Hypoglycemia & Insulinoma - Rose

Question 1

What is the definition of hypoglycemia?

What is Whipple’s Triad?

Answer 1

Plasma glucose low enough to causes signs or symptoms, including impairment of brain function. Typically <70 mg/dl, AND

Whipple’s triad:

• Symptoms/signs consistent with hypoglycemia
• Low measured plasma glucose concentration
• Resolution of symptoms/signs with increasing plasma glucose

Question 2

What are some physiologic defenses the human body has against hypoglycemia?

Answer 2

• Increased sympathetic outflow + decreased insulin result in:
  
  • Increased hunger –> ingestion of carbohydrates
  • Increased glycongenolysis
  • Increased gluconeogenesis
  • Limit glucose utilization (of non-crucial organs)

Question 3

Order the following physiologic hormone responses to hypoglycermia in order of earliest reponse to latest:

• Increased cortisol
• Increased glucagon
• Increased glucagon
• Decreased insulin
• Increased growth hormone

Answer 3

From earliest to latest:

1. Decreased insulin
2. Increase in glucagon
3. Increase in epinephrine
4. Increases in cortisol & growth hormone

Question 4

In the context of hypoglycemia, describe:

• the adrenergic receptors that epinephrine targets in the liver
• the ways in which epinephrine acts on the **liver **to promote an increase in glucose.

Answer 4

• Liver
  
  • ß2: Increased glycogenolysis & gluconeogenesis

Question 5

In the context of hypoglycemia, describe:

the adrenergic receptors that epinephrine targets in the pancreatic islets
the ways in which epinephrine acts on the pancreatic islets to promote an increase in glucose.

Answer 5

• Pancreatic islets
  
  • a2: Decreased insulin
  • ß: Increased glucagon

Question 6

In the context of hypoglycemia, describe:

the adrenergic receptors that epinephrine targets in muscle
the ways in which epinephrine acts on muscle to promote an increase in glucose.

Answer 6

• Muscle
  
  • ß2
    
    • Increased glycolysis
    • Decreased glucose transport (decreased glucose utilization)

Question 7

In the context of hypoglycemia, describe:

the adrenergic receptors that epinephrine targets in fat
the ways in which epinephrine acts on fat to promote an increase in glucose.

Answer 7

• Fat
  
  • ß: Increased lipolysis & fatty acid release (decreased glucose utilization)

Question 8

What are five neurogenic (autonomic) symptoms of hypoglycemia?

Answer 8

• Tremor
• Palpitations
• Anxiety / arousal
• Sweating
• Hunger

Question 9

What are six neuroglycopenic (CNS) symptoms of hypoglycemia?

Answer 9

• Cognitive impairment
• Behavioral Changes
• Psychomotor abnormalities
• Visual changes
• Seizures
• Coma

Question 10

Name five general differential diagnoses for the cause of hypoglycemia, along with specific examples if you are able.

Answer 10

• Drugs
  
  • Insulin or an insulin secretogogue
• Critical illness
  
  • Liver, kidney, heart failure
  • Sepsis
  • Severe malnourishment
• Cortisol deficiency
• Endogenous hyperiinsulin
  
  • Insulinoma
  • Nesidoblastosis
  • Post gastric bypass
• Insulin Autoimmune
  
  • anti-insulin Abs
  • anti-insulin receptor Abs

Question 11

Describe an insulinoma.

Typically, what size are they? Where do they occur?

Answer 11

Insulin-secreting tumors of pancreatic origin that cause hypoglycemia.

In 90% of cases: a benign, solitary, intrapancreatic tumor <2cm

Can occur anywhere in the pancreas

Question 12

How common are insulinomas by incidence?

What about in terms of pancreatic neoplasms?

Answer 12

Uncommon-

1-4 : 1,000,000

Only 1-2% of pancreatic neoplasms

Question 13

In general, how is diagnosis of an insulinoma made?

Answer 13

Hormonal studies made when pt is hypoglycemic

Imaging is used to localize the insulinoma after the diagnosis is already made.

Question 14

How is a supervised fast useful for detecting hypoglycemia?

What is the maximum length of time a supervised fast be carried out for?

Answer 14

• Fasting will provoke the hormonal responses that maintain euglycemia
• Normally, symptomatic hypoglycemia should not occur after a prolonged fast due to gluconeogenesis
• No more than 72 hours

Question 15

What are the four possible end points for a supervised fast study?

(Think: Proof of the problem and patient safety)

Answer 15

• glucose < 45 mg/dl
• clear signs/symptoms of hypoglycemia
• 72 hours have elapsed
• glucose < 55 mg/dl + Whipple’s triat

Question 16

Describe the synthesis, modification, and transport of insulin in a pancreatic beta cell

Answer 16

• Synthesized as preproinsulin by ribosomes in the rER
• Cleaved to proinsulin and tranported into the Golgi
• Packaged into secretory granules and transported close to the cell membrane
• In the secretory granules, cleaved again into insulin and C-peptide

Question 17

How could you determine if a patient’s insulin was endogenously produced or taken as an exogenous drug, via a blood test?

Answer 17

• Endogenous insulin is secreted with C-peptide and some uncleaved proinsulin
• Exogenous insulin does not come with either of these
• Measure C-peptide or proinsulin

Question 18

During a supervised fast, what levels of glucose and insulin are expected for

A normal patient?

A patient with an insulinoma?

Answer 18

• Normal
  
  • Euglycemia (>60 mg/dl)
  • Decrease in insulin (<3 microU/ml)
• Insulinoma
  
  • Hypoglycemia (<55 mg/dl)
  • Innapropriately high insulin (>3 microU/ml)

Question 19

What is the mechanism of action of a sulfonylurea drug?

Answer 19

Class of drugs used to treat diabetes. Increase insulin release from the pancreas.

Question 20

What etiologies of hypoglycemia will demonstrate elevated insulin during a 72 hour fast?

Answer 20

• Insulinomas
• Sulfonylurea drugs
• Insulin autoimmune (?)
• Exogenous insulin

Question 21

What etiologies of hypoglycemia with demonstrate elevated C-peptide during a 72-hour fast?

Answer 21

• Insulinomas
• Sulfonylurea drugs

Recall: exogenous insulin does not contain C-peptide

Question 22

Seeing as both insulinomas and sulfonylurea use increase both insulin and C-peptide levels, how can you tell the two apart?

Answer 22

Sulfonylurea screen

(It is possible to screen for the drugs in the plasma, and sometimes the urine)

Question 23

What etiologies of hypoglycemia demonstrate in increased level of proinsulin during a 72 hour fast?

Answer 23

• Insulinoma
• (Sulfonylureas not mentioned, so perhaps this could be used to tell the two apart as well?)

Question 24

How does an insulinoma affect ß-hydroxybutyrate levels?

Answer 24

• ß-hydroxybutyrate is a ketone body
• Insulin has an antiketogenic effect
• Therefore, insulinoma patients will have lower levels while fasting
• At the end of the fast, insulinoma pts will have < 2.7 mmol/l

Question 25

How does an insulinoma pt respond to 1mg of IV glucagon?

Answer 25

• Lecture says that pts will have “a subsequent increase in plasma glucose at the end of a supervised fast” [which sounds exactly like how a normal person would respond.]
• An article I found says: “The capillary blood glucose response to lmg of intramuscular glucagon was determined in 13 patients with insulinoma and in 33 normal controls; the insulinoma patients showed a normal initial rise, but this was followed by an abnormally large fall, reaching hypoglycaemic levels between 90 and 180 minutes in every case” (PMC473794)

Question 26

Describe how a “Mixed Meal Test” works and what it is useful for.

Answer 26

• Measure glucose, proinsulin, insulin, & C-peptide premeal (fasting) then every 30 minutes post meal (mixture of fats, carbs, and protein)
• Used to evaluate pts with postprandial symptoms
• Trying to confirm if hypoglycemia is the cause of symptoms and to clarify if insulin mediated
• Helpful in pts with postprandial symptoms following GI procedures such as Roux en Y gastric bypass.

Note: Not standardized / validated like the 72 hour fast.

Question 27

If a patient is already taking insulin or a sulfonylurea drug, at which glucose level should you consider there is perhaps another etiology (e.g. insulinoma) going on?

Answer 27

<70 mg/dl