INTRODUCTION TO DIABETES,

NEONATAL DIABETES
PATHOPHYSIOLOGY AND
MANAGEMENT OF DKA

Dr. Rashid Musa

Consultant Paediatrician
Type 1 diabetes mellitus
 Metabolic syndrome characterized by chronic hyperglycemia
secondary to chronic immune-mediated destruction of pancreatic
β-cells, leading to partial, or in most cases, absolute insulin
deficiency

 1a- autoimmune
 1b- non immune /idiopathic(15%).
 Majority of cases (type 1A) result from autoimmune-mediated
pancreatic β-cell destruction, occurring at a variable rate.
 Patient becomes clinically symptomatic when approximately 90%
of pancreatic β-cells are destroyed.
Type 1 diabetes mellitus

 Diabetes-associated
autoantibodies include:
 glutamic acid decarboxylase 65 autoantibodies (GAD);
 Tyrosine phosphatase-like insulinoma antigen 2 (IA2);
 insulin autoantibodies (IAA); and
 β-cell specific zinc transporter 8 autoantibodies (ZnT8).

 Thepresence of one or more of

these auto-antibodies confirms
the diagnosis of type 1 diabetes
Type 1 diabetes mellitus

 Possibility of other types of diabetes should be considered in a

child who has negative diabetes-associated autoantibodies like:
 Monogenic diabetes
 an autosomal dominant ,family history of diabetes ( eg maturity onset diabetes of
the young (MODY)
 age less than 12 months and especially in first 6 months of life (NDM-neonatal
diabetes mellitus])

 Mitochondrial diabetes: characterized by progressive non-autoimmune

β-cell failure, associated sensorineural deafness, optic atrophy, or
syndromic features.
 a history of exposure to drugs known to be toxic to β-cells or cause
insulin resistance , e.g, immunosuppressive drugs such as tacrolimus or
cyclosporin; gluocorticoids or some antidepressants.
Pathophysiology of type 1diabetes
Genetic predisposition
 Highest risk genotypes
 Polymorphisms of the class II human leukocyte antigen (HLA)
 90% -95% newly diagnosed Type 1 DM have either HLA DR 3 , DQB1 *
0201 or DR4 ,DQB1 *0302 while 30% are DR3/4 heterozygotes

 A number of other genes found to confer risk are :HLA DQ alpha &
beta, PTPN22, CTLA-4, BACH2.

 Lifelong risk
 6% in offsprings (men’s-3.6-8.5%, women’s-1.3-3.6%)
 5% in siblings and fraternal twins(4% by 20yrs,9.6% by 60yrs)
 36% in identical twins
 30% risk if both parents are diabetic
 0.4% in subjects with no family history

 Protective genes include: HLA-DR2 haploytpes, DR B1 * 0403,

DQB1 *0602
 Immune dysregulation
 Islet cell auto-antibodies are found in up to 85% of newly diagnosed
patients.
 Target auto antigens
 Insulin, proinsulin
 Glutamic acid decarboxylase(GAD) 65
 Inslet cell assoc phosphatase(IA2)
 Zinc transporter(Zn8)
 Glycolipids, ganglioside GT3
 Carboxypeptidase H, PM-1 polar antigen
 Islet cell proteins of varying size and unknown function - 37 or 40 kD, 38 kD, 52 kD, 69
kD
 Peripherin , chromogranin A
 Heat shock protein 65
 Insulin receptor
 Endocrine cell antigens
 Cytoskeletal proteins - tubulin, actin, reticulin
 Nuclear antigens - single-stranded DNA and RNA
Immune dysregulation
 Association with other autoimmune diseases
 Autoimmune thyroiditis
 Autoimmune adrenalitis
 Polyglandular autoimmune disease

 Mutation in foxP3 gene that is important in development of T

regulator cells
Environmental factors
 Hygiene hypothesis
 Perinatal factors
 Mother >25yrs, PET, neonatal respiratory disease, ABO incompatibility-
jaundice
 Viruses
 E.g enterovirus, mumps, rubella, and coxsackievirus B4, corona virus
19 (SARS-CoV-2 can induce beta-cell apoptosis)
 Direct beta cell infection- Rare.
Environmental factors
 Diet
 Cow milk
 Bovine serum albumin ?early introduction, ?high volume. Proposed in a
Finish study but no evidence in cross sectional or prospective studies
 Beta casein causing CMI response
 Vitamin D and Omega3- shown to be protective, studies are
insufficient

 Cereals- in high risk infants, timing of introduction before 3mo trigger

production of Islet cell antibodies (ICAs)

 Nitrates in water - Colorado, Yorkshire, increased incidence

 Time course of the development of type 1 diabetes. Genetic markers are present
from birth, immune markers first appear at the time of the environmental triggering
events, and sensitive metabolic markers of deficient insulin secretion begin to appear
soon after the onset of beta-cell dysfunction. However, clinically evident type 1
diabetes does not occur until there has been a much greater loss of functioning beta-
 Criteria for the diagnosis
ofClassic
1. diabetes mellitus
symptoms of diabetes or hyperglycemic crisis, with plasma
glucose concentration ≥11.1 mmol/L (200 mg/dL).
or

2. Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL). Fasting is defined as

no caloric intake for at least 8 hours
or

3. Two-hour post-load (post prandial) glucose ≥11.1 mmol/L (≥200 mg/dL)

during an OGTT.
 The test should be performed using a glucose load containing the equivalent
of 75 g anhydrous glucose dissolved in water or 1.75 g/kg of body weight to a
maximum of 75 g.
or

4. HbA1c ≥6.5%b
NEONATAL DIABETEs MELLITUS
 Neonatal diabetes(ND) is a “monogenetic” disease
 It is a rare genetic disease (1 in 90,000 live births).
 Defined by the presence of severe hyperglycaemia associated with
insufficient or no circulating insulin, occurring mainly before 6
months of age and rarely between 6 months and 1 year.

mutation of one of the several genes that are involved in the normal development and function of pancreatic beta cells including insulin
production and secretion
Neonatal Diabetes Mellitus
 Usually diagnosed before 6 months of age.
 However, age of diagnosis varies depending on genetic causes:
 diabetes due to a 6q24 locus abnormality appears before the age of 1 month
in 93% of cases and before the age of 3 months in 100% of cases.
 In ABCC8 and KCNJ11 gene mutations, it appears before the age of 1 month
in 30% of cases and between 1 and 6 months in 66% of cases
 patients have a birth-weight below the 10th percentile in 62% of
cases
 Causes of ND
1. Abnormal β Cell Function
 mutations of the ABCC8( dominant or recessive )or KCNJ11
(dorminant) genes encoding respectively the SUR1 and Kir6.2
subunits of the ATP-dependent potassium channel
• The potassium channel is for secretion of insulin in response to glucose
levels
• 40% of patients with neonatal diabetes have a potassium channel gene
mutation.
• Mutations in KCNJ11 and ABCC8 can cause transient neonatal diabetes,
permanent neonatal diabetes, or DEND (Developmental delay, Epilepsy
and Neonatal Diabetes) syndrome

 Mutations of the Insulin Gene (INS)

 Mutations of the Glucokinase Gene (MIM *138079)
 abnormalities of the 6q24 locus and
Causes of neonatal diabetes Mellitus

2. Abnormal Pancreas Morphology

 Secondary to mutations of genes involved in development of the
pancreas at various stages in early morphogenesis eg RFX-6 gene

3. Autoimmune Neonatal Diabetes Mellitus

 Autoimmune diabetes is very rare before 6 months of age
 FOXP3 gene may be responsible for enteropathy, immune
dysregulation and polyendocrinopathy(IPEX Syndrome) -is a
cause of neonatal diabetes associated with early autoimmunity
directed against the beta cells of the pancreas
 Trisomy 21 was seven times more likely in their PNDM cohort than
in the general population
Clinical description of Neonatal diabetes
 There are two clinical forms of ND based on the
duration of insulin-dependency:

 Transient form: Associated with abnormalities of

the 6q24 locus, treatment may be stopped at any
time from the first weeks of life to 5 years of age

 Permanent forms, life-long treatment is

necessary.

 ABCC8, KCNJ11, and INS genes are linked to both

permanent and transient forms
Treatment
 Sulfonylureas(glibenclamide) provide a better metabolic
equilibrium than insulin by normalizing the HbA1c while strongly
reducing the incidence of hypoglycemia in cases of neonatal
diabetes with ABCC8 or KCNJ11 mutations.
 sulphonylureas were able to improve neurological,
neuropsychological and visual motor impairment if they are
introduced early in the child's life
 NOTE: Up to 86% of patients who go into remission have recurrent
diabetes when they reach puberty, with no difference due to the
genetic origin
DIABETES KETOACIDOSIS

 DKA is a complex disordered metabolic state

 DIABETIC
KETOACIDOSIS
Is a major life threatening complication of
It occurs
mostly in type
1 DM
diabetes biochemically characterized by:

Hyperglycemia: blood
glucose >11mmol/l
(~200 mg/dl)
Ketoacidosis: Venous pH
<7.3 or bicarbonate <15
mmol/l
Ketonuria(blood ß-
hydroxybuyrate ≥3 mmol/L) or
moderate or
large ketonuria.
There is an overall shift in metabolism from the normal fed
state characterized by carbohydrate metabolism to a
starvation state characterized by fat metabolism.
CLASSIFICATION

 Severity of DKA can be classified as follows:

SEVERITY VENOUS pH HCO3- (mmol/l)

Mild <7.3 <15

Moderate <7.2 <10

Severe <7.1 <5

DKA at onset of diagnosis of diabetes
 Frequency of DKA At disease onset
 wide geographic variation in the frequency DKA
 rates inversely correlate with regional incidence of type 1 diabetes.
 Frequencies range from 15–70% in Europe and North America.
 DKA at diagnosis is more common in :
 younger children (<2 yr of age)
 those from ethnic minority groups, and
 in children whose families do not have ready access to medical care for
social/economic reasons
DKA In children with established
The risk of DKA in established type 1 diabetes is 1–10% per patient
diabetes
per year
 Risk is increased in :
• Children who omit insulin .
• Children with poor metabolic control or previous episodes of
DKA.
• Gastroenteritis with persistent vomiting and inability to
maintain hydration.
• Children with psychiatric disorders, including those with
eating disorders.
• Children with difficult or unstable family circumstances (e.g.,
parental abuse).
• Peripubertal and adolescent girls.
• Children with limited access to medical services.
• Insulin pump therapy (as only rapid- or short-acting insulin is
used in pumps, interruption of insulin).
 Some drugs eg clonazepam, olanzapine, cocaine, sodium-
Pathophysiology 1
 Secondary to insulin deficiency, and the action of
counter-regulatory hormones, blood glucose increases
leading to hyperglycemia and glucosuria. Glucosuria
causes an osmotic diuresis, leading to water &
electrolyte loss.

 In the absence of insulin activity, the body fails to

utilize glucose as fuel and uses fats instead. This leads
to ketosis.

 The excess of ketone bodies will cause metabolic

acidosis, the later is also aggravated by Lactic acidosis
caused by dehydration & poor tissue perfusion.
 Pathophysiology

Despite their dehydration, patients generally

continue to maintain normal blood pressure or
even high blood pressure possibly due to:

1. Elevated plasma catecholamine concentration

2. Increased release of ADH in response to
hyperosmolarity → activation of V1 and V2
receptors → increase BP
3. Increased osmotic pressure from marked
hyperglycemia

Considerable UO persists because of glycosuria

until extreme volume depletion leads to a critical
decrease in renal blood flow and GFR
Pathophysiology 2
 Vomiting due to an ileus, plus
increased insensible water losses
due to tachypnea will worsen the
state of dehydration.

 Electrolyte abnormalities occur

secondary to loss in urine & trans-
membrane alterations following
acidosis & osmotic diuresis.
 Pathophysiology 3
 Because of acidosis, excess H ions in blood are exchanged
for K ions from the intracellular space. K ions enter the
circulation leading to hyperkalemia.

 K is lost in urine and also during vomiting

 This is aggravated by hyperosmolarity due to dehydration

and renal failure.

 Insulin stimulates sodium potassium ATPases. Without it, K

ions stay in extracellular space.

 So, depending on the duration of DKA, serum K+ at

diagnosis may be high, normal or low, but the intracellular
K+ stores are always depleted.
Acidosis
Severity depends
on:
1.Rate of ketoacid
production
2.Duration of
increased
ketoacid
production
3.Rate of acid
excretion in urine
4.Adequacy of
compensatory
respiratory
alkalosis
Pathophysiology 4
 The dehydration can lead to decreased kidney
perfusion and acute renal failure.

 Accumulation of ketone bodies contributes to the

abdominal pain and vomiting.

 The increasing acidosis leads to acidotic breathing

and acetone smell in the breath and eventually
causes impaired consciousness and coma.
 Dehydration is made
Pathophysiology- Dehydration

worse by vomiting (due

to ileus and ketone bodies)
and increased insensible
H2O losses (due to
tachypnea).
The initial half of
this amount is from
intracellular fluid
Dehydration can lead to
and precedes signs decreased kidney
of dehydration. The
other half of from perfusion and acute renal
extracellular fluid failure.
and is responsible
for signs of
dehydration. The combined effects of
serum hyperosmolarity,
dehydration and acidosis
result in increased
osmolarity in brain cells
that causes impaired
PATHOPHYSIOLOGY
Signs and symptoms
Metabolism of acetoacetic acid produces acetone
which accumulates in serum and is slowly disposed
of by respiration (giving acetone breath).

Accumulated ketones also overflow into urine =

ketonuria
Accumulation of ketone bodies (especially beta-
hydroxybutyrate) contributes to the abdominal
pain, nausea and vomiting.

Ketoacidosis is aggravated by lactic acidosis

caused by dehydration & poor tissue perfusion.

Acidosis leads to acidotic breathing (Kussmaul

respiration) in an attempt to rid the body of CO2.

DKA causes nausea, vomiting and abdominal pain

and can progress to cerebral edema, coma and death
References

1. ISPAD Clinical Practice Consensus Guidelines 2018:

Definition, epidemiology, and classification of
diabetes in children and adolescents
2. ISPAD Clinical Practice Consensus Guidelines 2014
Compendium Diabetic ketoacidosis and
hyperglycemic hyperosmolar state
3. Front. Pediatr., 30 September 2020 |
https://doi.org/10.3389/fped.2020.540718:
Neonatal Diabetes Mellitus
4. Published in final edited form as: Clin Perinatol.
2018 March ; 45(1): 41–59.
doi:10.1016/j.clp.2017.10.006. Neonatal Diabetes
Mellitus: An Update on Diagnosis and Management
 DKA
MANAGEMENT
Step 1 - Initial assessment
Acute management should follow the Pediatric advanced life support guidelines.

History
 Polyuria
 Polydipsia
 Tiredness
 Vomiting
 Confusion
 Abdominal pain
 Weight loss

For known DM patients ask about history of missed dose, acute stressors and
symptoms suggestive of infection
Initial assessment: Clinical signs-Assess dehydration

Three most useful individual signs for predicting

5% dehydration in young children aged 1
month to 5yr are:
 Prolonged capillary refill time
 Abnormal skin turgor
 Abnormal respiratory pattern (hyperpnea)

≥10% dehydration is suggested by :

 Presence of weak or impalpable
peripheral pulses.
 hypotension
 oliguria.
NB! For children in DKA - assume 10%
dehydration
 Initial Assessment and Monitoring

• Weigh the child.

• Measure blood glucose (both
blood glucose meter and
Carry out a clinical laboratory measurement if
assessment including history possible).
and • Measure ketones by urine
examination. Be careful to dipstick (and blood ketone
include: measurement if possible).
a. Severity of dehydration. • HbA1c,
If uncertain about this, • Urea, electrolytes and
assume 10% dehydration creatinine,
in significant DKA • Haemoglobin and white cell
b. Level of consciousness count. Venous or arterial pH and
c. Evidence of infection bicarbonate
• Microbiological samples
 During management of DKA, the child needs to be carefully
monitored as follows:

1 Record hourly: heart rate, blood pressure, respiratory

rate,
level of consciousness, glucose meter reading
2 Monitor urine ketones in every sample of urine passed

3 Record fluid intake, insulin therapy and urine output

4 Repeat blood urea and electrolytes every 2-4 hours

5 Measure blood ketones (β-hydroxybutyrate) if possible

 Step 2 - Correction of Shock -
ABC
Give oxygen to patients with severe circulatory impairment or shock.

IV cannula.

In the rare cases of shock or severe circulatory collapse, rapidly restore

circulatory volume with normal saline in a 20mL/kg bolus infused as quickly as
possible. Additional 10mL/kg boluses may need to be administered once or
twice. ( Resuscitation fluid)

A 20kg child in DKA presents with weak thready

pulses and low blood pressures
How much fluid would you give as resuscitation
fluid?

20ml/kg to run as a bolus

20x20=400mls normal saline

 Step 3 - Fluid replacement
If there is no shock but dehydration is ≥5%, give an IV bolus of 10 ml/kg Normal
Saline (0.9%) over 1 hour.
Once the blood glucose level is <15 mmol/l (<270 mg/ dl), add glucose

When oral fluid is tolerated, IV fluid should be reduced accordingly,

The more ill the child, the slower the rehydration should be because of
the risk of developing cerebral oedema.

Correction of deficit: Calculations done based on the degree of

dehydration.

For children- assume 10% dehydration

Deficit is corrected over 48hours

10mls/kg of fluid are given for every 1% dehydration

OR
Give 100mls /kg to cater for the 10% dehydration.
Maintenance fluids

Calculate maintenance fluids for a

period of 24hours

The 1st 10kgs - 100mls/kg Example :

Calculate
Next 10kgs – 50mls/kg maintenance fluids for
a 20kg child
Any weight above the 20kgs -
20mls/kg (100x10) + (50x10)
=1500mls in 24hours

KDHS 2014
IV fluids calculation - Example

8year old child, 20kgs, RBS of 28mmol/l and urine ketones+++, with
10% dehydration. Calculate the amount of fluid to be given hourly
over a period of 48hours.

 Rescusitation fluid : 20x20 = 400mls bolus

 Deficit : 100x20 = 2000 in 48hours
 Maintenance : (100x10) + (50x10)=1500 in 24hours
 1500x2=3000 in 48 hours
 Total fluid = (2000 + 3000) =5000mls in 48hrs
 Hourly rate for the next 48hours = 5000/48 = 104mls per hour
Step 4 - Correction of
hyperglycemia
Start insulin infusion after initial fluid
resuscitation.

Regular Insulin started at 0.05-0.1units /

kg /hr.

Younger children: lower rate started at

0.05 U/kg/hour
Preventing hypoglycemia

Add 5% glucose to the IV

fluid when :
The blood glucose falls to
15 mmol/L -17 mmol/L

If blood glucose falls very rapidly (>5

mmol/L/h) –normal decline is 2-5mmol/hr :
• Add glucose before plasma glucose
<15mmol/L
• Reduce insulin at 0.05 unit/kg/hour

• Use 10% or even 12.5% dextrose to

prevent hypoglycemia
• Continue Insulin infusion
Step 5 - Correcting electrolyte
abnormalities -hypokalemia`

When potassium is 2.5 - 3.5 mmol/L - KCL 40 mEq/L in

IV solution.

When potassium is 3.5 - 5.0 mmol/L - KCl 30 – 40

mEq/L in IV.
Maintain serum potassium level at 3.5 – 5.0 mmol/L.

Rate of potassium administration - 0.5mmol/kg/hr.

Once K administration is commenced repeat serum K

levels after 1 hour and 2-4 hourly thereafter.
Correcting electrolyte abnormalities -Potassium

If immediate serum potassium measurements

are unavailable an ECG may help determine
whether a child is hyper or hypokalemic.

ECG features of
hypokalemia:
 Prolonged PR
interval
 Prolonged QT
interval ECG features of
 ST depression
hyperkalemia:
 T wave flattening
Peaked T waves
and inversion
 Prominent U waves Shortening of the QT
interval
Step 6 - Role of bicarbonate

Bicarbonate should not be routinely given, but in very

rare cases and given with extreme caution. Consult the
senior consultant before initiating

If bicarbonate is considered necessary, cautiously give

1-2 mmol/kg IV over 60 minutes. Watch out for sudden
hypokalaemia when administering bicarbonate.

Step 7 - Treatment of infection

Infection can precipitate the development of DKA.

fever is a more reliable sign of infection.

If infection is suspected, treat with broad spectrum

antibiotics.
 Step 8 - Cerebral oedema

Cerebral oedema is a rare but often fatal

complication
of DKA.

It can be idiosyncratic, but its occurrence

may be related
to various factors including the degree of
hyperglycaemia, acidosis, dehydration and
electrolyte disturbance at presentation, as
well as over-rapid correction of acidosis,
dehydration or hyperglycaemia.
The rapidly rising intracranial pressure may present as:

Headache, vomiting or slowing of heart rate, in

combination
with an increase in blood pressure.
Change in neurological status (restlessness, irritability,
increased drowsiness, incontinence, seizures, coma).

Specific neurological signs (e.g. unreactive pupils, cranial nerve

palsies), abnormal respiratory pattern, decorticate posture.

Decreased oxygen saturation (cyanosis).

 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 10-15 minutes, and repeat if
there is no initial response in 30 minutes to 2 hours.

• Hypertonic saline (3%) 2.5-5ml/kg over 10-15 minutes

may be an alternative to mannitol, especially if there is
no initial response to mannitol.

• Elevate the head of the bed.

• Intubation may be necessary for a patient with impending
respiratory failure.
After treatment has been started, if available, a cranial CT scan should
be done to rule out other possible intracerebral causes of neurological
deterioration, especially thrombosis or haemorrhage which may
benefit from specific therapy.
Step 9 – monitoring of the
child
 If biochemical parameters of DKA do not improve, one should:

1 Reassess patient

2 Review insulin therapy

3 Consider other possible causes of impaired response to

insulin, e.g. infection or errors in insulin preparation

4 Consider that the primary illness may be a serious

infection (such as malaria) with stress hyperglycaemia
rather than diabetes
Biochemical parameters of DKA being monitored are:
 pH
 anion gap
 urine ketones

• Once the urine ketones are absent, consider

making the transition to subcutaneous (SC)
insulin.
Step 10 - Transitioning to
subcutaneous
insulin
Once the DKA has been adequately treated (hydration
corrected, glucose controlled, ketones cleared) the
child can be transitioned to subcutaneous insulin.

The first SC dose of short-acting insulin should be given 1-2

hours before stopping the insulin infusion.

Important: It is often easier to transition to

subcutaneous insulin at the next mealtime. If the child
is not newly diagnosed, determine insulin dose from
consideration of the dose before admission.
Introduction of oral fluids and transition to
subcutaneous insulin

Prepubertal children usually require 0.5-1 IU/kg/day

During puberty 1-2 IU/kg/day

This regimen can be given using two combinations:

• Short acting and long acting insulin analogues
• Short acting and intermediate acting insulin
analogues
If short acting /rapid acting and long acting insulin analogues
are used, 60% should be given as short acting divided up
into 3 premeal boluses

40% of the total daily dose is given as long acting and can be
split into a morning and an evening dose if one dose cannot
last 24hours.
Plan for discharge
Address the underlying cause of
DKA.
The patient and family must know
how :

To use a glucometer

to draw up insulin and give injections

to recognize and treat hypoglycemia Contact of the family

and educate them on
diabetes and triggers
the basic principles of diet in terms of DKA .
of both content and timing of
meals and snacks
References
 ISPAD clinical practice consensus
guidelines 2018
 Kenya national clinical guidelines for the
management of diabetes mellitus.
 Nelsons textbook of pediatrics 21st edition
 Up to date
 Dr. Anjumanara slides on DKA Management
Pathophysiology of DKA
Role of insulin and glucagon
Insulin
 activation of glucose transporter (GLUT) Glucagon
system.  Glucagon's principal target is

hepatocytes
hepatocytes:
 facilitates diffusion of glucose into
hepatocytes by stimulating
 promotes glycogenolysis by activating
glucokinase to form glucose-6-PO4
 stimulates glycogen synthase to form glycogen phosphorylase
glycogen from excess glucose (i.e.,
glycogenesis).
 promotes some lipogenesis  promotes gluconeogenesis by increasing
transamination/deamination.
 adipocytes:
 stimulate >30-fold glucose uptake by
fat cells (converts glucose to  it promotes gluconeogenic conversion of
glycerol).
lactate, pyruvate and alanine from
 insulin promotes storage of muscles.
free fatty acids (FFAs) in adipocytes

 lipoprotein lipase in endothelial cells

 In adipose tissue it promotes lipases
of fatty tissue capillaries releases FFAs
from micelles/chylomicrons. the FFAs and ketogenesis
diffuse into adipocytes where they
are re-esterified into triglycerides for
storage.

 myocytes:
 stimulates >30-fold uptake of