DIABETES MELLITUS

Moderator: Dr. Pooja Dewan

Presenters: Dr. Jiwan

Dr. Chandrika

INTRODUCTION

Chronic metabolic syndrome characterized by hyperglycemia

Pathophysiology:

Absolute insulin deficiency OR

Absolute insulin resistance OR

Combination of defects in both

ETIOLOGICAL CLASSIFICATION: ADA 2014

I. Type 1 diabetes (beta cell destruction: Insulin deficiency)

1 . Immune mediated

2 . Idiopathic

II. Type 2 diabetes (variable combination of insulin resistance and insulin deficiency)

1 . Typical

2 . Atypical

III. Other specific types

A. Genetic defects of beta cell function

1.Maturity onset diabetes of young(MODY)

2. Mitochondrial DNA mutation

3. Others

B. Genetic defects in insulin action1. Type A insulin resistance2. Leprechaunism (elfin features, insulin receptor defect, IUGR)3. Rabson–Mendenhall syndrome4. Lipoatrophic diabetes5. Others

C. Diseases of the exocrine pancreasPancreatitis, Trauma/pancreatectomy, Neoplasia, Cystic fibrosis, Hemochromatosis, Fibrocalculous pancreatopathy, etc

D. Endocrinopathies1. Acromegaly 5. Hyperthyroidism 2. Cushing’s syndrome 6. Somatostatinoma3. Glucagonoma 7. Aldosteronoma4. Phaeochromocytoma 8. Others

E. Drug- or chemical-induced

1. Vacor 7. β-Adrenergic agonists

2. Pentamidine 8. Thiazides

3. Nicotinic acid 9. Dilantin

4. Glucocorticoids 10. α-Interferon

5. Thyroid hormone 11. Others

6. Diazoxide

F. Infections

1. Congenital rubella 3. Enterovirus

2. Cytomegalovirus 4. Others

G. Uncommon forms of immune-mediated diabetes

1. ‘Stiff-man’ syndrome 4. IPEX

2. 2. Anti-insulin receptor antibodies 5. Others

3. 3. Autoimmune polyendocrine syndrome (APS) types I and II.

H . Other genetic syndromes sometimes associated with diabetes

1. Down syndrome

2. Klinefelter syndrome

3. Turner syndrome

4. Wolfram syndrome

5. Friedreich’s ataxia

6. Huntington’s chorea

7. Laurence–Moon–Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10. Prader–Willi syndrome

11. Other

IV. Gestational diabetes mellitus (GDM)

LESS COMMON TYPES OF DIABETES IN CHILDREN

Type 2 DM

Screening:

Children: age ≤18 yrs

*BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% ideal for height

†Native American, African American, Latino, Asian American, Pacific Islander

‡Acanthosis nigricans, hypertension, dyslipidemia, PCOS, or small-for-gestational-age birth

weight §Sleep apnea, hepatic steatosis, orthopedic complications, psychosocial concerns

Consider for all children who are overweight* and have ≥2 of any of the following risk factors:

• Family history of type 2 diabetes in first- or second-degree relative

• Race/ethnicity†

• Signs of insulin resistance or conditions associated with insulin resistance‡

• Maternal history of diabetes or GDM during child’s gestation

TYPE 2 DM CONTD...

Begin testing at age 10 yrs or onset of puberty

Test every 3 yrs

A1C test recommended for diagnosis in children and adolescents

At Diagnosis After Diagnosis

• Perform eye exam • Measure risk factors

o Blood pressure o Fasting lipidso Albumin excretion

Similar screening, treatment as for type 1 diabetes for • Hypertension • Albumin excretion • Dyslipidemia• Retinopathy

LESS COMMON TYPES OF DIABETES IN CHILDREN CONTD...

Monogenic diabetes

o Originally termed MODY

o Mild , non-ketotic diabetes

o Onset: 9-25 yrs

o AD inheritance

o Mutation in genes for development /function of beta cells

o Strict criteria for diagnosis:

o At least 3 generations affected with AD transmission

o At least 1 affected subject diagnosed < 25 yrs

LESS COMMON TYPES OF DIABETES IN CHILDREN CONTD...Neonatal diabetes

o Rare (1 in 100 000-400 000 births)

o 1st six months of life

o May present as late as 9-12mnth

o Alternative term: monogenic diabetes of infancy

o Permanent:

o 50% cases

o Lifelong treatment

o Transient:

o Remits within weeks or months

o 50-60%-permanent diabetes, typically around puberty

o Chr 6q24 (2/3rd cases)

LESS COMMON TYPES OF DIABETES IN CHILDREN CONTD...

Mitochondrial diabetes:o Maternally inherited diabetes

o Associated with sensorineural deafness

o Progressive non-autoimmune beta cell failure

o Presentation : variable

o Acute onset with or without ketoacidosis

o Gradual onset

o Avoid metformin : theoretical risk of severe lactic acidosis

LESS COMMON TYPES OF DIABETES IN CHILDREN CONTD...Cystic fibrosis and diabetes:

o CFRD : Most common comorbidity associated with cystic fibrosis

o Pathophysiology:

o Insulin deficiency

o Glucagon deficiency

o Insulin resistance (secondary to infections & medications : bronchodilators, glucocorticoids)

o Others: delayed gastric emptying, altered intestinal motility, liver disease

o Presentation : Adolescence & early adulthood

CYSTIC FIBROSIS AND DIABETES CONTD...

o Onset of CFRD : date a person with CF first meets diabetes diagnostic criteria , even if hyperglycemia subsequently abates.

o Poor prognostic sign

o Annual screening:

o Commence by age 10 years in all CF patients who do not have CFRD

o 2 hr OGTT , 75 gm ( 1.75 g/kg)

LESS COMMON TYPES OF DIABETES IN CHILDREN

CONTD...

Stress hyperglycemia:

Associated with acute illness/sepsis; traumatic injuries, febrile seizures, burns, fever.

Incidence of progression to overt diabetes: 0-32%

TYPE 1 DIABETES MELLITUS

Formerly called IDDM or juvenile diabetes

Severe insulinopenia and dependence on exogenous insulin to prevent ketosis and to preserve life

Onset- childhood (median age 7-15 yrs) but may present at any age

Autoimmune destruction of pancreatic islet beta cells

Diabetes associated auto antibodies:

1. GAD 2. IA2 3. IAA 4. ZnT8

Clinically symptomatic: destruction of 90% β – cells.

Genetic susceptibility

Exposure to unknown environmental triggers

chance??

Lack of Exposure to unknown environmental

triggers chance??

No autoimmunityautoimmunity

Progressive beta cell loss

No apparantbeta cell loss

why??

Clinical diabetes

Clinical remission(Honeymoon phase)

complications

NO diabetes

TYPE 1 DIABETES MELLITUS CONTD...

Genetic factors:

multiple genes

> 60 risk loci identified

HLA genotype : 50% risk

Highest risk haplotypes Protective haplotypes

1. DRB1*03:01-DQA1*05:01-DQB1*02:01 (DR3/DR4)

2. DRB1*04-DQA1*03:01-DQB1*03:02 (DQ2/DQ8)

1. DRB1*15:01-DQA1*01:02-DQB1*06:02

2. DRB1* 14:01-DQA1*01:01-DQB*05:03

3. DRB1*07:01- DQA1*02:01-DQB1*03:03

TYPE 1 DIABETES MELLITUS CONTD...

Environmental factors:

Largely unknown

Enteroviruses

Congenital rubella syndrome Prenatal infection : beta cell auto immunity in up to 70%

: development of T1DM in up to 40%

Time lag as high as 20 yrs

No increase risk when infection develops after birth.

The hygiene hypothesis Protective role of infections

Lack of exposure to childhood infections: increase chances of developing autoimmune diseases including T1DM.

TYPE 1 DIABETES MELLITUS CONTD...

Environmental factors contd...

Diet

Breast feeding: decrease risk of T1DM

: directly or delaying exposure to

cow’s milk protein

Psychological stress

The accelerator hypothesis: role of insulin resistance

T1DM and T2DM – same disorder of insulin resistance, set against different genetic backgrounds.

PATHOPHYSIOLOGY

Insulin

causes

Is secreted by

Secretion all mediated by

stimulted by secretion

inhibited by

A polypeptide hormone

Beta cells of pancreas

Blood glucose

epinephrine

glucose uptake synthesis of•Glycogen•Protein

•FatGlycogenolysis

GluconeogenesisKetogenesis

lipolysis

Activation of insulin receptors

PATHOPHYSIOLOGY CONTD....

Normal insulin secretion : interplay of neural, hormonal, substrate related mechanisms

Normal metabolism : regular swings between post prandial high insulin anabolic state and fasted low insulin catabolic state

T1DM : permanent low insulin catabolic state in which feeding cannot reverse but rather exaggerates these catabolic processes.

PATHOPHYSIOLOGY CONTD...

Liver is more sensitive than muscle or fat to a given concentration of insulin

With progressive failure of insulin secretion, initial manifestation is postprandial hyperglycemia.

Fasting hyperglycemia : late manifestation, reflects severe insulin deficiency and excessive endogenous glucose production

PATHOPHYSIOLOGY CONTD...

Hyperglycemia

Osmotic diuresis (glycosuria when exceeds renalthreshold)

Loss of calories and electrolytes; persistent dehydration

Release of stress hormones (cortisol, glucagon, epinephrine, growth hormone)

Metabolic decompensation Decrease insulin secretion(epi) Antagonizing insulin action(epi,corti,GH) Promote glyocogenolysis , gluconeogenesis , lipolysis , ketogenesis

( glucagon,epi,GH,corti) Decrease glucose utilization and glucose clearance (epi,corti,GH)

PATHOPHYSIOLOGY CONTD...

Insulin deficiency + glucagon excess

FFA ketone bodies

*Acetone

* β hydroxybutyrate

* acetoacetate

Exceeds capacity of

peripheral utilization and renal excretion

PATHOPHYSIOLOGY CONTD...

PATHOPHYSIOLOGY CONTD...

Accumulation of keto acids

Metabolic acidosis (diabetic ketoacidosis, DKA)

Compensatory rapid deep breathing(kussmaul breathing)

Ketones and cations loss in urine

Further increases water and electrolyte loss

Progressive dehydration acidosis hyperosmolarity

Diminished cerebral oxygen utilization

Impaired consciousness

comatose

CLINICAL MANIFESTATIONS

Initially : limited insulin reserve occasional hyperglycemia.

When s. glucose increases above renal threshold

Intermittent polyuria or nocturia

Further beta cell loss : chronic hyperglycemia causes more persistent diuresis with nocturnal enuresis and polydipsia.

Female patients : monilial vaginitis

CLINICAL MANIFESTATIONS CONTD...

Calories loss in urine (glycosuria) triggers compensatory hyperphagia.

Hyperphagia does not keep pace with glycosuria

loss of body fat weight loss.

Extremely low insulin levels keto acids accumulate abdominal discomfort, nausea and emesis.

Dehydration accelerates, polyuria persists weakness or orthostasis.

CLINICAL MANIFESTATIONS CONTD...

Hyperosmotic state : intravascular volume is

conserved at the expense of intracellular volume.

Ketoacidosis exacerbates prior symptoms and leads

to kussmaul respiration, fruity breath odor,

prolonged QTc interval, diminished neurocognitive

function, and possible coma.

SYMPTOMS & SIGNS

More Common Less Common Severe (Diabetic ketoacidosis)

Weight loss Excessive hunger Frequent vomiting and acute abdominal pain

Polyuria – in younger children bedwetting is common

Blurred vision Flushed cheeksAcetone smell on breath

Excessive thirst Mood changes Dehydration with continuing polyuria

Tiredness - not want- ingto work or play

Skin infections Decreased level of consciousness

Oral or vaginal thrush Kussmaul respiration (deep, rapid, sighing

Abdominal pain Coma , Shock

DIAGNOSTIC DILEMMAS

Sepsis

Asthma/Pneumonia

UTI

Gastroenteritis

Acute abdomen

High index of suspicion if inappropriate polyuria in any child with dehydration, and poor weight gain.

PREDIABETES

Patients with impaired fasting glucose(IFG) and/or impaired glucose tolerance : referred to as having ‘prediabetes’.

Intermediate stages between normal glucose homeostasis and diabetes

IFG : measure of disturbed carbohydrate metabolism in the basal state.

Fasting plasma glucose : 100-125 mg/dl = IFG

IGT : a dynamic measure of carbohydrate intolerance after a standardized glucose load.

2 hour post load glucose : 140-200 mg/dl = IGT

IFG and IGT are not interchangeable.

DIAGNOSITIC CRITERIA (ISPAD/ADA GUIDELINES)

Criteria for the diagnosis of diabetes mellitus

i. Classic symptoms of diabetes with plasma glucose concentration ≥11.1mmol/L (200mg/dL)

OR

ii. Fasting plasma glucose ≥7.0mmol/L (≥126mg/dL).

OR

iii. Two hour post-load glucose≥11.1mmol/L (≥200mg/dL) during an OGTT*

OR

iv. ? HbA1c > 6.5%

INVESTIGATIONS

Estimation of blood glucose

Sample: 1. whole blood

2. plasma

3. serum

Whole blood values : 10-15% lower than plasma

Lower glucose concentration in erythocytes

Normal range vary with hematocrit.

Plasma preferred.

SAMPLE COLLECTION:

Blood is collected into a tube containing sodium fluoride (NaF) and potassium oxalate (1:3 mixture).

Both the substances act as anticoagulant and NaFprevents glycolysis in RBCs and WBCs by inhibiting the enzyme enolase.

PRINCIPLE:

GLUCOSE OXIDASE METHOD

measure of true glucose content in body fluids

glucometers as well as autoanalyzers : based on this principle.

The intensity of the colored product is proportional to the glucose concentration and is measured photometrically between 490 and 540 nm.

GLUCOMETERS

Test strips: impregnated with glucose oxidase and other components. Each strip is used once and then discarded

Coding:

manual entry of code into glucometer : calibrate meter

to that batch of strips ( if carried out incorrectly, the meter reading can be up to 4 mmol/L (72 mg/dL) inaccurate)

Alternative: strips containing code information or microchip to be inserted into the meter.

‘Whole blood equivalent’ or ‘plasma equivalent’ values :

plasma equivalent reading using an equation built into

the glucose meter.

EXAMINATION OF URINE

FOR SUGAR :BENEDICTS TEST

>2%1.5-2%Neg 0.5-1%

FOR KETONES : ROTHERA’S NITROPRUSSIDE TEST

Ketonuria is seen in - Diabetic ketoacidosis, Starvation, Severe vomiting, Glycogen storage disorders and in high fat

diet.

KETOSTIX

Principle:

development of colors ranging from buff-pink to maroon when acetoacetic acid reacts with nitroprusside.

It does not detect betahydroxybutyrate

MANAGEMENT OF TYPE 1 DIABETES

IN CHILDREN AND ADOLESCENTS

MANAGEMENT

New Onset Diabetes without ketoacidosis

Management of DKA

NEW ONSET DIABETES WITHOUT KETOACIDOSIS

Goals of therapy:

Maintaining tight glycemic control

Avoid hypoglycemia

Eliminate polyuria, and nocturia

Prevent DKA

Allow normal growth & near normal lifestyle (education, modification in diet, exercise)

TREATMENT: INSULIN THERAPY

Insulin Requirements:

Factors:

Body Weight

Age: Pubertal Vs Younger

New onset: Honeymoon phase (residual beta cell function)

Long standing diabetes: No insulin reserves

EXOGENOUS VS ENDOGENOUS INSULIN

Exogenous insulin does not pass through liver unlike pancreatic insulin

Hypoglycemia can occur with exogenous insulin unlike endogenous insulin release which can be inhibited with onset of hypoglycemia

Exogenous insulin absorption affected by site of injection Vs endogenous insulin which is directly released into portal circulation.

TYPES OF INSULIN FOR USE IN T1DM

Insulin Type (trade name) Onset Peak Duration

Bolus (prandial) Insulins

Rapid-acting insulin analogues (clear):

• Insulin aspart (NovoRapid®)

• Insulin glulisine (Apidra™)

• Insulin lispro (Humalog®)

10 - 15 min

10 - 15 min

10 - 15 min

1 - 1.5 h

1 - 1.5 h

1 - 2 h

3 - 5 h

3 - 5 h

3.5 - 4.75 h

Short-acting insulins (clear):

• Insulin regular (Humulin®-R)

• Insulin regular (Novolin®geToronto)

30 min 2 - 3 h 6.5 h

Basal Insulins

Intermediate-acting insulins (cloudy):

• Insulin NPH (Humulin®-N)

• Insulin NPH (Novolin®ge NPH)

1 - 3 h 5 - 8 h Up to 18 h

Long-acting basal insulin analogues (clear)

• Insulin detemir (Levemir®)

• Insulin glargine (Lantus®)

90 minNot

applicable

Up to 24 h

(glargine 24 h,

detemir 16 - 24 h)

INSULIN REGIMENS

Basal-bolus Regimen: Slow onset, long duration background insulin for b/w meal glucose control and rapid onset insulin at each meal

X Twice daily insulin: NPH combined with regular insulin (70/30, 75/25): No longer preferred: Peaks with NPH & Lente leading to hypoglycemia; Unpredicatableinteraction with plain insulin

X Lente and ultralente no longer available

NPH AND REGULAR(MIXED-SPLIT)

Advantages

2-3 shots per day

“Easier” – less carb counting and calculations

Disadvantages

Strict dietary plan

Less flexible

Less physiologic

BASAL/BOLUS

Advantages

More physiologic

More flexible

Less hypoglycemia

Disadvantages

More labor-intensive (CHO counting, insulin calculations)

At least 4 injections per day

DIABETES CONTROL AND COMPLICATIONS TRIAL

1983-1993, early termination given results

Intensive therapy delays onset and progression of long-termcomplications in type 1 diabetes

Conventional Therapy Intensive Therapy

1-2 injections/day ≥3 injections/day

Mean A1c 9% Mean A1c 7%

APPROXIMATE DAILY INSULIN REQUIREMENTS

Pre-pubertal 0.7 U/kg/d

Mid-pubertal 1.0 U/kg/d

End of pubertal 1.2 U/kg/d

INITIATING THERAPY IN A CHILD NOT IN DKA

Day 1

Give short-acting (regular) insulin (0.1 U/kg) every second hour until blood glucose is < 11 mmol/l(200 mg/dL), then every 4-6 hours.

If hourly monitoring of blood glucose cannot be provided, begin with half the above dose.

Day 2 (from morning/breakfast):

Total daily dose 0.5-0.75U/kg/day.

A. TWO INJECTIONS PER DAY

1. A starting point is to give two-thirds of the total dailyinsulin in the morning before breakfast and one-thirdbefore the evening meal.

2. On this regimen, at the start, approximately one-thirdof the insulin dose may be short-acting (regular)insulin and approximately two-thirds may beintermediate-acting insulin.

EXAMPLE

For a 36 kg child who is started on 0.5 U/kg/day, the total daily dose is 18 Units. Two-thirds of this is given in the morning (before breakfast) – (12 Units), and one-third before the evening meal – 6 Units. At each injection, 1/3 is short-acting and 2/3 is intermediate-acting.

Short acting Intermediate acting

Before breakfast 4 Units 8 Units

Before evening meal

2 Units 4 Units

REMEMBER

For mixed insulin, always think of the components

separately (i.e. 10 units of mix 30/70 equals 3 units of

short-acting (regular) and 7 units of intermediate-acting

(NPH)), and adjust doses as above.

B. BASAL BOLUS REGIMEN If short-acting (regular) and intermediate-acting insulin

70% of the total daily dose as short-acting (regular) insulin

(divided up between 3-4 pre-meal boluses) PLUS

30% of the total daily dose as a twice daily injection of intermediate-acting insulin

If short-acting (regular) and long-acting analogue insulins:50% of the total daily dose as short-acting (regular) insulin

(divided up between 3-4 pre-meal boluses) PLUS

50% of the total daily dose as a single evening injection of long-acting analogue insulin. (Sometimes this dose does not last for 24 hours and then can be split into two doses morning and evening).

BASAL/BOLUS

I:CHO = 450/total daily insulin dose = amount of carbs 1 units will cover

Correction Factor (adjustment of insulin dose based on blood glucose): “1800 rule” = 1800/TDD

Glargine can not be mixed with any other insulins

INSULIN DOSE ADJUSTMENTS

Subsequently, doses can be adjusted daily according to blood glucose levels

1 U of rapidly acting insulin can drop blood sugar by 50 mg/dL

Adjustments needed as child returns to daily activities: Insulin requirements decrease

Adjustments also once diet modifications made

RECOMMENDED TARGET BLOOD GLUCOSE LEVELS:

Before meals 4-7 mmol/l (72-126 mg/dl)

After meals 5-10 mmol/l (90-180 mg/dl)

At bed time 6-10 mmol/l (108–180 mg/dl)

At 3am 5-8 mmol/l (90-144 mg/dl)

FACTORS AFFECTING TITRATION

The level of blood glucose can rise in the early morning (“dawn phenomenon”) and so care should taken if increasing the evening intermediate/long-acting dose as hypoglycemia can occur in the middle of the night and this can be dangerous.

Insulin requirements can decrease for a time during the “honeymoon period” before rising again.

The total daily dose required will generally increase as the child grows, and once puberty ensues a higher dose per kg per day is often needed.

MIXING INSULINS IN THE SAME SYRINGE

Common to combine intermediate-acting and short-acting/rapid-acting insulins, to cover both basal needs plus the extra need from eating. Can be combined in the same syringe.

Begin by injecting air into both bottles. The short-acting insulin is generally drawn into the syringe first.

If the intermediate-acting insulin is a “cloudy” insulin, mix by tipping the vial/bottle up and down 10 – 20 times. Do not shake the insulin as this damages the insulin. The doses can be adapted every day according to food intake, physical activity, and blood glucose readings.

GIVING AN INJECTION WITH A SYRINGE

Insulin syringes ( needle < 8mm) made for correct strength of insulin (U-100 or U-40), adequate gradations

Check the expiry date, and the name (correct amount of the correct insulin)

Pull the plunger down to let air in the syringe, equalling the amount of insulin to be given. Inject this air into the vial.

Draw up the insulin

Take a small pinch of skin with the index finger and thumb. The pinch needs to be at least to the depth of the needle. This is especially important in lean people, otherwise the injection may go too deep into the muscle layer, hurt more, and absorption will be affected.

Insert the needle at a 45 degree angle into the pinched-up skin to a distance of 4-6 mm. Give the injection.

Leave the needle in for about 5-10 seconds, then gradually let go of the skin and pull out the needle.

Dispose of the syringe appropriately depending on local advice e.g. sharps container, tin, or strong plastic bottle.

GIVING AN INJECTION WITH A SYRINGE

INJECTION SITES

1. Good technical skill concerning syringes/ pens 2. Injections in the abdominal area preferred ,evenly absorbed , less affected by exercise3. Children and adolescents encouraged to inject consistently within the same area (abdomen, thing, buttocks) at a particular time of day, but must avoid injecting repeatedly into the same spot to avoid lipohypertrophy.

INSULIN STORAGE

Store at 4-8 deg. C in a refrigerator

In hot climates where refrigeration not available, cooling jars, earthenware pitcher (matka) or a cool wet cloth around the insulin.

Insulin must never be frozen.

Avoid direct sunlight or extreme heat (in hot climates or in a vehicle)

Dont use insulins that have changed in appearance (clumping, frosting, precipitation, or discolouration).

After first usage, an insulin vial should be discarded after 3 months if kept at 2-8 deg.C or 4 weeks if kept at room temperature.

INSULIN THERAPY

If initial regimen fails to meet glycemic targets, more

intensive management may be required:

Three methods of intensive diabetes management can

be used at any age:

Similar regimen with more frequent injections

basal bolus regimens using long and rapid acting insulin

analogues

continuous subcutaneous insulin infusion (CSII, insulin pump

therapy)

GLYCEMIC TARGETS

Age (years) A1C (%) FPG / premeal PG

(mg/dL)

Considerations

<5 7.5- 9.0% 100-200 Caution is required to minimize

hypoglycemia because of the potential

association between severe hypoglycemia

and later cognitive impairment. Consider

target of <8.5% if excessive hypoglycaemia

occurs

5-11 6.5-8.0% 150-200 Targets should be graduated to the child’sage. Consider target of <8.0% if excessive hypoglycaemia occurs

12-15 6.0-7.5% 120-180 Appropriate for most adolescents

*Postprandial monitoring is rarely done in young children except for those on pump therapy for whom targets are not availableA1C = Glycated Hemoglobin; FPG = Fasting Plasma Glucose; PG = Plasma Glucose; N/A = Not Available

GLYCEMIC TARGETS

Children with persistently poor glycemic control (e.g.A1C >10%) should be assessed by a specialized pediatric diabetes team for a comprehensive interdisciplinary assessment and referred for psychosocial support as indicated . Intensive family and individualized psychological interventions aimed at improving glycemic control should be considered to improve chronically poor metabolic control.

CHRONIC POOR METABOLIC CONTROL

Diabetes control may worsen during adolescence,

possibly due to the following factors:

Adolescent adjustment issues

Psychosocial distress

Intentional insulin omission

Physiologic insulin resistance

INSULIN THERAPY

It is reasonable to introduce a basic insulin regimen (e.g. minimum 3 injections per day) but a more intensive system is indicated if success not achieved despite good effort

Insulin Pump Therapy

Low Glucose Suspend

Sensor AugmentedInsulin Pump

HONEYMOON PHASE

Educate that it may happen

Diabetes is not cured!

Occurs within first 3 months of diagnosis

Insulin requirements <0.5 units/kg/day

Lasts weeks to up to 2 years

Resolution of glucotoxicity, recovery of residual β-cell function

INSULIN DELIVERY

Vials and syringes

Pens

Insulin pump

INSULIN PUMP THERAPY-CONTINUOUS SUBCUTANEOUS

INSULIN INFUSION (CSII).

Alternative to treatment with MDI if HbA1c is persistently above the individual goal , hypoglycemia is a major problem or quality of life needs be improved

More physiological insulin replacement therapy

Newer generation of ‘‘smart’’ pumps automatically calculate meal or correction boluses based on insulin-to-carbohydrate ratios

Rapid acting analog insulins are used in most pumps

Motivation appears to be a crucial factor for the long-term success of this form of therapy

INSULIN PUMP & CATHETER

INSULIN PUMP

Only NovoLog or Humalog insulin

Hourly basal rate:

1. 80% of total daily insulin dose

2. Divided by 2

3. Divide by 24

Same I:CHO and correction factor

INSULIN PUMP

Advantages

Mimics physiologic pancreatic secretion

Lifestyle

Accurate dosing

Less hypoglycemia

Disadvantages

No depot to protect from DKA

Labor intensive

Expensive

INHALED & ORAL INSULIN THERAPY

Inhaled insulin (EXUBERA) -This new form of insulin therapy investigated in children above 12 years of age as part of a study in adults , not approved for clinical use in children. The sale of inhaled insulin discontinued in 2007.

Oral insulin(ORALIN)-evaluated in comparison with OHA, mostly in T2DM , data appears promising but further evaluation in T1DM needed.

GLUCOSE MONITORING

Self-monitoring of blood glucose is an essential part of

management of type 1 diabetes

Subcutaneous continuous glucose sensors allow

detection of asymptomatic hypoglycemia and

hyperglycemia

Subcutaneous continuous glucose sensors may have a

beneficial role in children and adolescents but evidence

is not as strong as in adults

GLYCOSYLATED HEMOGLOBIN(HBA1C)

Glucose nonenzymatically attached to hemoglobinduring the life cycle of the circulating RBCs (HbA1 or HbA1c)

HbA1c reflects levels of glycemia over the preceding 4–12 wk, weighted toward the most recent 4 wks

A target range for all age-groups <7.5% is recommended

FRUCTOSAMINE AND OTHER GLYCATED PRODUCTS

Fructosamine measures the glycation of serum proteins such as albumin and reflects glycemia over the preceding 3–4 wk

Used for assessment of shorter periods of control than HbA1c.

Fructosamine or glycated albumin useful in individuals with abnormal red cell survival time.

Fructosamine and other glycated products have not been evaluated in terms of later vascular risk.

COMPLICATIONS OF INSULIN THERAPY

Hypoglycemic Reactions

Hyperglycemic episodes

Somogyi Phenomenon

Dawn Phenomenon

Brittle Diabetes

HYPOGLYCEMIA ( BGL < 70 MG/DL)

All families should understand the importance of hypoglycemia (severity and frequency) along with treatment and follow up strategies

HYPOGLYCEMIA – KEY MESSAGE

Hypoglycemia is a major obstacle for children with type

1 diabetes and can affect their ability to achieve

glycemic targets

Significant risk of hypoglycemia often necessitates less

stringent glycemic goals, particularly for younger

children

There is no evidence in children that one insulin regimen

or mode of administration is superior to another for

reducing non-severe hypoglycemia.

EXAMPLES OF CARBOHYDRATE FOR TREATMENT OF MILD TO

MODERATE HYPOGLYCEMIA

Patient Weight <15 kg 15 to 30 kg >30 kg

Amount of carbohydrate 5g 10 g 15 g

Carbohydrate Source

Glucose tablet (4 g) 1 2 or 3 4

Dextrose tablet (3 g) 2 3 5

Apple or orange juice; regular soft drink; sweet beverage (cocktails)

40 ml 85 ml 125 ml

HYPOGLYCEMIA

Frequent use of continuous glucose monitoring in a

clinical care setting may reduce episodes of

hypoglycemia

In children, the use of mini-doses of glucagon has been

shown to be useful in the home management of mild or

impending hypoglycemia associated with inability or

refusal to take oral carbohydrate

Dose = 10 mcg x (years of age)

Dose range 20 – 150 mcg

RECOMMENDATION

In the home situation, severe hypoglycemia in an unconscious child >5 years of age should be treated with 1 mg of glucagon subcutaneously or intramuscularly. In children ≤5 years of age, a dose of 0.5 mg of glucagon should be given. The episode should be discussed with the diabetes healthcare team as soon as possible and consideration given to reducing insulin doses for the next 24 hours to avoid further severe hypoglycemia

RECOMMENDATION

Dextrose 0.5 to 1g/kg (5-10 ml/kg of 10% D) should be given over 1 to 3 minutes to treat severe hypoglycemia with unconsciousness when IV access is available

DAWN & SOMOGYI PHENOMENON

Dawn phenomenon-

Overnight GH secretion & insulin clearance

Normal physiological process in nondiabeticadolescents(compensate with more insulin output),T1DM cant compensate

Somogyi phenomenon

A theoretical rebound from late night or early morning hypoglycemia

Uncommon, counterregulatory response

BRITTLE DIABETES

Unexplained wide fluctuations in blood glucose

Recurrent DKA (though on large doses of insulin)

Inherent physiological abnormality rarely a cause

Psychosocial or psychiatric problems contribute

Clinicians to refrain using it as a diagnostic term

SICK DAY MANAGEMENT

Never omit insulin

Insulin requirements are often greater with illness

Hypoglycemia may be a problem, especially in younger children

Test blood sugars every 2-4 hours

Check urine ketones

SICK DAY MANAGEMENT

Drink plenty of fluids (1 cup per hour)

Sugar-containing liquids for hypoglycemia

Need extra insulin to clear ketones

NPH/R: extra 20% of total dose as R q4 hours

Basal/bolus: correction dose q3 hours + additional 20% of calculated correction

ED for persistent vomiting

NUTRITION

Healthy, balanced diet

50-60% total calories from carbohydrate

<30% fat

10-20% protein

Carbohydrate counting

No forbidden foods - moderation

Eating too much will not cause ketosis

BF (20%) + L (20%) + D (30%) + 3 b/w meal snacks (10% each)

EXERCISE

Increases sensitivity to insulin

Helps control blood sugar

Lowers cardiovascular risk

Blood sugar usually decreases but may initially increase

Hypoglycemia may occur during, immediately after, or 8-24 hours later

May need extra snacks or decreased insulin (learn from experience)

Usually 15 gm CHO for every 30 min vigorous exercise

Do not exercise if ketones are present

COMORBID CONDITIONS / CONSIDERATIONS

Immunization

Smoking

Contraception / Sexual health counseling

Psychological / Psychiatric

Eating disorders

RECOMMENDATIONS

Influenza immunization should be offered to children

with diabetes as a way to avoid an intercurrent illness

that could complicate diabetes management

Formal smoking prevention and cessation counselling

should be part of diabetes management for children

with diabetes.

Adolescent females with type 1 diabetes should

receive counselling on contraception and sexual

health in order to avoid unplanned pregnancy

RECOMMENDATIONS

Children and adolescents with diabetes, along with

their families, should be screened regularly for

psychosocial or psychological disorders and should be

referred to an expert in mental health and or

psychosocial issues for intervention when required

Adolescent females with type 1 diabetes should be

regularly screened using nonjudgmental questions

about weight and body image concerns, dieting, binge

eating, and insulin omission for weight loss

COMORBID ASSOCIATIONS

Always consider the possibility of autoimmune thyroid

and adrenal disease, and celiac disease, particularly

when there are suggestive signs or symptoms

SCREENING FOR COMORBID CONDITIONS

Condition Indications for screening Screening test Frequency

Autoimmune

thyroid disease

All children with type 1diabetes

Serum TSH level + thyroperoxidase antibodies

At diagnosis and every2 years thereafter

Positive thyroid antibodies,thyroid symptoms or goiter

Serum TSH level + thyroperoxidase antibodies

Ever y 6–12 months

Addison’s disease

Unexplained recurrent hypoglycemia anddecreasing insulinrequirements

8 AM serum cortisol+ serum sodium andpotassium

As clinically indicated

Celiac disease Recurrent gastrointestinal symptoms, poor lineargrowth, poor weightgain, fatigue, anemia,unexplained frequent hypoglycemia or poormetabolic control

Tissue transglutaminase+ immunoglobulin Alevels

As clinically indicated

DIABETES CHRONIC COMPLICATIONS

Nephropathy, retinopathy, neuropathy and hypertension

are relatively rare in pediatric diabetes

Screening efforts should focus most attention on post-

pubertal patients with longer duration and poorer

control of their diabetes

Complication Indications & intervals forscreening

Screening method

Nephropathy • Yearly screening commencing

at 12 years of age in those with

duration of type 1 diabetes ≥ 5

years (ACR-alb/creatinine ratio)

• First morning (preferred) or random ACR

• Abnormal ACR requires confirmation at least 1

month later with a first morning ACR, and if

abnormal, followed by timed, overnight or 24-

hour split urine collections for albumin

excretion rate

• Repeated sampling should be done ever y 3–

4 months over a 12-month period to

demonstrate persistence

Retinopathy • Yearly screening commencing

at 15 yrs of age with duration of

DM ≥ 5 yrs

• Screening interval can

increase to 2 yrs if good

glycemic control, duration of

diabetes < 10 yrs, and no

retinopathy at initial

assessment

• 7-standard field, stereoscopic-colour fundus

photography with interpretation by a trained

reader (gold standard); or

• Direct ophthalmoscopy or indirect slit-lamp

fundoscopy through dilated pupil; or

• Digital fundus photography

Complication Indications & intervals forscreening

Screening method

Neuropathy • Postpubertal adolescents with

poor metabolic control should

be screened yearly after 5

years’ duration of DM

• Question and examine for

symptoms of numbness, pain,

cramps and paresthesia, as well

as sensation, vibration sense,

light touch & ankle reflexes

Dyslipidemia • Delay screening post-

diabetes diagnosis until

metabolic control has

stabilized

• Screen at ≥12 years of age or <12 years of age with BMI > 95th percentile, family historyof hyperlipidemia or prematureCVD

• Fasting total cholesterol,

high-density lipoprotein

cholesterol, triglycerides,

calculated low-density

lipoprotein cholesterol

Hyper tension • Screen all children with

type 1 diabetes at least twice

a year

• Use appropriate cuff size

ADULT VS CHILD DIABETES

Guidelines for children and adolescents differ from those ofadults in a number of ways:

Less aggressive A1C target acceptable in younger children

Less intensive screening for complications of diabetes in the

younger years due to lower incidence

Greater caution around DKA management given cerebral

edema risk

Greater awareness of unique psychosocial needs as children

progress through developmental stages

DIABETIC KETOACIDOSIS (DKA)

Medical emergency

Profound insulin deficiency

Can be

the 1st presentation of T1DM

In children with diabetes if insulin is omitted

Insufficient insulin at times of acute illness

BIOCHEMICAL CRITERIA FOR DKA

Hyperglycaemia (blood glucose >11mmol/l (~200 mg/dl))

Venous pH <7.3 or bicarbonate <15 mmol/l

Ketonemia and ketonuria

blood β- hydroxybutyrate (BOHB) concentration should be measured whenever possible;

a level ≥3mmol/L : indicative of DKA

Euglycemic ketoacidosis : only modestly increased blood glucose in partially treated or with little or no carbohydrate consumption.

SEVERITY OF DKA

Mild : venous pH<7.3 or bicarbonate <15mmol/L

Moderate : pH<7.2, bicarbonate <10mmol/L

Severe : pH<7.1, bicarbonate <5mmol/L.

DKA PROTOCOL : MILWAUKEE PROTOCOL

Time Therapy Comments

1st hour •10-20 ml/kg IV bolus NS or RL•Insulin drip at 0.05-0.1 u/kg/hr

Quick volume expansion; may be repeated. Continuous monitoring. Mannitol at bedside; 1g/kg iv push for cerebral edema

2nd hour until DKA resolution

•0.45% NS : plus continue insulin drip•20 m Eq/l Kphos and 20 mEq/l Kac•5% glucose if BG> 250 mg/dl

IV rate=85ml/kg+maintainence-bolus

23 hoursIf K <3mEq/l, give 0.5-1 mEq/kg(oral)OR increase IV K to 80 mEq/l

Variable Oral intake with s/c insulin No emesis; CO2 > 16 mEq/l; normal electrolytes.

DKA PROTOCOL : MILWAUKEE PROTOCOL CONTD...

Maintenance (24 hrs)= 100 ml/kg(1st 10 kg) + 50 ml/kg(for 2nd 10 kg) + 25 ml/kg (for remaining kg)

Example: 30 kg child

1st hour : 300 ml iv bolus NS or RL

2nd and subsequent hours: (85x 30) + 1750 – 300 over

23 hours

(0.45% NS with 20 mEq/l Kphos and 20 mEq/l KAc )

DKA MONITORING FORM

ISPAD CLINICAL PRACTICE CONSENSUS GUIDELINES

2014

Accepted and supported by:

Law- son Wilkins Paediatric Endocrine Society (LWPES)

European Society for Paediatric Endocrinology (ESPE),

and

International Society for Paediatric and Adolescent

Diabetes (ISPAD)

COMPONENTS OF MANAGING DKA (ISPAD 2014)

1. Initial assessment and monitoring

2. Correction of shock

3. Correction of fluid replacement

4. Insulin treatment

5. Potassium replacement

6. Role of bicarbonate

7. Treatment of infection (if present)

8. Management of cerebral oedema

9. Monitoring of the child

10. Transitioning to subcutaneous insulin

INITIAL ASSESSMENT AND MONITORING:

Clinial assessment: history, examination. Include:

Severity of dehydration. If uncertain assume 10% dehydration in significant DKA

1 mnth -5 yrs age: 3 important signs to predict 5% dehydration

Prolonged CRT

Abnormal skin turgor

Abnormal respiratory pattern(hyperpnea)

>10% dehydration: weak or impalpable peripheral pulses, hypotension and oliguria.

INITIAL ASSESSMENT AND MONITORING CONTD...

Level of consciousness

Evidence of infection

Weight of the child

Measure blood glucose ( both glucometer and lab)

Measure ketones by urine dipstick (and blood ketonemeasurement if possible)

Other investigations:

1. Serum electrolytes 4. KFT

2. CBC 5. microbiological samples

3. ABG/VBG: pH, HCO3 6. HbA1c

INITIAL ASSESSMENT AND MONITORING CONTD...

Monitor:

Record hourly : heart rate, blood pressure, respiratory rate, level of consciousness, glucose meter reading

Monitor urine ketones in every sample of urine passed

Record fluid intake, insulin therapy and urine output

Repeat blood urea and electrolytes every 2-4 hours

CORRECTION OF SHOCK

Ensure A, B, C

Oxygen support

Resuscitation fluids:

severely volume depleted but not in shock : NS @ 10-20 ml/kg over 1-2 h

DKA in shock : NS in 20 ml/kg boluses infused as quickly as possible with reassessment after each bolus.

Shock must be adequately treated before proceeding

FLUID REPLACEMENT

Subsequent fluid management (deficit replacement) : with an isotonic solution ( NS, RL) for atleast 4–6 h

Deficit replacement after 4–6 h : with a solution of tonicity ≥0.45% saline with added potassium chloride, potassium phosphate.

The decision to change from an isotonic to a hypotonic solution depends on the patient’s hydration status, serum Na, and osmolality

Aim to provide maintenance and deficit replacement (up to 10%) over 48 hours.

FLUID REPLACEMENT CONTD...

This volume should be distributed evenly over the 48 hours.

Do not add the urine output to the replacement volume

Reassess clinical hydration regularly

Once BGL <15 mmol/l (<270 mg/dl), add dextrose to the saline

add 100ml of 50% dextrose to every litre of saline, or use 5% dextrose saline

INSULIN TREATMENT

It should be started 1-2 hours after initiating fluid therapy

earlier onset of insulin treatment has been associated with cerebral oedema.

Insulin is best given intravenously by an infusion.

Intravenous infusion of 0.05-0.1 unit/kg/hour.

given in two ways:

A. Using a syringe pump - dilute 50 units short-acting (regular,soluble) insulin in 50 ml NS, 1 unit = 1 ml). OR

B. Use a side drip - put 50 Units of short-acting (regular) insulin in 500 ml of NS ( 1 Unit = 10ml).

INSULIN TREATMENT CONTD...

An IV bolus should not be used at the start of therapy

Unnecessary

Increase risk of cerebral edema

Exacerbate hypokalemia

If insulin cannot be given intravenously by a side drip or infusion pump, use deep subcutaneous or intramuscular insulin:

Give 0.1 unit/kg of short-acting (regular, soluble) or rapid-acting insulin SC or IM into the upper arm, and repeat this dose every 1-2 hours.

INSULIN TREATMENT CONTD...

The dose of insulin should usually remain at 0.05–0.1unit/kg/h at least until resolution of DKA

i.e. pH>7.30, bicarbonate >15mmol/L, BOHB <1mmol/L,or closure of the anion gap),

which invariably takes longer than normalization of BGconcentrations.

POTASSIUM REPLACEMENT

Potassium replacement is needed for every child in DKA.

Blood potassium level : initial assessment

If potassium levels cannot be done, ECG monitoring

Hypokalaemia : Flattening of the T wave, widening of the QT interval and the appearance of U waves .

Hyperkalaemia : Tall, peaked, symmetrical T waves and shortening of the QT interval.

Ideally start replacing potassium once the serum potassium value is known or urine output has been documented. If this value cannot be obtained within 4 hours of starting insulin therapy, start potassium replacement anyway.

POTASSIUM REPLACEMENT CONTD...

Replace by adding KCl to the IV fluids @ 40mmol/L. Increase according to measured potassium levels.

The maximum recommended rate of intravenous potassium replacement : 0.5 mmol/kg/hour

If given with the initial rapid volume expansion, concentration of 20 mmol/l should be used

If hypokalaemia persists despite maximum rate ,the rate of insulin infusion can be reduced.

ROLE OF BICARBONATE:

Severe acidosis is reversible by fluid and insulin.

Bicarbonate therapy:

No clinical benefit

Paradoxical CNS acidosis

Rapid correction causes hypokalemia

Role in life threatening hyperkalemia : 1-2 mmol/kg over 60 min

TREATMENT OF INFECTION

Difficult to exclude infection in DKA : increase TLC due to stress and acidosis.

Fever : more reliable sign

Treat with broad spectrum antibiotics.

CEREBRAL OEDEMA

Rare but often fatal complication of DKA.

Cause : controvertial

can be idiosyncratic

may be related to factors : degree of hyperglycaemia, acidosis, dehydration and electrolyte disturbance at presentation, as well as over-rapid correction of acidosis, dehydration or hyperglycaemia.

CEREBRAL OEDEMA CONTD...

Signs & symptoms:

Headache

slowing of heart rate

Change in neurological status (restlessness, irritability, increased drowsiness, and incontinence)

Specific neurological signs (e.g., cranial nerve palsies, papilledema)

Rising blood pressure

Decreased O2 saturation

CEREBRAL OEDEMA CONTD...

If cerebral oedema is suspected TREAT URGENTLY:

Exclude hypoglycaemia as a cause of the change in neurological state.

Reduce the rate of fluid administration by one third

Give mannitol 0.5-1 g/kg IV over 20 minutes, and re-peat if there is no initial response in 30 minutes to 2 hours.

Hypertonic saline (3%) 5ml/kg over 30 minutes may be an alternative to mannitol, esp if there is no initial response to mannitol

CEREBRAL OEDEMA CONTD...

Elevate the head of the bed

Intubation : impending respiratory failure

After treatment has been started, a cranial CT scan to rule out other possible intracerebral causes of neurological deterioration

especially thrombosis or haemorrhage

Cerebral oedema is an unpredictable complication of DKA.

Survivors are often left with significant neurological deficits.

MONITORING THE CHILD

If no improvement in biochemical parameters of DKA (pH, anion gap, urine ketones):

reassess patient

review insulin therapy

consider infection or errors in insulin preparation.

Consider possibility of serious infection (such as malaria) with stress hyperglycaemia rather than diabetes.

TRANSITIONING TO SUBCUTANEOUS INSULIN:

Once the DKA has been adequately treated (hydrationcorrected, glucose controlled, ketones cleared) the childcan be transitioned to subcutaneous insulin.

The first SC dose of short-acting insulin: 1-2 hours beforestopping the insulin infusion.

easier to transition to subcutaneous insulin at the nextmealtime

THANK YOU ALL!

THANK YOU

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