Approach to

Hypoglycemia
Diabetics and Non-Diabetics

Homeostasis of Glucose

Cause of Hypoglycemia
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 of Hypoglycemia
Seemingly well individual
5. Endogenous hyperinsulinism
Insulinoma
Functional -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

Cause of Hypoglycemia
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% function 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 deficiency)

Poisoning

Ethanol inhibits gluconeogenesis

Ethanol-induced hypoglycemia occurs 12-72

hours after ingestion

Neoplasm

Nonislet-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(GLP1) and Somatostatin

Insulinoma

Pancreatic -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 years is 6% and 20 years 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.

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
post absorptive period (i.e., hours
after a meal)
Reactive (postprandial) hypoglycemia.

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 (e.g., loss of consciousness,

traumatic injury or accident) attributed to postprandial
hypoglycemia require further workup.

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

Dumping Syndrome/ Alimentary Hypolycemia

Alimentary hypoglycemia presents 2 hours 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%
As low dose subcutaneous insulin therapy does
not prolong residual beta cell function

Partial Remission or
Honeymoon Phase
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

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 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 counter

regulatory hormones, as Glucagon, Epinephrine,
Cortisol, and Growth hormone

Pathophysiology of
Hypoglycemia

Glucagon stimulates both glycogenolysis and

gluconeogenesis

Epinephrine acts via -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
utilization of glucose.

Counterregulatory effects of Epinephrine during Hypoglycemia

Pathophysiology of
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

Hypoglycemia Unawareness

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 counterregulatory responses during subsequent
hypoglycemic episodes.

Diagnosis
Establishing the cause

History (liver failure, sepsis, autoimmune disease,

neoplasm, alcohol, drugs)

Establishing fasting hypoglycemia

Supervised 72 hour fasting 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 FASTING 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.

Whipple Triads
Signs

and symptoms of hypoglycemia

Documentation

of low blood glucose

when the signs and symptoms occur

Disappearance

symptoms

of the signs and

Result in Normal Subjects

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

Hypoglycemia Checklist

RECOGNIZE hypoglycemia and CONFIRM

DIFFERENTIATE mild-moderate vs. severe

TREAT hypoglycemia but AVOID

overtreatment

AVOID hypoglycemia in the future

Drug Induced Hypoglycemia

Can result 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

Recognize Risk Factors for

Severe Hypoglycemia
Risk factors in Type 1 DM
patients

Risk factors in Type 2 DM

patients

Adolescence

Elderly

Children unable to detect and/or

treat mild hypoglycemia

Poor health literacy, Food

insecurity

A1C <6.0%

Increased A1C

Long duration of diabetes

Duration of insulin therapy

Prior episode of severe

hypoglycemia

Severe cognitive impairment

Hypoglycemia unawareness

Renal impairment

Autonomic neuropathy

Neuropathy

Principles of Treatment

Priority in treating hypoglycemia to maintain plasma

glucose greater 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 Insulinoma.

Patients with autoantibodies against the insulin receptor

can be treated with high-dose glucocorticoid (prednisone,
60 mg/d) to prevent hypoglycemia

Principles of Treatment

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.

Principles of Treatment

However, the glycemic response to oral glucose

is transient, usually less than 2 hours in insulininduced 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)

Principles of Treatment

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.

Principles of Treatment

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

Principles of Treatment

Sort term treatment of hypoglycemia associated with nonbeta

cell tumors involves short-term measures pending effective
medical, surgical, or radio therapeutic treatment can be done
by glucocorticoid or growth hormone

Remissions of autoimmune hypoglycemia's 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.

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

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 post hypoglycemic 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]

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 (N 660 pmol/L)
C-peptide - 3200 pmol/L (N 0.03-1 nmol/L)
Proinsulin - 800 pmol/L (N 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) Diabetes mellitus

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, Cpeptide 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 workup 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 (N 660 pmol/L)
C-peptide - <33 pmol/L(N 0.03-1nmol/L)
Proinsulin - 0.9 pmol/L(N 2-31 pmol/L)

What is he most likely diagnosis?

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

Comment
The low

serum C-peptide and

proinsulin values indicate that the
hyperinsulinemia (140 microU/mL (840
pmol/L) was due to exogenous insulin
administration.

ALHAMDULILLAH