HypoBG Flashcards
What are symptoms of hypoglycemias?
What are the cutoffs?
<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
Autonomic nervous system response to hypoglycemias
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
counter regulatory hormones
glucagon
cortisol
growth hormone
catecholamines
cholinergic neurotransmitters
insulin
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
glucagon what does it do
increases hepatic glycogenolysis and gluconeogenesis (of liver but not kidney)
Increased lipolysis
Increased ketogenesis
Decreased appetite
Increased energy expenditure
Increased glucose
causes transient HI
infants of diabetic mothers
SGA
LGA
asphyxia
stress
Syndromes w HI
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
Glutamate dehydrogenase
gene
location
GLUD-1
mitochondria
channel involved in insulin production
- name
- parts
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)
Glutamate dehydrogenase hyperinsulinism
- frequency
- other name
- inheritance
- what gene and what kind of mutation
- pathophys
- presentation
- diazoxide?
- 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
Glucokinase CH
- mutation/gene
- pathophys
- inheritance
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
SCHAD
- what does it stand for
- gene
- pathophys
- diazoxide
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
how does diazoxide work
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)
side effects of diazoxide
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
Beckwith Wiedeman
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
how do somatostatin analogues work
Acts via a G-protein-coupled receptor to lower intracellular calcium and hyperpolarize ß cell membrane -> inhibit insulin release
octreotide s/e
NEC in young infants,
vomiting,
abdominal distension,
steatorrhea,
later risk of cholelithiasis
med tx options HI
diazoxide
somatostatin analogue
glucagon
Causes of hypoBG + high insulin
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
Causes of hypoBG without high insulin
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
Insulinoma common mutation
commonly mutation in YY1 gene
insulinoma tx
surgical resection
diazoxide
octreotide
Continuous dextrose administration or frequent (q2-3h) feedings
Radio-ablation to reduce tumour burden/symptoms
lab test to dx insulinoma/HI
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
Insulinoma img
- Pancreatic, dual phase, thin section helical CT can identify
- MRI with gadolinium
- 111-In-Octreotide scan
- PET/CT scans using gallium-labeled somatostatin analogs such as DOTA-1-NaI3-octreotide (DOTA-NOC) scan
- Endoscopic US
- selective calcium-stimulated angiography
Autoimmune hypoBG
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
Whipple’s triad
Whipple’s triad:
1) symptoms/signs consistent with hypoglycemia,
2) documented low BG,
3) relief of symptoms when BG raised
**infants may not demonstrate because they can’t communicate sx
EtOH-induced hypoglycemia: how
EtOH metabolism reduces NAD+ to NADH, decreasing gluconeogenesis.
Hyperinsulinism DDx
- Iatrogenic or factitious
○ Insulin administration
○ Sulfonylurea - Autoimmune hypoglycemia (idiopathic insulin Ab, insulin receptor Ab)
- Insulinoma
- Congenital hyperinsulinism
Late dumping syndrome
post gastric surgery
carbs absorbed rapidly
exaggerated hyperinsulinemic response
