VI. Hypoglycemia Flashcards
TRUE or FALSE: Survival of the brain, and therefore the individual, requires a virtually continuous supply of glucose from the circulation.
TRUE
Hypoglycemia causes functional brain failure, which is typically corrected after the plasma glucose concentration is raised.
What is the Whipple triad
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
In which population is documentation of Whipple triad particularly important?
Those who do not have insulin- sulfonylurea-, or glinide-treated diabetes because hypoglycemic disorders are uncommon in such individuals
3 sources of glucose
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
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
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.
The organ that is the main source of net endogenous glucose production (through glycogenolysis and gluconeogenesis)
Liver
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
Muscle > Fat
Essentially the sole metabolic fuel for the brain under physiologic conditions
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.
In healthy adults, the physiologic postabsorptive (fasting) plasma glucose concentration ranges from approximately __ to __ mg/dL, with a mean of __ mg/dL.
70 to 110
90
In the postabsorptive steady rate, rates of glucose production and utilization average approximately __ mg/kg per minute.
2.2 mg/kg per minute
Threefold higher in infants (greater brain mass relative to weight)
Predominant source of endogenous glucose production in the postabsorptive state
Liver
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
C
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
A
Glucagon doesn’t affect glucose production in the kidneys nor the rate of glucose clearance by insulin-sensitive tissues
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
D
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
15 to 20 g
70 g
8 hours
Responses of the body to prolonged fasting ~24 to 48 hours
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.
First, second, and third responses to hypoglycemia
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
Clinical hypoglycemia - that sufficient to cause symptoms and signs - is most convincingly documented by
Whipple triad
What are neuroglycopenic symptoms
Direct result of brain glucose deprivation:
Warm, weak, difficulty thinking/confused, tired/drowsy, faint, dizzy, difficulty speaking, blurred vision
What are neurogenic (or autonomic) symptoms
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
Subjective awareness of hypoglycemia is largely the result of the perception of ___ symptoms
Neurogenic
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.
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.
Glycemic threshold for:
Decreased insulin
Increased glucagon
Increased epinephrine
Increased cortisol and growth hormone
Symptoms
Decreased cognition
Decreased brain glucose metabolism
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
What signals the fist, second, and third lines of defense against hypoglycemia
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
How does epinephrine increase glucose?
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
What limits the magnitude of glycemic response to epinephrine despite alpha2-adrenergic stimulation of insulin secretion?
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)
Circulating epinephrine, as well as the plasma norepinephrine, in response to hypoglycemia are derived largely from the
Adrenal medulla
How do recurrent hypoglycemia and poorly controlled diabetes shift the glycemic thresholds for symptoms and signs of hypoglycemia?
They shift to lower plasma glucose concentrations in patients with recurrent hypoglycemia and to higher concentrations in those with poorly controlled diabetes
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
Lower
Reduced
The most common cause of hypoglycemia
Drugs (insulin secretagogues and insulin)
Approximate frequency of hypoglycemia in T1DM patients
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.
TRUE or FALSE: Lower HbA1c levels are associated with increased mortality in patients with T2DM at higher risk of hypoglycemia.
TRUE
TRUE or FALSE: Systematic long-term follow-up of the DCCT patients suggests that recurrent iatrogenic hypoglycemia causes chronic cognitive impairment in young adults.
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.
Most instances of sudden hypoglycemic death are thought to be the result of ___.
Cardiac arrhythmias triggered by an intense sympathoadrenal response to hypoglycemia
ADA/ES Workgroup on Hypoglycemia definition of hypoglycemia in diabetes
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.
Recommended definition of clinical hypoglycemia in persons without diabetes
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.
Why was 70 mg/dL chosen as the glucose alert level
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.
International Hypoglycaemia Study Group 3 levels of iatrogenic hypoglycemia in diabetes
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
Definition of the following clinical classifications of hypoglycemia in diabetes:
- Severe hypoglycemia
- Documented symptomatic hypoglycemia
- Asymptomatic hypoglycemia
- Probable symptomatic hypoglycemia
- Pseudohypoglycemia
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
What happens with the defenses against hypoglycemia in patients with established T1DM (absolute deficiency of endogenous insulin)?
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
What causes hypoglycemia unawareness / impaired awareness of hypoglycemia?
Largely the result of reduced release of the sympathetic neurotransmitters norepinephrine and acetylcholine
How does Hypoglycemia-Associated Autonomic Failure (HAAF) develop?
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
What is the consequences of HAAF?
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)
TRUE or FALSE: The pathophysiology of glucose counterregulation is the same in T1DM and T2DM but with different time courses.
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.
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
A and C
It is distinct from classic diabetic autonomic neuropathy.
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.
2 to 3 weeks
3 recognized causes of reversibly attenuated sympathoadrenal response to hypoglycemia (and therefore 3 forms of HAAF)
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)
Part of the brain that is the central integrator of the sympathoadrenal response to hypoglycemia
Hypothalamus
Conventional risk factors for hypoglycemia in diabetes
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)
Clinical risk factors for hypoglycemia
- Presence of HAAF
- History of severe hypoglycemia
- Chronic kidney disease
- Long duration of diabetes
- Malnutrition
Risk factors for HAAF
- 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)
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.
TRUE
Measures for Hypoglycemia Risk Factor Reduction
- Acknowledge the problem
- 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 - Consider the conventional risk factors for hypoglycemia
- Consider the risk factors for HAAF
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
B, C, D
Which among the two is more often associated with hypoglycemia, glyburide (glibenclamide) or glimepiride?
Glyburide (glibenclamide - since longer acting)
Describe a reasonable individualized glycemic goal
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.
What is the treatment of hypoglycemia in diabetes?
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.
Alternatives to oral glucose in a patient who is unable or unwilling (because of neuroglycopenia) to take carbohydrate orally
Glucagon 1.0 mg in adults, subcutaneously or intramuscularly
IV glucose (dextrose) at initial dose of 25 g
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
E
C - because it acts by stimulating glycogenolysis
D - because it can stimulate insulin secretion
TRUE or FALSE: Plasma glucose concentrations used to document Whipple triad may be measured with a blood glucose self-monitor.
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.
Possible reason for “pseudohypoglycemia”, an artifact of continued glucose metabolism by the formed elements of the blood after blood sample is drawn
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
Antecubital venous glucose levels are as much as ___ lower than arterial glucose levels when insulin secretion is increased.
One third
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.
TRUE
TRUE or FALSE: The glycemic thresholds of responses to hypoglycemia shift to higher plasma glucose concentrations in patients with recurrent hypoglycemia.
FALSE
The glycemic thresholds of responses to hypoglycemia shift to lower plasma glucose concentrations in patients with recurrent hypoglycemia.
Most common cause of hypoglycemia in general, and also the most common cause of hypoglycemia in hospitals
Drugs
Drugs, other than antihyperglycemic agents and alcohol, that are reported to cause hypoglycemia with Moderate Quality of Evidence
GC PIG Q
Gatifloxacin
Cibenzoline
Pentamidine
Indomethacin
Glucagon (during endoscopy)
Quinine
Mechanism of alcohol-induced hypoglycemia
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
TRUE or FALSE: Hepatogenous hypoglycemia commonly occurs in cirrhosis and hepatitis.
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
Mechanisms of the following causes of hypoglycemia:
- Renal failure
- Severe cardiac failure
- Sepsis
- Inanition
- 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
Mechanism of postabsorptive hypoglycemia
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
Glycemic intolerance of fasting is largely corrected by replacement of which of the following hormones:
a. Glucocorticoid
b. Growth hormone
c. Both
d. Neither
A
Non-islet cell tumor hypoglycemia (NICTH) is often the result of overproduction of incompletely processed ___.
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
2 categories of the differential diagnosis of hypoglycemia in a seemingly well individual
1) accidental, surreptitious, or even malicious hypoglycemia
2) endogenous hyperinsulinism
TRUE or FALSE: Long-term survival is the rule after successful surgical removal of an insulinoma.
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)
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
Nesidioblastosis (clinically indistinguishable from insulinoma)
Condition wherein there is hyperinsulinemia, the cause is in the pancreas, and hypoglycemia typically occurs after a meal instead of during fasting
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
Mechanism of post-gastric bypass hypoglycemia
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
TRUE or FALSE: In autoimmune hypoglycemia, the plasma insulin level is very low.
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
Timing of hypoglycemia in the following conditions:
- Insulinoma
- Nesidioblastosis
- Noninsulinoma pancreatogenous hypoglycemia syndrome
- Post-gastric bypass hypoglycemia
- Autoimmune hypoglycemia
- 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
Tablet 38.4 Causes of Hypoglycemia in Adults, page 1531
*
History in diagnosing hypoglycemia includes
Specific symptoms, their timing in relation to meals, their duration, and any factor that aggravate or alleviate them
Diagnostic tests in the workup for hypoglycemia if the cause is not evident
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
Key pathophysiologic feature of endogenous hyperinsulinsm
Failure of insulin secretion to fall to very low rates as plasma glucose concentrations fall to hypoglycemic levels
Traditional critical diagnostic criteria for endogenous hyperinsulinism (assuming Whipple triad is documented)
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
Table 38.9 Patterns of Findings During Fasting or After a Mixed Meal in Workup for Hypoglycemia, page 1543
*
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
Oral hypoglycemia agent
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
Not insulin- or IGF-mediated
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
Normal
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
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)
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
Insulinoma, NIPHS, PGBH
Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin»_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
Exogenous insulin
Diagnostic interpretation?
- Glucose <55 mg/dL
- Insulin»_space;3 uU/mL
- C-peptide»_space;0.2 nmol/L
- Proinsulin»_space;5 pmol/L
- Beta-hydroxybutyrate <=2.7 mmol/L
- Glucose increase after glucagon >25 mg/dL
- (-) Circulating OHA
- (-) Insulin antibody
Insulin autoimmune
(But concentrations of free C-peptide and proinsulin are low)
What to do if Whipple triad has not been documented and the measurements described have not been obtained during an episode of spontaneous hypoglycemia
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
Tests used to diagnose pancreatic causes of hypoglycemia
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%.
Procedure of choice for confirming NIPHS and hypoglycemia occurring after Roux-en-Y gastric bypass
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
Treatment of hypoglycemia disorders
Tailored to the specific hypoglycemic disorder identified
Enzymes of which of the following processes are absent during fetal life:
a. Gluconeogenesis
b. Glycogenesis
c. Glycogenolysis
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
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.
2
In most infants, the plasma glucose concentration is usually steady or is increasing by __ to __ hours of life.
4 to 6
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.
Ketone bodies or lactate
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 ___.
50%
Middle childhood (~5-10 years of age)
Overall, the rates of glucose flux (production and utilization) are nearly 3 times ___ (higher or lower) in infants and children than in adults.
Higher
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.
TRUE
TRUE or FALSE: Newborns in the first few hours of life are relatively hypoinsulinemic compared with older children.
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.
Pediatric Endocrine Society suggests delaying diagnostic evaluations for hypoglycemia until __ to __ days after birth.
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.
Signs and symptoms of hypoglycemia in a neonate or child
Nonspecific: jitteriness/tremors, hypotonia, changes in the level of consciousness, apnea/bradycardia, cyanosis, tachypnea, poor such or feeding, hypothermia, and/or seizures
According to the American Academy of Pediatrics and Pediatric Endocrine Society, hypoglycemia persisting beyond ___ is not likely to be transitional.
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.
Infants at risk for hypoglycemia:
- 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
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
Less than 48 hours old: 50 mg/dL
After 48 hours of age: 60 mg/dL
Usual diagnostic tests in the evaluation for neonatal hypoglycemia
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
Treatment for childhood hypoglycemia
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
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)
TRUE
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 ___.
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.
Fig 38.14. Diagnostic algorithm for determining the etiology of hypoglycemia in children, page 1547
*
Mechanism of intolerance of fasting in children
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
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
B - They are low
Most common cause of nontransient neonatal hypoglycemia
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
Mutations which are the most common and most severe causes of congenital hyperinsulinism
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)
Treatment for congenital hyperinsulinism
Medical: frequent feedings, diazoxide, octreotide
If no sustained response: Near-total pancreatectomy
Focal lesions can be detected noninvasively with 18F-dihydroxyphenylalanine PET
Second most common form of congenital hyperinsulinism
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
Causes of transient hyperinsulinism causing neonatal hypoglycemia
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
Causes of hyperinsulinism causing childhood hypoglycemia
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)
Features of glycogen storage diseases (GSDs)
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
Types of Glycogen storage diseases (GSDs)
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
Features of hypoglycemia caused by enzymatic defects in gluconeogenesis
- 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
Examples of deficiency of enzyme involved in protein metabolism and presentation
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
Presentation of defects that ultimately impair fatty acid oxidation
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
Summarize diagnostic interpretation in hypoglycemia in childhood
*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
