VI. Hypoglycemia

Question 1

TRUE or FALSE: Survival of the brain, and therefore the individual, requires a virtually continuous supply of glucose from the circulation.

Answer 1

TRUE

Hypoglycemia causes functional brain failure, which is typically corrected after the plasma glucose concentration is raised.

Question 2

What is the Whipple triad

Answer 2

Symptoms, signs, or both consistent with hypoglycemia

A low reliably measured plasma glucose concentration

Resolution of those symptoms or signs after the plasma glucose concentration is raised

Question 3

In which population is documentation of Whipple triad particularly important?

Answer 3

Those who do not have insulin- sulfonylurea-, or glinide-treated diabetes because hypoglycemic disorders are uncommon in such individuals

Question 4

3 sources of glucose

Answer 4

Intestinal absorption following digestion of dietary carbohydrates
Glycenolysis
Gluconeogenesis (from precursors including lactate (and pyruvate), amino acids (especially alanine and glutamine), and, to a lesser extent, glycerol

Question 5

The only organs that express glucose-6-phosphatase, the enzyme necessary for release of glucose into the circulation, at levels sufficient to permit substantial contributions to the systemic glucose pool

Answer 5

Liver and kidneys

The liver and kidneys also express the enzymes necessary for gluconeogenesis.

Many tissues express the enzymes required to synthesize and hydrolyze glycogen.

Question 6

The organ that is the main source of net endogenous glucose production (through glycogenolysis and gluconeogenesis)

Answer 6

Liver

Question 7

Tissues that can take up and store glucose as glycogen, or metabolize glucose to pyruvate, which, among other fates, can be reduced to lactate or transaminated to form alanine

Answer 7

Muscle > Fat

Question 8

Essentially the sole metabolic fuel for the brain under physiologic conditions

Answer 8

Glucose

Although the adult human brain constitutes only about 2.5% of body weight, its oxidative metabolism accounts for approximately 25% of the basal metabolic rate and more than 50% of whole-body glucose utilization.

During extended fasting, markedly elevated circulating ketone levels can support the majority of the energy needs and reduce its utilization of glucose.

Notably, ketogenesis is suppressed during episodes of insulin-mediated hypoglycemia.

Question 9

In healthy adults, the physiologic postabsorptive (fasting) plasma glucose concentration ranges from approximately __ to __ mg/dL, with a mean of __ mg/dL.

Answer 9

70 to 110
90

Question 10

In the postabsorptive steady rate, rates of glucose production and utilization average approximately __ mg/kg per minute.

Answer 10

2.2 mg/kg per minute

Threefold higher in infants (greater brain mass relative to weight)

Question 11

Predominant source of endogenous glucose production in the postabsorptive state

Answer 11

Liver

Question 12

TRUE about the effects of insulin on glucose influx into circulation EXCEPT:
a. Decreases glygocenolysis and gluconeogenesis in the liver
b. Decreases gluconeogenesis in the kidneys
c. Increases variable glucose utilization by other tissues (e.g., muscle, fat, liver, kidneys)
d. All of the above are TRUE

Answer 12

C

Question 13

TRUE about the effects of glucagon on glucose influx into circulation:
a. Increases glygocenolysis and gluconeogenesis in the liver
b. Increases gluconeogenesis in the kidneys
c. Decreases variable glucose utilization by other tissues (e.g., muscle, fat, liver, kidneys)
d. All of the above

Answer 13

A

Glucagon doesn’t affect glucose production in the kidneys nor the rate of glucose clearance by insulin-sensitive tissues

Question 14

TRUE about the effects of epinephrine on glucose influx into circulation:
a. Increases glygocenolysis and gluconeogenesis in the liver
b. Increases gluconeogenesis in the kidneys
c. Decreases variable glucose utilization by other tissues (e.g., muscle, fat, liver, kidneys)
d. All of the above

Answer 14

D

Question 15

Average glucose pool (free glucose in the ECF and in cells of certain tissues, primarily the liver)

Average glucose content of glycogen

Average length of time for which preformed glucose can provide a supply of energy

Answer 15

15 to 20 g

70 g

8 hours

Question 16

Responses of the body to prolonged fasting ~24 to 48 hours

Answer 16

Plasma glucose declines. Hepatic glucogen content falls to less than 10 g

Because amino acids are the main gluconeogenic precursors that result in net glucose formation, muscle protein is degraded.

Glucose utilization by muscle and fat virtually ceases.

As lipolysis and ketogenesis accelerate and circulating ketone levels rise, ketones become a major fuel for the brain.

Question 17

First, second, and third responses to hypoglycemia

Answer 17

First - Decrease in insulin secretion (primary glucose regulatory factor)

Second - Increase in glucagon secretion (primary glucose conterregulatory factor)

Third - Increase in epinephrine secretion (critical when glucagon is deficient)

Cortisol and growth hormone - NOT critical

Question 18

Clinical hypoglycemia - that sufficient to cause symptoms and signs - is most convincingly documented by

Answer 18

Whipple triad

Question 19

What are neuroglycopenic symptoms

Answer 19

Direct result of brain glucose deprivation:
Warm, weak, difficulty thinking/confused, tired/drowsy, faint, dizzy, difficulty speaking, blurred vision

Question 20

What are neurogenic (or autonomic) symptoms

Answer 20

Largely the result of the perception of physiologic changes caused by the sympathoadrenal discharge triggered by hypoglycemia

Cholinergic: Sweaty, hungry, tingling
Adrenergic: Shaky/tremulous, heart pounding, nervous/anxious

Question 21

Subjective awareness of hypoglycemia is largely the result of the perception of ___ symptoms

Answer 21

Neurogenic

Question 22

TRUE or FALSE: The glycemic threshold for a decrease in the cerebral metabolic role of glucose, measured with 11C-glucose PET, is at a higher plasma glucose concentration than the glycemic thresholds for the hormonal and sympathetic responses.

Answer 22

FALSE

The glycemic threshold for a decrease in the cerebral metabolic role of glucose, measured with 11C-glucose PET, is at a LOWER plasma glucose concentration than the glycemic thresholds for the hormonal and sympathetic responses.

Hence, the signaling of glucose regulatory and counterregulatory hormones and sympathetic responses to hypoglycemia are NOT mediated by a decrease in brain glucose metabolism.

Question 23

Glycemic threshold for:
Decreased insulin
Increased glucagon
Increased epinephrine
Increased cortisol and growth hormone
Symptoms
Decreased cognition
Decreased brain glucose metabolism

Answer 23

Decreased insulin: 80-85 mg/dL

Increased glucagon: 65-70 mg/dL
Increased epinephrine: 65-70 mg/dL
Increased cortisol and growth hormone: 65-70 mg/dL

Symptoms: 50-55 mg/dL –> Prompt behavioral defense (food ingestion)

Decreased cognition: <50 mg/dL –> Compromises behavioral defense
Decreased brain glucose metabolism: <50 mg/dL

Question 24

What signals the fist, second, and third lines of defense against hypoglycemia

Answer 24

Signals of defense against hypoglycemia:
- Decrease in insulin is signaled primarily by declining glucose levels at the beta cells
- Increase in glucagon is signaled primarily by a decrease in intra-islet insulin
- Increase in epinephrine is signaled by CNS due to falling glucose levels, acting through the hypothalamus

Question 25

How does epinephrine increase glucose?

Answer 25

Largely by beta2-adrenergic stimulation of hepatic and renal glucose production

Others:
- Limitation of glucose clearance by insulin-sensitive tissues
- Mobilization of gluconeogenic precursors such as lactate and amino acids from muscle and glycerol from fat
- Alpha2-adrenergic limitation of insulin secretion

Question 26

What limits the magnitude of glycemic response to epinephrine despite alpha2-adrenergic stimulation of insulin secretion?

Answer 26

Beta2-adrenergic stimulation also stimulates insulin secretion

This explains why glycemic sensitivity to epinephrine is increased in patients who cannot increase insulin secretion (e.g., T1DM)

Question 27

Circulating epinephrine, as well as the plasma norepinephrine, in response to hypoglycemia are derived largely from the

Answer 27

Adrenal medulla

Question 28

How do recurrent hypoglycemia and poorly controlled diabetes shift the glycemic thresholds for symptoms and signs of hypoglycemia?

Answer 28

They shift to lower plasma glucose concentrations in patients with recurrent hypoglycemia and to higher concentrations in those with poorly controlled diabetes

Question 29

Glucose concentrations measured in whole blood are approximately 15% ___ (lower/higher) than those in plasma and may be further ___ reduced/increased) if the hematocrit is high

Answer 29

Lower
Reduced

Question 30

The most common cause of hypoglycemia

Answer 30

Drugs (insulin secretagogues and insulin)

Question 31

Approximate frequency of hypoglycemia in T1DM patients

Answer 31

Approximately 2 episodes of symptomatic hypoglycemia per week, and roughly 1 episode per year of severe, at least temporarily disabling hypoglycemia, often with seizure or coma

T1DM patients have more frequent hypoglycemia, but for T2DM patients, the incidence of hypoglycemia increases progressively over time as patients approach the absolute endogenous insulin-deficient end of the spectrum of T2DM.

Since T2DM has higher prevalence, most episodes of iatrogenic hypoglycemia, including severe hypoglycemia, occur in persons with T2DM.

Question 32

TRUE or FALSE: Lower HbA1c levels are associated with increased mortality in patients with T2DM at higher risk of hypoglycemia.

Answer 32

TRUE

Question 33

TRUE or FALSE: Systematic long-term follow-up of the DCCT patients suggests that recurrent iatrogenic hypoglycemia causes chronic cognitive impairment in young adults.

Answer 33

FALSE

Systematic long-term follow-up of the DCCT patients suggests that recurrent iatrogenic hypoglycemia does not chronic cognitive impairment in young adults, but the possibility that it does so in young children and elderly remains.

Question 34

Most instances of sudden hypoglycemic death are thought to be the result of ___.

Answer 34

Cardiac arrhythmias triggered by an intense sympathoadrenal response to hypoglycemia

Question 35

ADA/ES Workgroup on Hypoglycemia definition of hypoglycemia in diabetes

Answer 35

All episodes of abnormally low plasma glucose concentration that expose the individual to potential harm

*It is not possible to define a plasma glucose concentration that categorically defines hypoglycemia.

Question 36

Recommended definition of clinical hypoglycemia in persons without diabetes

Answer 36

A plasma glucose concentration low enough to cause symptoms or signs

*It is not possible to define a plasma glucose concentration that categorically defines hypoglycemia.

Question 37

Why was 70 mg/dL chosen as the glucose alert level

Answer 37

1) It approximates the lower limit of the nondiabetic postabsorptive plasma glucose range and the normal glycemic thresholds for activation of physiologic glucose counterregulatory systems.
2) It is low enough to reduce glycemic defenses against subsequent hypoglycemia in nondiabetic persons.
3) It gives the patient time to take action to prevent a clinical hypoglycemic episode.
4) It provides some margin for the limited accuracy of glucose monitoring devices at low plasma glucose concentrations.

Question 38

International Hypoglycaemia Study Group 3 levels of iatrogenic hypoglycemia in diabetes

Answer 38

Level 1: A glucose alert value of 70 mg/dL or less

Level 2: A glucose level of less than 54 mg/dL, which is sufficiently low to indicate serious clinically important hypoglycemia

Level 3: Severe hypoglycemia as defined by ADA

Question 39

Definition of the following clinical classifications of hypoglycemia in diabetes:
- Severe hypoglycemia
- Documented symptomatic hypoglycemia
- Asymptomatic hypoglycemia
- Probable symptomatic hypoglycemia
- Pseudohypoglycemia

Answer 39

Severe hypoglycemia - an event requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions (plasma glucose may not be available, but neurologic recovery attributable to restoration of plasma glucose to normal is sufficient evidence that the event was induced by low plasma glucose)

Documented symptomatic hypoglycemia - an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration of <=70 mg/dL

Asymptomatic hypoglycemia - an event NOT accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration of <=70 mg/dL

Probable symptomatic hypoglycemia - an event during which symptoms typical of hypoglycemia are NOT accompanied by a plasma glucose determination but were presumably caused by a plasma glucose concentration <=70 mg/dL

Pseudohypoglycemia - an event during which the persons with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia, with a measured plasma glucose concentration that is >70 mg/dL but is approaching that level

Question 40

What happens with the defenses against hypoglycemia in patients with established T1DM (absolute deficiency of endogenous insulin)?

Answer 40

Insulin concentrations do not decrease in response to therapeutic hyperinsulinemia - First physiologic defense is lost

Despite the presence of functional alpha cells, there is no increase in glucagon - Second defense is lost

The increase in epinephrine secretion, the third physiologic defense against hypoglycemia, is typically attenuated. This is a marker of attenuation of the sympathoadrenal response –> hypoglycemia unawareness

Question 41

What causes hypoglycemia unawareness / impaired awareness of hypoglycemia?

Answer 41

Largely the result of reduced release of the sympathetic neurotransmitters norepinephrine and acetylcholine

Question 42

How does Hypoglycemia-Associated Autonomic Failure (HAAF) develop?

Answer 42

Advanced T2DM and T1DM (absolute beta-cell failure) –>

Relative or mild-moderate absolute therapeutic hyperinsulinemia –> Falling glucose levels –>

Beta-cell failure –> No decrease in insulin and no increase in glucagon –>

Episodes of hypoglycemia, together with exercise and sleep –>

HAAF

Question 43

What is the consequences of HAAF?

Answer 43

1) Decreased adrenomedullary epinephrine response –> Defective glucose counterregulation
2) Decreased sympathetic neural response –> Impaired awareness of hypoglycemia

Both leads to recurrent hypoglycemia (which further attenuates the sympathoadrenal response to falling plasma glucose concentrations)

Question 44

TRUE or FALSE: The pathophysiology of glucose counterregulation is the same in T1DM and T2DM but with different time courses.

Answer 44

TRUE

In contrast to the compromised defenses in T1DM, defenses against hypoglycemia are intact early in the course of T2DM. However, they become compromised over time.

Question 45

TRUE about HAAF (as many as may apply):
a. It is a functional form of autonomic failure
b. It is the same as classic diabetic autonomic neuropathy
c. It reduces baroreflex sensitivity and may predispose patients to cardiac arrhythmias

Answer 45

A and C

It is distinct from classic diabetic autonomic neuropathy.

Question 46

As little as __ to __ weeks of scrupulous avoidance of hypoglycemia reverses impaired awareness of hypoglycemia and improves the attenuated epinephrine component of defective glucose counterregulation in most affected patients.

Answer 46

2 to 3 weeks

Question 47

3 recognized causes of reversibly attenuated sympathoadrenal response to hypoglycemia (and therefore 3 forms of HAAF)

Answer 47

Antecedent hypoglycemia-related HAAF

Exercise-related HAAF (exemplified by late postexercise hypoglycemia, which typically occurs 6 to 15 hours after strenuous exercise and is often nocturnal)

Sleep-related HAAF (result of further attenuation of the sympathoadrenal reponse to hypoglycemia during sleep)

Question 48

Part of the brain that is the central integrator of the sympathoadrenal response to hypoglycemia

Answer 48

Hypothalamus

Question 49

Conventional risk factors for hypoglycemia in diabetes

Answer 49

Absolute or Relative Insulin Excess:
- Insulin or insulin secretagogue doses are excessive, ill-timed, or the wrong type
- Exogenous glucose delivery is decreased (e.g., after missed meals, during the overnight fast)
- Glucose utilization is increased (e.g., during exercise)
- Endogenous glucose production is decreased (e.g., after alcohol ingestion)
- Sensitivity to insulin is increased (e.g., after weight loss, with improved fitness or improved glycemic control, in the middle of the night)
- Insulin clearance is decreased (e.g., with renal failure)

Question 50

Clinical risk factors for hypoglycemia

Answer 50

• Presence of HAAF
• History of severe hypoglycemia
• Chronic kidney disease
• Long duration of diabetes
• Malnutrition

Question 51

Risk factors for HAAF

Answer 51

• Absolute endogenous insulin deficiency
• A history of severe hypoglycemia, impaired awareness of hypoglycemia, or both, and recent antecedent hypoglycemia, prior exercise, or sleep
• Aggressive glycemic therapy per se (lower HbA1c levels, lower glycemic goals, or both)

Question 52

TRUE or FALSE: The degree of beta-cell failure determines the extent to which insulin levels will not decrease and glucagon levels will not increase as glucose levels fall in response to therapeutic hyperinsulinemia.

Answer 52

TRUE

Question 53

Measures for Hypoglycemia Risk Factor Reduction

Answer 53

1. Acknowledge the problem
2. Apply the principles of aggressive glycemic therapy:
   Diabetes self-management
   Frequent self-monitoring of blood glucose
   Flexible and appropriate insulin (and other drug) regimens
   Individualized glycemic goals
   Ongoing professional guidance and support
3. Consider the conventional risk factors for hypoglycemia
4. Consider the risk factors for HAAF

Question 54

Which of the following has been shown to reduce hypoglycemia events:
a. CSII (compared to MDI)
b. Insulin analogues
c. Hybrid closed-loop insulin replacement systems (specifically those that temporarily suspend insulin infusion when a low glucose concentration is predicted)
d. Pancreatic islet transplantation

Answer 54

B, C, D

Question 55

Which among the two is more often associated with hypoglycemia, glyburide (glibenclamide) or glimepiride?

Answer 55

Glyburide (glibenclamide - since longer acting)

Question 56

Describe a reasonable individualized glycemic goal

Answer 56

The lowest HbA1c that does not cause severe hypoglycemia and preserves awareness of hypoglycemia

*The frequency of hypoglycemia was inversely related to the HbA1c level in both DCCT and EDIC.

Question 57

What is the treatment of hypoglycemia in diabetes?

Answer 57

A reasonable dose is 20 g of glucose (glucose tablet or carbohydates). Clinical improvement should occur in 15-20 minutes. With ongoing hyperinsulinemia, the glycemic response to oral glucose is transient, typically lasting less than 2 hours. Therefore, ingestion of a snack or meal shortly after the glucose level is raised is usually advisable.

Question 58

Alternatives to oral glucose in a patient who is unable or unwilling (because of neuroglycopenia) to take carbohydrate orally

Answer 58

Glucagon 1.0 mg in adults, subcutaneously or intramuscularly

IV glucose (dextrose) at initial dose of 25 g

Question 59

TRUE about glucagon as treatment for hypoglycemia EXCEPT:
a. Can cause nausea and even vomiting
b. Often causes substantial, albeit transient, hyperglycemia
c. Ineffective in glycogen-depleted individuals (e.g., after a binge of alcohol ingestion)
d. Has been reported to cause hypoglycemia in nondiabetic individuals
e. All are TRUE

Answer 59

E

C - because it acts by stimulating glycogenolysis
D - because it can stimulate insulin secretion

Question 60

TRUE or FALSE: Plasma glucose concentrations used to document Whipple triad may be measured with a blood glucose self-monitor.

Answer 60

FALSE

Plasma glucose concentrations used to document Whipple triad must be measured with a reliable laboratory method and not with a blood glucose self-monitor.

Question 61

Possible reason for “pseudohypoglycemia”, an artifact of continued glucose metabolism by the formed elements of the blood after blood sample is drawn

Answer 61

If the sample is collected in a container that does not include an inhibitor of glycolysis, such as sodium fluoride or ethylenediaminetetraacetic acid-citrate (EDTA), and separation of the plasma or serum from the formed elements is delayed, particularly in the setting of erythrocytosis, leukocytosis, or thrombocytosis

Question 62

Antecubital venous glucose levels are as much as ___ lower than arterial glucose levels when insulin secretion is increased.

Answer 62

One third

Question 63

TRUE or FALSE: Because of the provision of alternative fuels (specifically ketones) to the brain, plasma glucose concentrations lower than the overnight fasted physiologic range occur in healthy individuals, especially women and children, during extended fasting.

Answer 63

TRUE

Question 64

TRUE or FALSE: The glycemic thresholds of responses to hypoglycemia shift to higher plasma glucose concentrations in patients with recurrent hypoglycemia.

Answer 64

FALSE

The glycemic thresholds of responses to hypoglycemia shift to lower plasma glucose concentrations in patients with recurrent hypoglycemia.

Question 65

Most common cause of hypoglycemia in general, and also the most common cause of hypoglycemia in hospitals

Answer 65

Drugs

Question 66

Drugs, other than antihyperglycemic agents and alcohol, that are reported to cause hypoglycemia with Moderate Quality of Evidence

Answer 66

GC PIG Q

Gatifloxacin
Cibenzoline

Pentamidine
Indomethacin
Glucagon (during endoscopy)

Quinine

Question 67

Mechanism of alcohol-induced hypoglycemia

Answer 67

Alcohol-induced hypoglycemia:
- Inhibits gluconeogenesis
- Typically follows a binge of alcohol consumption during which the person eats little food (i.e., in the setting of glycogen depletion)
- Can be fatal, but with restoration of euglycemia and supportive care, recovery is the rule

Question 68

TRUE or FALSE: Hepatogenous hypoglycemia commonly occurs in cirrhosis and hepatitis.

Answer 68

FALSE

Hepatogenous hypoglycemia
- Occurs most commonly when destruction of the liver is rapid and massive (e.g., in toxic hepatitis)
- Unusual in common forms of cirrhosis or hepatitis
- Also unusual in metastatic liver disease despite extensive hepatic replacement

Question 69

Mechanisms of the following causes of hypoglycemia:
- Renal failure
- Severe cardiac failure
- Sepsis
- Inanition

Answer 69

• Renal failure - multifactorial - drugs, sepsis, or inanition
• Severe cardiac failure - possibility of inhibited gluconeogenesis
• Sepsis - cytokine-mediated increase in glucose utilization and decreased responsiveness to appropriate glucose counterregulatory signals (NOT glucose counterregulatory failure)
• Inanition - total body fat depletion –> limited supply of gluconeogenic precursors

Question 70

Mechanism of postabsorptive hypoglycemia

Answer 70

Postabsorptive hypoglycemia:
- Typically after a period of caloric deprivation caused by an intercurrent illness
- Can occur in patients with deficient secretion of cortisol, growth hormone, or both
- Reported in patients with profound muscle atrophy; presumably the result of substrate limitation of gluconeogenesis

Question 71

Glycemic intolerance of fasting is largely corrected by replacement of which of the following hormones:
a. Glucocorticoid
b. Growth hormone
c. Both
d. Neither

Answer 71

A

Question 72

Non-islet cell tumor hypoglycemia (NICTH) is often the result of overproduction of incompletely processed ___.

Answer 72

NICTH:
- Rare
- Usually large, clinically apparent, and mesenchymal in origin
- Often the result of overproduction of incompletely processed pro-insulin-like growth factor 2 (pro-IGF2)
- Ratio of plasma IGF2 to IGF1 is elevated
- Endogenous insulin secretion is suppressed appropriately
- Treatment of the tumor is SELDOM curative, but may alleviate hypoglycemia
- Treatment with a glucocorticoid, growth hormone, or both, is sometimes effective

Question 73

2 categories of the differential diagnosis of hypoglycemia in a seemingly well individual

Answer 73

1) accidental, surreptitious, or even malicious hypoglycemia
2) endogenous hyperinsulinism

Question 74

TRUE or FALSE: Long-term survival is the rule after successful surgical removal of an insulinoma.

Answer 74

TRUE

Insulinomas:
- Insulin-secreting pancreatic beta-cell tumors
- The prototypical, but not the only, cause of endogenous hyperinsulinemic hypoglycemia
- History of episodes of neuroglycopenia occurring in the postabsorptive (fasting) state
- Long-term survival is the rule after successful surgical removal
- In unreseactable disease: empirical treatment can be tried (diet, diazoxide, octreotide); chemotherapy (e.g., everolimus)

Question 75

Term used to refer to the condition in which there is diffuse islet involvement with islet hypertrophy, sometimes with hyperplasia, and enlarged and hyperchromatic beta-cell nuclei

Answer 75

Nesidioblastosis (clinically indistinguishable from insulinoma)

Question 76

Condition wherein there is hyperinsulinemia, the cause is in the pancreas, and hypoglycemia typically occurs after a meal instead of during fasting

Answer 76

Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
- Spells of neuroglycopenia caused by endogenous hyperinsulinemic hypoglycemia occurring typically, but not invariably, after a meal
- Syndrome is diffuse, and imaging studies are uniformly negative
- Medical therapy: Diet (frequent feedings), alpha-glucosidase inhibitor, diazoxide, octreotide
- Documentation of diffuse beta-cell hyperfunction depends on a positive selective arterial calcium stimulation test –> used to guide partial pancreatectomy if medical therapy fails

Question 77

Mechanism of post-gastric bypass hypoglycemia

Answer 77

Accelerated absorption of ingested glucose triggers a large insulin secretory response

Post-gastric bypass hypoglycemia (Roux-en-Y gastric bypass)
- Postprandial endogenous hyperinsulinemic hypoglycemia
- Accelerated absorption of ingested glucose triggers a large insulin secretory response that is mediated, at least in part, by a robust increase in GLP1
- Treatment: Low-carbohydrate diet, acarbose, somatostatin analogues, diazoxide, and possibly feeding into the bypassed stomach
- Still experimental: GLP1 receptor blockade

Question 78

TRUE or FALSE: In autoimmune hypoglycemia, the plasma insulin level is very low.

Answer 78

FALSE

Autoimmune hypoglycemia
- Affected individuals often have a history of other autoimmune disorders
- Hypoglycemia occurs in the late postprandial period as insulin, which is secreted in response to the meal and then bound to the circulating antibody, dissociates from the antibody in an unregulated fashion
- Diagnosed by high-titer serum insulin antibodies
- Another clue is very high measured plasma insulin levels during hypoglycemia
- No consistently effective therapy, but is sometimes self-limited

Question 79

Timing of hypoglycemia in the following conditions:
- Insulinoma
- Nesidioblastosis
- Noninsulinoma pancreatogenous hypoglycemia syndrome
- Post-gastric bypass hypoglycemia
- Autoimmune hypoglycemia

Answer 79

• Insulinoma - during fasting
• Nesidioblastosis - during fasting
• Noninsulinoma pancreatogenous hypoglycemia syndrome - after a meal
• Post-gastric bypass hypoglycemia - after a meal
• Autoimmune hypoglycemia - late postprandial period

Question 80

Tablet 38.4 Causes of Hypoglycemia in Adults, page 1531

Answer 80

*

Question 81

History in diagnosing hypoglycemia includes

Answer 81

Specific symptoms, their timing in relation to meals, their duration, and any factor that aggravate or alleviate them

Question 82

Diagnostic tests in the workup for hypoglycemia if the cause is not evident

Answer 82

Plasma glucose
Plasma insulin
C-peptide
Proinsulin
Beta-hydroxybutyrate
Circulating oral hypoglycemic agent during hypoglycemia
Plasma glucose reponse to IV injection of 1.0 mg of glucagon

Question 83

Key pathophysiologic feature of endogenous hyperinsulinsm

Answer 83

Failure of insulin secretion to fall to very low rates as plasma glucose concentrations fall to hypoglycemic levels

Question 84

Traditional critical diagnostic criteria for endogenous hyperinsulinism (assuming Whipple triad is documented)

Answer 84

Plasma insulin >=3 uU/mL (18 pmol/L)
Plasma C-peptide 0.06 ng/mL (0.2 nmol/L)
Plasma proinsulin 5.0 pmol/L
When plasma glucose is <55 mg/dL

Question 85

Table 38.9 Patterns of Findings During Fasting or After a Mixed Meal in Workup for Hypoglycemia, page 1543

Answer 85

*

Question 86

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin >=3 uU/mL
- C-peptide >=0.2 nmol/L
- Proinsulin >=5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (+) Circulating OHA
- (-) Insulin antibody

Answer 86

Oral hypoglycemia agent

Question 87

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin <3 uU/mL
- C-peptide <0.2 nmol/L
- Proinsulin <5 pmol/L
- Beta-hydroxybutyrate >2.7 mmol/L
- Glucose increase after glucagon <25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 87

Not insulin- or IGF-mediated

Question 88

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin <3 uU/mL
- C-peptide <0.2 nmol/L
- Proinsulin <5 pmol/L
- Beta-hydroxybutyrate >2.7 mmol/L
- Glucose increase after glucagon <25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 88

Normal

Question 89

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin <3 uU/mL
- C-peptide <0.2 nmol/L
- Proinsulin <5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 89

IGF

(Low beta-hxb and increase in plasma glucose concentration of >25 mg/dL over the low value over 30 minutes after glucose injection provide evidence of biologic actions of inappropriately high insulin (or IGF) levels, with suppression of lipolysis and ketogenesis and preservation of hepatic glycogen stores, respectively)

Question 90

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin >=3 uU/mL
- C-peptide >=0.2 nmol/L
- Proinsulin >=5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 90

Insulinoma, NIPHS, PGBH

Question 91

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin&raquo_space;3 uU/mL
- C-peptide <0.2 nmol/L
- Proinsulin <5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 91

Exogenous insulin

Question 92

Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin&raquo_space;3 uU/mL
- C-peptide&raquo_space;0.2 nmol/L
- Proinsulin&raquo_space;5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody

Answer 92

Insulin autoimmune

(But concentrations of free C-peptide and proinsulin are low)

Question 93

What to do if Whipple triad has not been documented and the measurements described have not been obtained during an episode of spontaneous hypoglycemia

Answer 93

Attempt to re-create the circumstances in which symptomatic hypoglycemia is likely to occur
- Fast should be continued until Whipple triad is documented, or until plasma glucose <55 mg/dL if Whipple triad was unequivocally documented previously
- Plasma glucose should be measured with a precise method, not with a point-of-care glucose monitor
- Most, but not all, do so in <48 hours
- A patient with a history suggestive of postprandial hypoglycemia should undergo a mixed meal test conducted over 5 hours

Question 94

Tests used to diagnose pancreatic causes of hypoglycemia

Answer 94

CT, MRI, and transabdominal Utz detect approximately 75% of insulinomas.

Endoscopic pancreatic utz, with the option of FNAB of a detected tumor, has a sensitivity greater than 90%.

Question 95

Procedure of choice for confirming NIPHS and hypoglycemia occurring after Roux-en-Y gastric bypass

Answer 95

Selective pancreatic arterial calcium injections, with an end point of at least a 2-fold increase (or perhaps >5-fold increase with contemporary assays) in hepatic venous insulin levels over baseline

*Can also regionalize insulinomas with high sensitivity if anatomic localization is negative or equivocal

Question 96

Treatment of hypoglycemia disorders

Answer 96

Tailored to the specific hypoglycemic disorder identified

Question 97

Enzymes of which of the following processes are absent during fetal life:
a. Gluconeogenesis
b. Glycogenesis
c. Glycogenolysis

Answer 97

A, but rapidly increase within the first few hours of life

B and C - present but hepatic glycogen stores do not increase much until the third trimester

Question 98

Plasma glucose concentrations decline after birth as placental blood flow (and maternal glucose supply) is interrupted, and they reach their nadir usually in the first __ hours of life.

Answer 98

2

Question 99

In most infants, the plasma glucose concentration is usually steady or is increasing by __ to __ hours of life.

Answer 99

4 to 6

Question 100

The brain relies almost exclusively on a constantly supply of glucose, but under special circumstances, it can use __ or __ as transient surrogate fuels if levels rise significantly enough.

Answer 100

Ketone bodies or lactate

Question 101

In the first year of life, the human brain accounts for nearly __% of the body’s glucose consumption due to the proportionally larger brain to body mass ratio, with the peak of cerebral glucose consumption occurring during ___.

Answer 101

50%
Middle childhood (~5-10 years of age)

Question 102

Overall, the rates of glucose flux (production and utilization) are nearly 3 times ___ (higher or lower) in infants and children than in adults.

Answer 102

Higher

Question 103

TRUE or FALSE: Transient low blood glucose concentrations are common in healthy infants in the first 24 to 48 hours of life as the glucose supply changes from a continuous transplacental supply to an intermittent supply from feeds, resulting in a quick depletion of the glycogen stores.

Answer 103

TRUE

Question 104

TRUE or FALSE: Newborns in the first few hours of life are relatively hypoinsulinemic compared with older children.

Answer 104

FALSE

Newborns in the first few hours of life are relatively hyperinsulinemic compared with older children due to a lower glycemic threshold for insulin secretion shortly after birth - 55-65 mg/dL compared with 80-85 mg/dL in older infants, children, and adults.

Question 105

Pediatric Endocrine Society suggests delaying diagnostic evaluations for hypoglycemia until __ to __ days after birth.

Answer 105

2 to 3 days

However, in infants who are at risk for hypoglycemia, glucose screening should be performed after the first feed, which should occur within 1 hour after birth.

Question 106

Signs and symptoms of hypoglycemia in a neonate or child

Answer 106

Nonspecific: jitteriness/tremors, hypotonia, changes in the level of consciousness, apnea/bradycardia, cyanosis, tachypnea, poor such or feeding, hypothermia, and/or seizures

Question 107

According to the American Academy of Pediatrics and Pediatric Endocrine Society, hypoglycemia persisting beyond ___ is not likely to be transitional.

Answer 107

48 hours

They emphasize the need for early identification of the infant at risk for severe hypoglycemia during the first 48 hours after delivery and for persistent hypoglycemia beyond 48 hours of life to determine the need for screening.

Question 108

Infants at risk for hypoglycemia:

Answer 108

• Infant of a diabetic mother
• Child with a family history of a genetic form of hypoglycemia or congenital syndrome associated with hypoglycemia
• Perinatal stress hyperinsulinism: birth asphyxia, IUGR, or toxemia, or infants receiving TPN

Question 109

Pediatric Endocrine Society suggested thresholds for plasma glucose concentration that should trigger further diagnostic testing in a child less than and more than 48 hours old

Answer 109

Less than 48 hours old: 50 mg/dL
After 48 hours of age: 60 mg/dL

Question 110

Usual diagnostic tests in the evaluation for neonatal hypoglycemia

Answer 110

Low blood glucose value with simultaneous measurement of carbon dioxide - to determine if there is an associated acidosis

Insulin level and ketone bodies - to determine if there is evidence of hyperinsulinism

Measures of counterregulatory hormones (cortisol, growth hormone)

Free fatty acids - to determine if there is a defect in fatty acid oxidation

Lactate level

C-peptide - if with concern for exogenous hyperinsulinism

Glucagon stimulation test at the time of hypoglycemia - for information about glycogen stores and possible hyperinsulinism

Question 111

Treatment for childhood hypoglycemia

Answer 111

If conscious and able to drink and swallow safely: 10-20 g of rapidly absorbed carbohydrates by mouth or a gastric tube; may be repeated after 15 mins, but if doesn’t improve within 30 minutes, parenteral glucose is recommended

If altered consciousness: slow IV bolus 2 mL/kg of 10% dextrose, followed by continuous infusion of dextrose at 6-9 mg/kg per minute; if IV access not available, 0.03 mg/kg up to a max of 1 mg glucagon intramuscularly

Question 112

TRUE or FALSE: The mean plasma glucose concentration in the postabsorptive state of children and neonates after 48 hours of age does not differ from that in adults (70-100 mg/dL)

Answer 112

TRUE

Question 113

Goal of treatment in children with the diagnosis of a disorder causing persistent hypoglycemia or a known risk of a persistent hypoglycemic disorder is to maintain a plasma glucose concentration above ___.

Answer 113

70 mg/dL

Therefore, a safety fast (6-hour fast), in which a term neonate over 3 days of life is asked to skip a single feed, should always be done before discharge to ensure that plasma glucose concentrations can be maintained above that range.

Question 114

Fig 38.14. Diagnostic algorithm for determining the etiology of hypoglycemia in children, page 1547

Answer 114

*

Question 115

Mechanism of intolerance of fasting in children

Answer 115

Intolerance of fasting:
- Plasma glucose <70 mg/dL and hyperketonemia after overnight fasting because of limited fasting tolerance
- Result partially from incomplete development of gluconeogenic mechanisms –> “ketotic hypoglycemia”
- Particularly common in preterm or SGA infants
- Typically occurs in 2-5 year old children and remits spontaneously before age 10 years
- Should be a diagnosis of exclusion

Question 116

Hyperinsulinism should be suspected in the following EXCEPT:
a. Plasma insulin is inappropriately normal or elevated for the level of hypoglycemia
b. Plasma or urine ketone levels and free fatty acids are high
c. There is a glycemic response to glucagon
d. Typically occurs in children who are LGA
e. Occurs after a short to moderate fasting period

Answer 116

B - They are low

Question 117

Most common cause of nontransient neonatal hypoglycemia

Answer 117

Congenital hyperinsulinism

• Caused by several inherited abnormalities of the different cellular mechanisms of glucose-stimulated insulin secretion
• Manifest with low plasma glucose, inappropriately high insulin and C-peptide, low beta-hydroxybutyrate, and brisk glycemic response to glucagon (analogous to hyperinsulinemic hypoglycemia in adults)
• Significant associated risk of hypoglycemic seizures and developmental delays, as well as hypertrophic cardiomyopathy
• The need for very high glucose infusion rates is a diagnostic clue
• Identification of the genetic mutation in patients is the key

Question 118

Mutations which are the most common and most severe causes of congenital hyperinsulinism

Answer 118

Inactivating SUR1 or Kir6.2 mutations –> Reduced K ATP channel activity, and consequently, increased constitutive insulin secretion

Hence, most do not respond to K ATP channel opener diazoxide (Many other patients with hyperinsulinemic hypoglycemia respond to it)

Question 119

Treatment for congenital hyperinsulinism

Answer 119

Medical: frequent feedings, diazoxide, octreotide

If no sustained response: Near-total pancreatectomy

Focal lesions can be detected noninvasively with 18F-dihydroxyphenylalanine PET

Question 120

Second most common form of congenital hyperinsulinism

Answer 120

Hyperinsulinemia and hyperammonemia syndrome
- Caused by activating, dominantly inherited mutations of the glutamate dehydrogenase gene
- Typically develops after several months of life
- Responsive to diazoxide

Question 121

Causes of transient hyperinsulinism causing neonatal hypoglycemia

Answer 121

1) Maternal diabetes - due to hyperglycemia in utero with chronic stimulation of fetal insulin secretion in utero
2) Perinatal stress, prematurity, or SGA - usually responsive to diazoxide and resolves by 6 months of age

Question 122

Causes of hyperinsulinism causing childhood hypoglycemia

Answer 122

Nissen fundoplication –> postprandial hypoglycemia analogous to that occuring after gastric bypass

Insulin-secreting tumors of the pancreatic islet cells

Accidental, surreptitious, or even malicious (check C-peptide)

Question 123

Features of glycogen storage diseases (GSDs)

Answer 123

Glycogen storage diseases (GSDs):
- Present early in childhood
- Characterized by hypoglycemia after short fasting periods
- May have mild to moderate ketosis
- May present with or without hepatomegaly
- No response to glucagon stimulation

Question 124

Types of Glycogen storage diseases (GSDs)

Answer 124

GSD type 0 - glycogen synthase deficiency; no hepatomegaly; preprandial ketotic hypoglycemia and postprandial hyperglycemia and lactic acidemia

GSD type 1a (von Gierke disease) - glucose-6-phosphatase hydrolase defect; hepatomegaly (both glycogen and fat accumulation); severe fasting hypoglycemia; other metabolic problems can be reversed by effective prevention of hypoglycemia with frequent feedings during waking hours and continuous intragastric glucose infusion during sleep or bedtime administration of large doses of uncooked cornstarch; liver transplantation also corrects these

GSD type 1b - glucose-6-phosphatase microsomal transporter defect; clinical presentation and biochemical findings identical to type 1a, but also with chronic or intermittent neutropenia and neutrophil dysfunction, hence prone to infections

GSD type III - hepatic amylo-1,6-glucosiase deficiency; less prominent hyperglycemia; treated with avoidance of hypoglycemia; high protein diet can be of benefit

GSD type VI - hepatic glycogen phosphorylase deficiency; less prominent hyperglycemia; treated with avoidance of hypoglycemia;

GSD type IX - hepatic phosphorylase kinase deficiency; less prominent hyperglycemia; treated with avoidance of hypoglycemia

Question 125

Features of hypoglycemia caused by enzymatic defects in gluconeogenesis

Answer 125

• Hypoglycemia after moderate fasting periods that occur when hepatic glycogen stores are depleted
• Present with lactic acidemia, ketosis, hyperlipidemia, and no response to glucagon stimulation, except in fructose-1,6-bisphosphatase deficiency, which may have a response in the fed state

Question 126

Examples of deficiency of enzyme involved in protein metabolism and presentation

Answer 126

Branched-chain ketoaciduria (maple syrup urine disease and tyrosinemia)
- Fasting hypoglycemia
- Profound acidosis an d failure to thrive
- May be due to defective gluconeogenesis due to liver disease

Question 127

Presentation of defects that ultimately impair fatty acid oxidation

Answer 127

Hypoglycemia with hypoketonemia during extended fasting

Reduced plasma carnitine levels (20-50% of normal) are the rule in these disorders, but extremely low carnitine levels characterize the carnitine transport defect - a true carnitine deficiency state that is responsive to carnitine supplementation

The diagnosis of specific fatty acid oxidation defects is typically accomplished by blood acylcarnitine profiling, although molecular diagnosis is increasingly possible

Most common is medium-chain acyl-CoA dehydrogenase deficiency

Treatment includes frequent feedings and a low-fat diet rich in medium-chain triglycerides in carnitine palmitoyl transferase 1 (CPT1) deficiency and carnitine supplementation in primary carnitine deficiency

Question 128

Summarize diagnostic interpretation in hypoglycemia in childhood

Answer 128

*NEFAs - non-esterified fatty acids
B-hxb - beta-hydroxybutyrate

If with acidosis, high lactate = Defect in gluconeogeneosis or glucose release (Short fasting period)

If with acidosis, high ketones = Defect in glycogenolysis, ketotic hypoglycemia, grwoth hormone or cortisol deficiency (Moderate fasting period)

If no acidosis, low NEFAs, low B-hxb = Hyperinsulinism (Short to moderate fasting period)

If no acidosis, high NEFAs, low B-hxb = Defect in FA oxidation or ketogenesis (Prolonged fasting period)

If no acidosis, high NEFA, high B-hxb = Defect in glucose production or release, including hypocortisolism