6, Class II HLA region of the major
histocompatibility complex (MHC)
Whites HLA-DR3 or HLA-DR4, Blacks HLA-DR7, Japanese HLA-DR9

~11 other loci, insulin gene chromosome 11 (INS-VNTR),

T-cell activation and regulation genes (CTLA-4), protein
tyrosine phosphatase N22 (PTPN22), genes in interleukin
pathway (IL-2R)
HLA, CTLA-4, and PTPN22 are associated with other autoimmune
diseases

Symptoms of Type 1 Diabetes Mellitus

ISPAD CPG 2014 Compendium

Type 2 DM

Formerly known as adult onset DM,

Non insulin dependent DM (NIDDM)
or
Maturity onset Diabetes of
the Young (MODY)
Usually Obese ( dont look at me
again :P )

Mostly not insulin dependent

Infrequently develops DKA
Most prevalent form of DM among
adults
Presentation is more insidious
Uncommon history of polyuria and
polydipsia
Most common cause of consult is
excessive weight gain. . . . . . . . . .
Nelsons Textbook of Pediatrics 19th Edition

Type 2 DM: nature, presentations

Mean age of presentation: 13.8

years (10-18 years old)
Autoimmune markers may be
positive in 30% of DM type 2
cases
Acanthosis nigricans may reflect
insuliin resistance
PCOS , premature adrenarche
and hirsutism in some females

Nelsons Textbook of Pediatrics 19th Edition

Causes T2: Gestational Diabetes as a

Driver of T2

Diabetes in pregnancy can

lead to a cycle of diabetes
Dabalea
D, Hanson
RL, Bennett
PH, et al. Increasing prevalence
affecting
future
generations.
of Type II diabetes in American Indian children. Diabetologia.
1998;41(8):904910

Different cases of an 11 8month year old female patients

Type 1 DM

Type 2 DM

Chief complaint: Urinates 2 to 3

times at night times 2 weeks
A1C 8.2% at outside clinic
Weight 63 kg, body mass index
(BMI) >85th percentile for
age/gender
Reported 15 lb weight gain
last year, recent loss
Blood pressure (BP) 92/65
Menses at 10 years irregular
Prenatal excessive maternal
weight gain, no diabetes
Family history
Mother from Arizona, HA, +
for obesity
Father non-Hispanic White,
hypertension

Chief complaint: Urinates 2 to 3

times at night times 2 months
A1C 8.2% at outside clinic
Weight 78 kg, BMI >95th
percentile for age/gender
Reported 30 lb weight gain
last year, recent loss
BP 128/83
Menses at age 10 years
irregular
Prenatal excessive maternal
weight gain, ? diabetes,
Family history
Mother from Arizona, AI/HA, +
for obesity
Father is non-Hispanic White,
hypertension

Presentation, Diagnostic Criteria,

Screening
Presentation

T1 rapid onset, severe hyperglycemia, acidosis, diabetic

ketoacidosis (DKA)
Results of TrialNet show T1 can be indolent

T2 indolent, mild hyperglycemia, rare acidosis, no DKA

AA high rate of mild DKA, higher glucose/A1C,
symptomatic at presentation

Diagnostic criteria is the same for T1 and T2

Symptoms of diabetes plus casual glucose 200 mg/dL
Fasting plasma glucose 126 mg/dL
2-hour postload glucose 200 mg/dL during oral glucose
tolerance test (OGTT)

?A1C >6.5%
Used in adults but not established in children

Presentation, Diagnostic Criteria,

Screening

ISPAD CPG 2014 Compendium

Presentation, Diagnostic Criteria, Screening

Type 1 DM

Evidence of insulin
deficiency
hyperglycemia and
acidosis, DKA
mistaken for flu
Hardest diagnosis in
infants/toddlers
No other family
member
Other autoimmune
diseases

Type 2 DM
Evidence of insulin
resistance,
hypertension,
dyslipidemia, NASH
Presentation during or
after puberty
T2 in first-degree
relative
Acanthosis nigricans,
sleep apnea, polycystic
ovary syndrome
(PCOS), candidiasis

Zeitler P. Approach to the obese adolescent with new-onset diabetes. J Clin Endocrinol Metab.

Screening for T1

Immune Tolerance Network

The reason to screen and In the context of

research trials
intervene early in T1D:

TrialNet, Immune
Tolerance Network,
TEDDY, etc.

Common, serious in
terms of morbidity and
Screen with antibodies,
mortality
? genes
Latency period without
Reason
symptoms
Prevention studies
Screening test with
Oral insulin, omegas,
vitamin D, anti-CD3
sensitivity and
Natural history study
specificity
Intervention early is
more effective,

Further Screening for T2

American Diabetes Association (ADA) / American
Academy of Pediatrics (AAP) Consensus
Statement,
2000
Criteria*:
Overweight (BMI 85th percentile for age
and sex, weight for height 85th percentile, or weight
120% of ideal for height)
PLUS: any 2 of the following risk factors:
Family history of diabetes mellitus (DM) 2 in first- or seconddegree relative
Race/ethnicity
Signs of insulin resistance

Age of Initiation: Age 10 or at onset of puberty

Frequency: Every 2 years in the context of health visit
Test: Fasting plasma glucose preferred
* Clinical judgment should be used.

American Diabetic Association. Type 2 diabetes in children and

adolescents. Diabetes Care. 2000;23(3):381389

11 8/12-Year-Old Female Patients: going back

Obtain the following workup:
Random plasma glucose,
247 mg/dL, repeat A1C 8.5%
CO2 16 meq/L, venous pH
7.32, LDL 165 mg/dL,
triglycerides
200 mg/dL

ANTIBODIES GADA+
Treatment: In- or out-patient?
What kind of insulin
treatment?
Intensive?

All patients and families

receive diabetes and lifestyle
education.

Obtain the following work up:

Random plasma glucose 247
mg/dL, repeat A1C 8.5%
CO2 20 meq/L, venous pH
7.38, LDL 178 mg/dL,
triglycerides 215 mg/dL

ANTIBODIES ALL NEGATIVE

Treatment: In- or out-patient?
Do you start insulin?
Metformin alone is first-line
therapy when glucose level is
<250 mg/dL and patient is
non-ketotic
All patients and families
receive diabetes and lifestyle
education.

Diagnostics: Determining Diabetes Type

in Youth
with BMI >85th Percentile
New onset of
diabetes
BMI >85th percentile

Positiv
e
Type 1

Pancreatic
autoantibodie
s

Consider
MODY;
if not obese,
NHW
Negativ
e

Likely Type
2

Monitor
course
Insulin
requireme
nt

No

Type 2

Yes
C-peptide normal/elevated
Type 2 ?adherence
Severe
resistance/deficiency
Zeitler P. Approach to the obese adolescent with new-onset
diabetes.
J Clin Endocrinol Metab. 2010;95(12):51635170

Treatment: Diabetes is Hard to Manage

Early and Persistent Glucose Control is Important.
Age

Pre-Meal BG

HS/Night BG

A1c

Toddler
(05 years)

100180

110200

7.5 &
8.5%

90180

School-age
(611 years)

<8%

Adolescent
(1219
years)

90130

90150

<7.5%

Type 2

80130

90150

<7.0%

Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a
statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186212

Treatment
Type 2 DM
Early
and Persistent Glucose Control is Important.
Type
1
DM
Glucose monitoring

Self-monitoring glucose, continuous

glucose monitoring, understanding
glucose targets, A1C quarterly
Medications
Insulin therapy: Multiple injections,
pens, pumps, changing dosages prn
Medical nutrition therapy
Balancing food: Managing carbs,
weight
Psychosocial support
Assess, treat co-morbidities,
complications
BP, cholesterol, thyroid, celiac, eye
exams, microalbuminuria, disordered
eating
Visits to health care team
Routine pediatric care, flu shots,
hepatitis B immunization, transition
planning
Sick day management

Glucose monitoring
Self-monitoring glucose,
understanding glucose targets, A1C
quarterly
Medications
Glucose lowering agents
Metformin, insulin therapy
Others not approved
Medical nutrition therapy
Weight reduction, lifestyle counseling
Psychosocial support
Assess, treat co-morbidities,
complications
BP, cholesterol, disordered eating,
PCOS, NASH, microalbuminuria, eye
exams
Visits to health care team
Routine pediatric care, flu shots,
hepatitis B immunization, transition
planning
Sick day management

Treatment: T2 ISPAD Guidelines, 2009

Rosenbloom AL, Silverstein JH,

Amemiya S. Type 2 diabetes in
children and adolescents. Pediatric
Diabetes. 2009;10(12):1721

Treatment: Lifestyle Tips for Teens with

Diabetes Series from National Diabetes
Education Program

Complications T1: Catastrophe

at DiagnosisDKA
Severe metabolic disturbance
Insulin deficiency, secondary counter-regulatory hormone elevation

North America and Europe statistics

30% of new cases, 20% of deaths from diabetes <20 years

1/200 episodes result in cerebral edema

1/3 die, 1/3 permanently impaired, 1/3 recover

Costs: >2.5 billion dollars

Risk factors for cerebral edema
Young age, poverty, no knowledge of signs and symptoms, lack of
access to care
Lower pCO2 , higher BUN at DX, Rx with HCO3, smaller increase in Na

Mechanism(s)
Osmotic cellular swelling versus vasogenic process
Glaser NS, Wooten-Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J
Pediatr. 2004;145(2):164171

Complications and Co-Morbidities T2

TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical

trial to maintain glycemic control in youth with type 2
diabetes. New Eng J Med. 2012:110

5. Prevention
Home
Communities
Health Care
Access,
Adherence
Schools and
Child Care
Worksites
Age,
Sex, SES,
Race/Ethnicity
Culture
Psychosocial
Factors - Stress
Genes,
GeneEnvironment
Interactions
Intrauterine
Environment

Socio-ecological Model
Built Environment
Government
Public Health
Sectors of
Agriculture
Influence
Education
Media
Behavior
Land Use and
al
Transportation
Settings
Communities
Individua
Foundations
l Factors
Industry
Physical
Food &
Beverag
Food
Activity
e Intake
Beverage
Energy Intake
Energy Expenditure
Retail
Energy Balance
Leisure and
Obesity
Recreation
Insulin Resistance/Deficiency
Entertainment
Type 2 Diabetes
Social
Norms
Subculture

Conclusion

Type 1 diabetes

Genetic predisposition
and environmental
triggers cause
autoimmunity,
+antibodies
Rare in family
members
Screening in research
Presentation rapid,
severe, but not always
Treatment with
education, support and
intensive insulin, plus
technology,
risk of hypoglycemia,
A1C main outcome
measure
Complications related
to dysglycemia, occur
in youth but rare, comorbidities related to

Type 2 diabetes

Food

Pancreas

Gut

Insulin
Glucose

Muscle

Genetic predisposition
and environmental
trigger of obesity, insulin
resistance and
deficiency
Common in first-,
second-degree relatives
Screening criteria but
rare to find
asymptomatic
Presentation slow, mild,
but not always, and
maybe less than
thought
Treatment needs to be
more aggressive than
monotherapy to
maintain glycemic
control
Complications common,
early, co-morbidities

DI

DM DKA

Diabetetic Ketoacidosis

Video?
https://www.youtube.com/watch?
v=XX1ps4WHAtg

Diabetic Ketoacidosis: Definition

End result of DM metabolic abnormalities

Occurs in 20-40% children with new onset
DM, or DM with poor meds compliance

Diabetic Ketoacidosis: Risk Factors

Younger age (<2 years old

Delayed diagnosis
Lower socioeconomic status
Countries with low prevalence of
type
DM
Poor 1
metabolic
control with DM
patients
Previous DKA episodes
AGE with inability to maintain
hydration
Psychiatric and/or eating disorders
Challenging social and family
circumstances
Peripubertal and adolescent girls
Limited access to health care
services
Failures of insulin pump therapy

Diabetic Ketoacidosis: Criteria for Diagnosis

BIOCHEMICAL
CRITERIA
Hyperglycemia [blood
glucose (BG) >11
mmol/L
(200 mg/dL)]
Venous pH<7.3 or
bicarbonate <15
mmol/L
Ketonemia and
ketonuria.

Diabetic Ketoacidosis: Criteria for Diagnosis

CLINICAL SIGNS OF DKA
Dehydration (which may be difficult to detect)
Tachycardia
Tachypnea (which may be mistaken for pneumonia or
asthma)
Deep, sighing (Kussmaul) respiration; breath has the smell of
acetone (variously described as the odor of nail polish
remover or rotten fruit)
Nausea, vomiting (which may be mistaken for Gastroenteritis)
Abdominal pain that may mimic an acute abdominal
condition
Confusion, drowsiness, progressive reduction in level of
consciousness and, eventually, loss of consciousness.

Diabetic Ketoacidosis: Emergency Assessment

Initial
Resuscitation
first (PALS)
Blood
Glucose

Blood or
urine
ketones

Serum
Electrolyte
s

ABG

Adequate
hydration/
fluid
resuscitati
on

Double line
necessary

Guidelines and Protocols are

available for DKA, but always
remember that the basis of
management must be
primarily based on

CLINICAL JUDGEMENT

Diabetic Ketoacidosis: Management

Considerati
ons
Must be
admitted on
experienced
centers
Meticulous
monitoring
Referral to
specialists

Goals of
Therapy
Correct dehydration
Correct acidosis
Reverse ketosis
Slowly correct
hyperosmolality
Restore blood
glucose to normal
Monitor for DKA
complications

Diabetic Ketoacidosis: Management

Fluid replacement
should begin
before starting
insulin therapy
Insulin Therapy
Potasium

Bicarbonate
Cerebral edema
precautions

Begin with 0.05-0.1 U/kg 1-2 AFTER

starting fluid replacement therapy
If patient hyperK, defer K replacement
until (+) UO.
20meqs/L IV at rate of >10mL/kg/hr (E)
During life threatening events only
WOF: headache, bradycardia, change in
neuro status, irritability, etc
Ready for possible mannitol or
hypertonic saline

Diabetic Ketoacidosis: Complications

Inadequate rehydration
Hypoglycemia
Hypokalemia
Hyperchloremic acidosis
Cerebral edema

Hyperglycemic Hyperosmolar State

Extreme elevations in serum glucose
concentrations and hyperosmolality without
significant ketosis
Less frequent than DKA
Clinical manifestations (compared to DKA)
Gradual increasing polyuria and polydipsia

Treatment: more aggressive fluid

replacement than DKA

Hyperglycemic Hyperosmolar State

Zeitler P, Haqq A, Rosenbloom A, Glaser N.

Hyperglycemic hyperosmolar syndrome in children:
pathophysiological considerations and suggested
guidelines for treatment. J Pediatr 2011: 158: 914
14 e1112.

Diabetic Ketoacidosis: Prevention

Treat the underlying cause

If documented recurrent DKA,
think of psychosocial problems
and failure to take insulin (E)

Thank You