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PEDS ENDO RC TD 2022 > Hypoglycemia > Flashcards

Hypoglycemia Flashcards

1
Q

What are symptoms of hypoglycemias?
What are the cutoffs?

A

<3.3 mmol/L: Autonomic responses of hypoglycemia, due to release of autonomic neurotransmitters
Tremor, anxiety, palpitations, and sweating (sympathetic nervous system)
Hunger (parasympathetic vagal response)

<2.8 mmol/L*: cerebral neuroglycopenia
Impaired cognition, weakness, lethargy, confusion, incoordination, blurred vision

If counterregulatory responses are inadequate to reverse -> seizures or coma (BG ~1.6 mmol/L*), can result in brain damage or death

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2
Q

Autonomic nervous system response to hypoglycemias

A

alpha adrenergic:
- inhibition of insulin release
- increase in cerebral blood flow (peripheral vasoconstriction

beta adrenergic:
- hepatic and muscle glycogenolysis
- stimulation of plasma glucagon release
- lipolysis to raise please FFA
impaired glucose uptake by muscles
increase cerebral blood flow (increase cardiac output)

adrenomedullary discharge of catecholamines
- augmentation of all the above alpha and beta adrenergic effects

cholinergic
- raises level of pancreatic polypeptire
- increases motility of stomach
- produces hunger
- increases sweating

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3
Q

what are the counter regulatory hormones

A

glucagon
cortisol
growth hormone
catecholamines
cholinergic neurotransmitters

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4
Q

insulin

A

stimulate glycogen synthesis
inhibit glycogenolysis and gluconeogenesis
Anabolic effect on fat tissues – stimulate lipogenesis, inhibit FFA release and their beta-oxidation, inhibit ketone body formation

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5
Q

what does glucagon do

A

increases hepatic glycogenolysis and gluconeogenesis (of liver but not kidney)

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6
Q

causes of transient hyperinsulinism

A

infants of diabetic mothers
SGA
LGA
asphyxia
stress

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7
Q

syndromes associated with hyperinsulinism

A

Beckwith Wiedeman
Sotos
Glycosylation disorder

Kabuki’s syndrome
Trisomy 13
Central hypoventilation syndrome
Leprechaunism (insulin resistance syndrome)
Mosaic Turner syndrome

Usher syndrome
Timothy syndrome
Costello syndrome

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8
Q

Gene for Sulfonylurea receptor 1 (SUR-1)

A

ABCC8

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9
Q

Gene for Kir6.2

A

KCNJ11

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10
Q

Gene for Glucokinase

A

GCK

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11
Q

Glutamate dehydrogenase

A

GLUD-1

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12
Q

Gene assoc w hyperinsulinism

A

Sulfonylurea receptor 1 (SUR-1) – ABCC8
Kir6.2 – KCNJ11
Glucokinase – GCK
Glutamate dehydrogenase (GHD) – GLUD-1
Mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) – HADH (hydroxyacyl-coenzyme A dehydrogenase)
SLC16A1
HNF4A, HNF1A
HK1
PGM1
PMM2

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13
Q

channel involved in insulin production
- name
- parts

A

ATP-sensitive potassium channel CHI

K+-selective pore-forming subunit = Kir6.2 (KCNJ11)
- Allows potassium influx across the membrane

Regulatory subunit = SUR-1 (ABCC8)
- Functions as a binding site (diazoxide, sulfonylureas

4 subunits each – outer (SUR-1) and inner, pore-making (Kir6.2)

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14
Q

what CHI is not responsive to diazoxide

A

ATP-sensitive potassium channel CHI

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15
Q

Glutamate dehydrogenase hyperinsulinism
- frequency
- other name
- inheritance
- what gene and what kind of mutation
- pathophys
- presentation
- diazoxide?

A
  • Second most common form of CHI
  • AKA hyperinsulinism and hyperammonemia syndrome
  • AD inheritance
  • Gain-of-function mutation of a mitochondrial enzyme GDH (gene GLUD1)
    (Key regulator of amino acid and ammonia metabolism in ß-cell liver, and brain)
  • missense mutation -> reduce sensitivity of the enzyme to allosteric inhibition by GTP - Loss of inhibitory control -> excess insulin
  • In liver, increased GDH activity  excessive ammonia production and impaired urea synthesis
  • Fasting and postprandial hypoglycemia
  • persistent asymptomatic elevated ammonia (usually mild, 2-5x ULN)
  • Not LGA at birth
  • Can have usual pattern of generalized seizures (regardless of severity and frequency of hypoglycemic episodes)

Diazoxide responsive

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16
Q

Glucokinase CH
- mutation/gene
- pathophys
- inheritance

A

Activating mutation in GCK
glucokinase = glucose sensor in pancreatic ß-cells
- controls the rate-limiting step of glucose metabolism (catalyses glucose to glucose-6-phosphate) and responsible for glucose-stimulated insulin secretion

AD inheritance

severity and age of onset vary

17
Q

SCHAD
- what does it stand for
- gene
- pathophys
- diazoxide

A

Short-chain 3-hydroxyacyl-CoA dehydrogenase hyperinsulinism

Gene – HADH

SCHAD catalyzes the 3rd of 4 steps in mitochondrial fatty acid oxidation spiral

Loss-of-function mutation impairs the enzymatic inhibitory effect of SCHAD on GDH = rise in intracellular ATP = inappropriate leucine sensitive HI

AR inheritance

Has fasting hypoglycemia

Lab: increased levels of plasma 3-hydroxybutyryl-carnitine and urine 3-hydroxyglutarate

No hepatic dysfunction, cardiomyopathy, or effects on skeletal muscle

Clinical presentation heterogenous in terms of severity and age of onset (even adult)

Responsive to diazoxide

18
Q

how does diazoxide work

A

acts by stabilizing the KATP channel of the ß cell to open state and hyperpolarize the cell membrane (i.e. inhibit membrane depolarization)
-> reduces calcium influx through voltage-gated calcium channel
-> reduce insulin secretion

Need functionally intact SUR1 and Kir6.2 (thus channel defects do not respond)

19
Q

side effects of diazoxide

A

edema (due to sodium retention) - often need to start thiazide diuretic

gastric irritation

hypertrichosis and coarse facial changes (reduced only by decreasing or stopping)

rare:
hyperuricemia,
leukopenia,
thrombocytopenia

20
Q

Beckwith Wiedeman

A

Hyperinsulinism

Somatic overgrowth,
macroglossia,
hemihypertrophy,
transverse creases of ear lobes,
hypoglycemia,
predisposition to childhood tumors

85% sporadic, 15% AD inheritance

Hypoglycemia occurs in up to 50% - variable severity, some transient, others persistent

Mechanism of hyperinsulinism – unknown (may be heterogenous given variable genotype)

Response to medical therapy is variable – from medical therapy to partial pancreatectomy

Most cases of hypoglycemia resolve spontaneously

21
Q

how do somatostatin analogues work

A

Acts via a G-protein-coupled receptor to lower intracellular calcium and hyperpolarize ß cell membrane -> inhibit insulin release

22
Q

side effects of octreotide

A

NEC in young infants,
vomiting,
abdominal distension,
steatorrhea,
later risk of cholelithiasis

23
Q

med options for tx of HI

A

diazoxide
somatostatin analogue
glucagon

24
Q

Causes of hypoBG + high insulin

A

i) Congenital hyperinsulinism
ii) Perinatal stress
iii) Insulinoma
iv) Sulfonylurea (and other insulin secretagogues)
v) Exogenous insulin
vi) Infants of mothers with gestational diabetes
vii) SGA or LGA infants
viii) Dumping syndrome (post abdo surgery)
ix) Autoimmune hypoglycemia

25
Q

Causes of hypoBG without high insulin

A

i) Metabolic disorders
ii) Cortisol deficiency
iii) Growth hormone deficiency
iv) FAO defect
v) Glycogen storage disorders
vi) Low energy stores (eating disorder, etc.)
vii) Critical stress
viii) Benign ketotic hypoglycemia
ix) Hepatic failure
x) Renal insufficiency
xi) Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHIS)
xii) Carnitine deficiency
xiii) Propranolol
xiv) Salicylates
xv) PEG asparaginase

26
Q

Insulinoma common mutation

A

commonly mutation in YY1 gene

27
Q

insulinoma treatment

A

surgical resection
diazoxide
octreotide
Continuous dextrose administration or frequent (q2-3h) feedings
Radio-ablation to reduce tumour burden/symptoms

28
Q

lab test to dx insulinoma

A

Glucagon stimulation test

Test BG at time zero, then give glucagon 15mcg/kg to a max of 1mcg and test BG at 10, 20, 30 and 40min post draw. A BG increase by 1.7mmol/L supports the diagnosis of hyperinsulinism

29
Q

insulinoma - imaging

A
  1. Pancreatic, dual phase, thin section helical CT can identify
  2. MRI with gadolinium
  3. 111-In-Octreotide scan
  4. PET/CT scans using gallium-labeled somatostatin analogs such as DOTA-1-NaI3-octreotide (DOTA-NOC) scan
  5. Endoscopic US
  6. selective calcium-stimulated angiography
30
Q

Autoimmune hypoglycemia

A

causes binding to insulin and detach from insulin long after meal, so initially there is hyperglycemia when insulin is bound after a meal and cannot be used and then hypoglycemia when the antibody detaches later. Since this occurs a while after the meal the C-pepite has mostly cleared, unless the antibody is a variant that also binds to the C-peptide

PEDS ENDO RC TD 2022 (14 decks)

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