Hypoglycemia

Question 1

What are symptoms of hypoglycemias?
What are the cutoffs?

Answer 1

<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

Question 2

Autonomic nervous system response to hypoglycemias

Answer 2

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

Question 3

what are the counter regulatory hormones

Answer 3

glucagon
cortisol
growth hormone
catecholamines
cholinergic neurotransmitters

Question 4

insulin

Answer 4

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

Question 5

what does glucagon do

Answer 5

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

Question 6

causes of transient hyperinsulinism

Answer 6

infants of diabetic mothers
SGA
LGA
asphyxia
stress

Question 7

syndromes associated with hyperinsulinism

Answer 7

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

Question 8

Gene for Sulfonylurea receptor 1 (SUR-1)

Answer 8

ABCC8

Question 9

Gene for Kir6.2

Answer 9

KCNJ11

Question 10

Gene for Glucokinase

Answer 10

GCK

Question 11

Glutamate dehydrogenase

Answer 11

GLUD-1

Question 12

Gene assoc w hyperinsulinism

Answer 12

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

Question 13

channel involved in insulin production
- name
- parts

Answer 13

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)

Question 14

what CHI is not responsive to diazoxide

Answer 14

ATP-sensitive potassium channel CHI

Question 15

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

Answer 15

• 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

Question 16

Glucokinase CH
- mutation/gene
- pathophys
- inheritance

Answer 16

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

Question 17

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

Answer 17

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

Question 18

how does diazoxide work

Answer 18

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)

Question 19

side effects of diazoxide

Answer 19

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

Question 20

Beckwith Wiedeman

Answer 20

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

Question 21

how do somatostatin analogues work

Answer 21

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

Question 22

side effects of octreotide

Answer 22

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

Question 23

med options for tx of HI

Answer 23

diazoxide
somatostatin analogue
glucagon

Question 24

Causes of hypoBG + high insulin

Answer 24

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

Question 25

Causes of hypoBG without high insulin

Answer 25

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

Question 26

Insulinoma common mutation

Answer 26

commonly mutation in YY1 gene

Question 27

insulinoma treatment

Answer 27

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

Question 28

lab test to dx insulinoma

Answer 28

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

Question 29

insulinoma - imaging

Answer 29

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

Question 30

Autoimmune hypoglycemia

Answer 30

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