Approach to

Hypoglycemia

Diabetics and Non-Diabetics

 Cause
Ill or medicated individual
1. Drugs
Insulin or insulin secretagogue
Alcohol
Others
2. Critical illnesses
Hepatic, renal, or cardiac failure
Sepsis (including malaria)
Inanition
3. Hormone deficiency
Cortisol
Glucagon and epinephrine (in insulin-deficient diabetes mellitus)
4. Nonislet cell tumor
 Cause
Seemingly well individual
5. Endogenous hyperinsulinism
Insulinoma
Functional β -cell disorders (nesidioblastosis)
Noninsulinoma pancreatogenous hypoglycemia
Post gastric bypass hypoglycemia
Insulin autoimmune hypoglycemia
Antibody to insulin
Antibody to insulin receptor
Insulin secretagogue
Other
6. Accidental, surreptitious, or malicious hypoglycemia
 Causes

Drugs (most from DiabeticPatient)

 Insulin- most common cause,
 Timing, dose, type
 clearance of insulin (eg, renal failure);
 altered counter regulation
 Sulfonylureas
 Metformin does not cause hypoglycemia
 High dose salicylates, b –blockers, quinine,quinolones
Renal failure

 Second gluconeogenic organ

 decreased clearance of renally excreted drugs or their metabolites
(eg, insulin, chlorpropamide, metabolite of glyburide)

Hepatic Failure

 Decreased glycogenolysis
 Decresed gluconeogenesis
 Large functional reserve,( 20% func required to prevent
hypoglycemia)
 Genetic defects in glycometabolic pathways
 Finally, compromised drug metabolism (tolbutamide, glyburide,
glipizide )
Endocrinopathies

 Adrenal (glucocorticoid) insufficiency

 Growth hormone deficiency

 Glucagon deficiency

 Pituitary disease ( decreased combined corticotropin and GH

deficiecy)
Poisoning
(ethanol, propanolol, salicylates)

 Ethanol inhibits gluconeogenesis

 Ethanol-induced hypoglycemia occurs 12-72 hrs after ingestion

Neoplasm
 Non–islet-cell tumors
 Mesenchymal tumors,
 hepatocellular carcinoma,
 adrenocortical tumors,
 carcinoid tumors,
 leukemia, and lymphomas
 Most of these tumors secrete IGF –II molecule
 Some also secrete Glucagon- like peptide(GLP-1) and Somatostatin
Insulinoma
 Pancreatic β-cell tumors that secrete Insulin
 Small,solitary, benign( < 10% malignant)
Inability of insulinoma cells to suppress insulin secretion during low
levels of circulating glucose, leading to severe hypoglycemia

Diagnosis and Tumor Localization

 Very high Insulin levels
 spiral CT, arteriography, ultrasonography

Treatment of Choice
 Enucleation
 Recurrence at 10 yrs is 6% and 20 yrs is 10%
 Insulinoma
 Treatment:
• Surgical resection
• Diazoxide
• Octreotide
• Inteferon alpha
• Malignant:
• Octreotide-idium 111
• Chemo: streptozozin, doxorubicin
Islet Hyperplasia

 Also called nesidioblastosis or diffuse islet hyperplasia

or the syndrome of noninsulinoma pancreatogenous hyperinsulinism

 Represent hyperplastic processes and budding of islet cells from

ducts (nesidioblastosis). Now interpreted as precursor to MEN 1,
with molecular evidence.
 Heterozygous knockout of the MEN1 gene in the mouse show
multiple giant hyperplastic islets that precede insulinoma.

 Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), these

infants have an identifiable genetic mutations in sulfonylurea
receptor 1 (SUR1) ,potassium channel Kir6.2, glucokinase.
Autoimmune causes

 Anti-insulin receptor antibody

 Rarely, hypoglycemia is caused by autoantibodies that bind the
insulin receptor and mimic the biologic action of insulin
 Most patients have elevated ESR, +ve ANA

 Anti-insulin antibody
 autoantibodies against insulin bind free circulating plasma insulin
when its concentration is high and release insulin when the
concentration of free plasma insulin drops.
 Release of insulin at inappropriate times can cause hypoglycemia.
 Symptoms

Adrenergic Symptoms
 usually seen early with a rapid decline in blood glucose and include
tachycardia, tachypnea, vomiting, and diaphoresis

Neuroglycopenic
 usually associated with slower or prolonged hypoglycemia, include
poor feeding, altered mental status, lethargy, and seizures
 Definition of Hypoglycemia
1. Development of neurogenic or neuroglycopenic symptoms

Neurogenic (autonomic) Neuroglycopenic

Trembling Difficulty Concentrating
Palpitations Confusion
Sweating Weakness
Anxiety Drowsiness
Hunger Vision Changes
Nausea Difficulty Speaking
Dizziness

2. Low blood glucose (<4 mmol/L if on insulin or

secretagogue)
3. Response to carbohydrate load
 Severity of Hypoglycemia
• Mild
– Autonomic symptoms present
– Individual is able to self-treat

• Moderate
– Autonomic and neuroglycopenic symptoms
– Individual is able to self-treat

• Severe
– Requires the assistance of another person
– Unconsciousness may occur
– Plasma glucose is typically <2.8 mmol/L
 Response to Hypoglycemia

Blood Glucose Symptoms

< 3.3 mmol/L Sweating, tremor, anxiety,
palpitations, hunger
2.8 – 3.1 mmol/L Early cognitive dysfn.
(confusion, mood changes)
2.5 – 2.8 mmol/L Lethargy, obtundation

< 1.7 mmol/L Coma

< 1.1 mmol/L Convulsions

…Death
 Classification of Hypoglycemia

Fasting hypoglycemia occurs in the postabsorptive period

(ie, hours after a meal)

Reactive (postprandial) hypoglycemia.

 Normal & target blood glucose ranges

 Normal blood glucose levels in people who

do not have diabetes
 Fasting: 70 – 110 mg/dl

 After meals: up to 140 mg/dl

 Target blood glucose levels in people

who have diabetes
• Before meals: 90 - 130 mg/dl
• 2 hours post meals: < 180 mg/dl
 Hypoglycemia: 70 mg/dl or below
 Reactive hypoglycemia is controversial

 low postprandial plasma glucose levels alone are not

sufficient

 10% to 30% of normal individuals undergoing oral GTT

have plasma glucose <50 mg/Dl, with no symptoms

 Only patients with severe (eg, loss of consciousness,

traumatic injury or accident) attributed to postprandial
hypoglycemia require further workup.
 Dumping Syndrome/ Alimentary Hypolycemia

 Alimentary hypoglycemia presents 2 hrs after a meal

Pathophysiology
 disruption of controlled gastric emptying
 decreased transit time
 rapid elevation in plasma glucose that triggers
exaggerated insulin response.
 abnormal insulin then causes a precipitous drop in blood
glucose
 Partial Remission or Honeymoon
Phase
 In approximately 60-80 % of children & adolescents,
insulin requirements decrease transiently following
initiation of treatment
 Most studies define partial remission phase as that
when the patient requires < 0.5 units of insulin/ kg
body weight/ day and has HbA1c <7%
 The partial remission phase commences within days
or weeks of the start of insulin therapy & may last for
weeks to months
 Frequent hypoglycemia attacks happen in this period
 During this phase blood glucose levels are frequently
stable within the normal range, despite fluctuations in
diet and exercise
 As low dose subcutaneous insulin therapy does not
prolong residual beta cell function
 Somogyi Phenomenon

 Hypoglycemia causing rebound hyperglycemia

referred to as Somogyi phenomenon
 Fasting hyperglycemia due to counter-regulatory
overshoot of blood glucose following
unrecognized nocturnal hypoglycemia
 Whilst the Somogyi phenomenon has been
shown to exist, the dawn phenomenon and the
waning of insulin levels are more likely causes of
Fasting hyperglycemia
 Pathophysiology of Hypoglycemia

Responses to Hypoglycemia is our ability to suppress insulin in

response to hypoglycemia

 In Diabetics, it does not occur as Insulin is supplied exogenously

 Main defense is increased release of counterregulatory hormones, as

Glucagon, Epinephrine, Cortisol, and Growth hormone

 Glucagon stimulates both glycogenolysis and gluconeogenesis

 Epinephrine acts via ß-adrenergic receptors and stimulates

glycogenoalysis and gluconeogenesis. Also acts on alpha-2-receptors
to inhibit insulin secretion

 Cortisol and Growth hormone contribute only after prolonged

hypoglycemia by limiting peripheral uitilization of glucose.
Counterregulatory effects of Epinephrine during Hypoglycemia
 Glucagon and epinephrine secretion rises when plasma
glucose concentrations fall below 65 to 70 mg/dL (3.6 to
3.9 mmol/L)

 Growth hormone secretion increases when plasma

glucose concentrations fall below 60 to 65 mg/dL (3.3 to
3.6 mmol/L)

 Cortisol secretion increases when plasma glucose

concentrations fall below 60 mg/dL (3.3 mmol/L).
 Hypoglycemia Unawareness

50% of type 1 DM patients undergo diminution in their epinephrine

response to hypoglycemia,

Further patients lose the autonomic warning symptoms of hypoglycemia

and may recognize (or even fail to recognize) the condition only when
somatic neurologic function becomes impaired.

Usually associated with duration of diabetes and autonomic neuropathy

May also occur when patients are switched to intensive insulin regimens.

The introduction of intensified treatment regimens can lower the glucose

level that triggers epinephrine release and adrenergic symptoms.

The DCCT trial showed that even brief periods of antecedent

hypoglycemia can suppress counter-regulatory responses during
subsequent hypoglycemic episodes.
 Diagnosis

Establishing the cause

 History (liver failure, sepsis, autoimmune disease, neoplasm, alcohol,
drugs)

Establishing fasting hypoglycemia

 Supervised 72 hour fast test
 In hospital setting to lower risk to the patient
 Usually hypoglycemia develops in first 48 hours of the fast in 95% of
cases
72-HOUR FAST
Protocol
Date the onset of the fast as the time of the last intake of calories

 Discontinue all non essential medications

Allow the patient to drink calorie-free and caffeine-free beverages

Collect blood specimens for measurement of plasma glucose, insulin,

C-peptide, and proinsulin every six hours until the plasma glucose
concentration is below 60 mg/dL (3.3 mmol/L) at this point, the
frequency of sampling should be increased to every one to two hours.
Test end points and duration

 the plasma glucose concentration is ≤45 mg/dL (2.5

mmol/L)
 the patient has symptoms or signs of hypoglycemia,
 72 hours have elapsed,
 or when the plasma glucose concentration is less than
55 mg/dL (3 mmol/L) if Whipple's triad is present
 Plasma beta-hydroxybutyrate and sulfonylurea levels are
measured
 1 mg of glucagon is given intravenously and the plasma
glucose measured 10, 20, and 30 minutes later.
 In normal subjects, the following thresholds have been identified in
graded glucose reductions

 Insulin secretion decreases,(BG < 80), followed by increase in

Glucagon and Epinephrine, growth hormone( BG <65) and Cortisol
(BG<60)respectively

 Normal subjects do not have symptomatic hypoglycemia after a

prolonged fast because

 Gluconeogenesis accounts for approximately 50 percent of glucose

production after an overnight fast and for almost all glucose
production after 42 hours or more of fasting
Interpretation of values after 72 hour test
 ].
Relation of Plasma Glucose and Proinsulin
Hypoglycemia Pathway
 Principles of Treatment

Principles of therapy

 Priority in treating hypoglycemia to maintain plasma glucose geater

than 50 mg/dl, either snacks vs IV dextrose

 The second priority is to address the underlying cause. removal or

adjustment of the offending drug, appropriate hormone replacement
for patients with deficiency, resection of the tumor in Insulioma.

 Patients with autoantibodies against the insulin receptor can be

treated with high-dose glucocorticoid (prednisone, 60 mg/d) to
prevent hypoglycemia
 Most episodes of asymptomatic hypoglycemia and mild to moderate
symptomatic hypoglycemia are effectively self-treated by ingestion
of glucose tablets or carbohydrate in the form of juices, soft drinks,
milk, crackers, candy, or a meal.

 A commonly recommended dose of glucose is 16-20 g of oral

glucose.

 However, the glycemic response to oral glucose is transient, usually

less than 2 hours in insulin-induced hypoglycemia

 Parenteral treatment is necessary when a hypoglycemic patient is

unable or unwilling (because of neuroglycopenia) to take
carbohydrate orally.

 Most common 1 amp of D40%,(?glucose)

 Glucagon is commonly injected subcutaneously or intramuscularly
standard dose, 1 mg .
 less useful in T2DM than it is in T1DM as stimulates insulin secretion

 Hypoglycemia related to endogenous hyperinsulinism is often curable

by the surgical removal of an insulinoma.

 If this is not possible because of multiple or metastatic tumors,

Diazoxide can be used, (100-800 mg/day) raises the plasma glucose
concentration by suppressing insulin secretion.

 Side effects include hypotension,brain edema,, gastrointestinal side

effects

 Other treatments include octreotide or calcium channel antagonists

 Sort term treatment of hypoglycemia associated with non–beta cell
tumors involves short-term measures pending effective medical,
surgical, or radiotherapeutic treatment can be done by glucocorticoid
or growth hormone

 Remissions of autoimmune hypoglycemias have been associated with

immunosuppressive therapy, including glucocorticoids, but controlled
trials are lacking.

 The treatment of hypoglycemia related to hepatic or renal disease,

cardiac failure, or sepsis includes short-term measures and, treatment
or management of the underlying disease process.
 Hypoglycemia Checklist

 RECOGNIZE hypoglycemia and

CONFIRM

 DIFFERENTIATE mild-moderate vs.

severe

 TREAT hypoglycemia but AVOID

Drug Induced Hypoglycemia

 Canresult in significant morbidity and

mortality
 Serious obstacle to meet glycemic
targets
 Counsel patients who drive on insulin
or secretagogues re: self-monitoring of
blood glucose and taking appropriate
precautions
 Steps to Address
Hypoglycemia
1. Recognize autonomic or neuroglycopenic
symptoms
2. Confirm if possible (blood glucose <4.0 mmol/L)
3. Treat with “fast sugar” (simple carbohydrate) (15
g) to relieve symptoms
4. Retest in 15 minutes to ensure the BG >4.0
mmol/L and retreat (see above) if needed
5. Eat usual snack or meal due at that time of day
or a snack with 15 g carbohydrate plus protein
 Examples of 15 g Simple
Carbohydrate
 15 g of glucose in the form of glucose
tablets
 15 mL (3 teaspoons) or 3 packets of sugar
dissolved in water
 175 mL (3/4 cup) of juice or regular soft
drink
 6 Lifesavers (1=2.5 g of carbohydrate)
 15 mL (1 tablespoon) of honey
 Recognize Risk Factors for
Severe Hypoglycemia
Risk factors in Type 1 DM Risk factors in Type 2 DM
patients patients

Adolescence Elderly
Children unable to detect and/or Poor health literacy, Food
treat mild hypoglycemia insecurity
A1C <6.0% Increased A1C
Long duration of diabetes Duration of insulin therapy
Prior episode of severe Severe cognitive impairment
hypoglycemia
Hypoglycemia unawareness Renal impairment
Autonomic neuropathy Neuropathy
Treatment of SEVERE Hypoglycemia
in Conscious Person
1. Treat with oral “fast sugar” (simple carbohydrate)
(20 g) to relieve symptoms

2. Retest in 15 minutes to ensure the BG> 4.0 mmol/L

and retreat with a further 15 g of carbohydrate if
needed

3. Eat usual snack or meal due at that time of day or

a snack with 15 g carbohydrate plus protein
Treatment of SEVERE Hypoglycemia in
Unconscious Person with IV Access
1. Treat with 10-25 g (20-50 cc of D50W) of glucose
intravenously over 1-3 minutes

2. Retest in 15 minutes to ensure the BG >4.0 mmol/L

and retreat with a further 15 g of carbohydrate if
needed

3. Once conscious, eat usual snack or meal due at that

time of day or a snack with 15 g carbohydrate plus
protein
Glucagon Kit for Treatment
of Hypoglycemia
Hypoglycemic Coma

Recovery from hypoglycemia may be delayed, because of cerebral

edema. Unconsciousness lasting more than 30 minutes after plasma
glucose is corrected is called posthypoglycemic coma, IV mannitol (40
g as a 20% solution over 20 minutes) or glucocorticoids (e.g.,
dexamethasone, 10 mg), or both can be used along with maintenance
of normal plasma glucose levels
 Recommendation 1

1. Mild to moderate hypoglycemia should be

treated by oral ingestion of 15 g
carbohydrate; glucose or sucrose
tablets/solutions are preferable to orange
juice and glucose gels [Grade B, Level 2]
Patients should retest blood sugar in 15
minutes and retreat with another 15 g of
carbohydrates if BG remains <4.0 mmol/L
[Grade D, Consensus]
 Recommendation 2

2. Severe hypoglycemia in a conscious

person should be treated by oral ingestion
of 20 g of carbohydrate, preferable as
glucose tablets or equivalent.
Blood sugar should be retested in 15
minutes, and then retreated with a further
15 g of glucose if BG remains <4.0 mmol/L
[Grade D, Consensus]
 Recommendation 3
3. Severe hypoglycemia in an unconscious
individual:
 No IV access: 1 mg of glucagon should be administered
subcutaneously or intramuscularly. Caregivers or support
persons should call for emergency services and the episode
should be discussed with the diabetes healthcare team as
soon as possible [Grade D, Consensus]
 With IV access: 10-25 g (20-50 cc of D50W) of glucose
should be given intravenously over 1-3 minutes [Grade D,
Consensus]
 Recommendation 4

4. For individuals at risk of severe

hypoglycemia, support persons
should be taught how to administer
glucagon by injection [Grade D, Consensus]
 Recommendation 5

5. Once the hypoglycemia has been

reversed, the person should have the
usual meal or snack that is due at
that time of the day to prevent
repeated hypoglycemia [Grade D, Consensus].
If a meal is > 1 hour away, a snack (including 15 g
of carbohydrate and protein source) should be
consumed [Grade D, Consensus]
 Recommendation 6 2013

6. Patients receiving antihyperglycemic

agents that may cause hypoglycemia
should be counseled about strategies
for prevention, recognition and
treatment of hypoglycemia related to
driving and be made aware of
provincial driving regulations [Grade D,
consensus]
Thanks.
CASE 1 — A 39-year-old man was referred for evaluation of repeated episodes of
sweating, slurred speech, and confusion during the last four years that could
be aborted by eating. On two occasions, he drove his car off the side of the
road; both times he was found to be confused, his serum glucose
concentrations ranged from 30 to 40 mg/dL (1.7 to 2.2 mmol/L), and he
improved after intravenous glucose administration.
After fasting for 12 hours, he began to sweat and became confused and
combative. Serum values at that time were as follows:
Glucose - 22 mg/dL
Insulin - 110 microU/mL (660 pmol/L)
C-peptide - 3200 pmol/L (0.03-1 nmol/L)
Proinsulin - 800 pmol/L (2-31 pmol/L)
Glucose increase after glucagon - 39 mg/dL (2.2 mmol/L)
Sulfonylurea – negative

What is the nost likely Diagnosis?

A) Surreptious Insulin use
B) Antibodies to Insulin receptor
C) Insulinoma
D) None of the above

 Comment — This is a classic case of insulinoma. The patient was healthy but had episodes of
neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low serum glucose concentrations at the
same time, and relief of symptoms by glucose administration) was satisfied. That the hypoglycemia was
caused by endogenous insulin was confirmed by the high serum insulin, C-peptide and proinsulin
concentrations, and supported by the low serum beta-hydroxybutyrate concentration and the small rise in
serum glucose after intravenous glucagon administration.
CASE 2 — A 27-year-old man was referred by his local physician for evaluation of
hypoglycemia found incidentally during a work-up for peptic ulcer disease.
Past medical history included gastric by pass surgery for morbid obesity 2
years ago. During the last four months, he had several episodes of weakness
and feeling "shaky inside" late in the evening. During the night he would
periodically drink soda. When symptomatic, reflectance meter blood glucose
values measured by the patient using equipment purchased for his seven-year-
old daughter (diagnosed with type 1 diabetes one year earlier) had been in the
range of 40 to 50 mg/dL (2.2 to 2.8 mmol/L). Serum values after an overnight
fast were:
Glucose - 36 mg/dL (2.0 mmol/L)
Insulin - 140 microU/mL (840 pmol/L)
C-peptide - <33 pmol/L(0.03-1nmol/L)
Proinsulin - 0.9 pmol/L(2-31 pmol/L)

What is he most likely diagnosis?

A) Insulinoma
B) Insulin antibodies
C) Exogenous Insulin administration
D) Alimentary hypoglycemia

The low serum C-peptide and proinsulin values indicate that the hyperinsulinemia
(140 microU/mL (840 pmol/L)) was due to exogenous insulin administration.
 CASE 8 — A 76-year-old woman was referred for the evaluation of postprandial adrenergic
symptoms with occasional visual changes. There was one episode of confusion while on a
telephone call to her daughter. During an episode of light headedness, sweating, weakness and
irritability two hours after breakfast (which occurred while under observation), serum values were
as follows:
 Glucose 51 mg/dl (2.8 mmol/L)
Insulin 6.4 microU/mL (45.9 pmol/L)
C-peptide 2.6 ng/mL (858 pmol/L)
Betahydroxybutyrate 0.1 mmol/L
Glucose increase after glucagon 46 mg/dL (2.6 mmol/L)
Sulfonylurea negative

 A mixed meal test was performed because of the presence of postprandial symptoms
accompanied by biochemical evidence of insulin-mediated hypoglycemia. Biochemical testing 180
minutes after a mixed meal revealed the following:
 Glucose 43 mg/dl (2.4 mmol/L)
Insulin 22.0 microU/ml (157.8 pmol/L)
C-peptide 4.7 ng/ml (1551 pmol/L)

 The biochemical tests confirmed insulin-mediated hypoglycemia. The differential diagnosis

included noninsulinoma pancreatogenous hypoglycemia (Islet cell hypertrophy/nesidioblastosis),
which is associated with postprandial hypoglycemia, insulin autoimmune hypoglycemia
(postprandial or fasting hypoglycemia), or insulinoma, which more commonly presents as fasting
hypoglycemia. (See "Noninsulinoma pancreatogenous hypoglycemia" and see "Insulinoma").