HYPOGLYCAEMIA

PRESENTED BY

UNDIE, MALIPEH-UNIM U.
HOUSE OFFICER
 OUTLINE
• Introduction
• Regulation of Plasma Glucose
• Hormonal Response to Hypoglycaemia
• Clinical Features
• Causes of Hypoglycaemia
• Management
• Conclusion
 INTRODUCTION
• Hypoglycaemia as the name implies is a plasma
glucose level lower than normal

• The lower level of normal is given by most

authorities as ≤ 2.5 – 3.0 mmol/l (45 – 54 mg/dl)

• However the clinical picture does not always follow

the biochemical values

• It occurs when hepatic glucose output falls below

the rate of glucose uptake by peripheral tissues
 INTRODUCTION
• Unlike other organs the brain can only utilize
glucose for energy and has only a few minutes
of glycogen stores making hypoglycaemia
potentially fatal

• Whipple’s triad; symptoms + low plasma

glucose + relief of symptoms after raising
plasma glucose used to make diagnosis
REGULATION OF PLASMA GLUCOSE
• Maintained between a range of 3.3 – 8.3
mmol/l despite wide variation of food intake
and activity
• At a glance, this is done by system of
regulatory hormones which control glucose
production, use and storage
• Diet provides major source of glucose,
between meals, glycogenolysis and
gluconeogenesis maintain plasma glucose
REGULATION OF PLASMA GLUCOSE
• Hepatic glycogen stores can maintain PG for 8 to
12 hours

• After this gluconeogenesis becomes major

pathway

• In fasting insulin levels are reduced leading to

increased glycogenolysis and gluconeogenesis,
reduced peripheral uptake of glucose and
increased lipolysis and proteolysis to provide
gluconeogenic precursors
REGULATION OF PLASMA GLUCOSE
• As glucose levels enter the hypoglycaemic
range counter regulatory hormones most
importantly glucagon are produced

• Others are epinephrine, cortisol and growth

hormone.

• They promote glycogen breakdown and

gluconeogenesis
HORMONAL RESPONSE TO
HYPOGLYCAEMIA
 CLINICAL FEATURES
• The manifestations of hypoglycaemia occur by
two mechanisms

• Autonomic responses include adrenergic

symptoms such as palpitations, tremor, and
anxiety as well as cholinergic symptoms such as
sweating, hunger, and paraesthesia

• Neuroglycopaenic responses from decreased CNS

activity. Headache, hypothermia, visual
disturbances, mental dullness, behavioral
changes, confusion, fatigue, seizure, loss of
consciousness, amnesia, seizures, coma. There
may be transient focal neurologic deficits
 CAUSES
• Side effect of treatment of Diabetes Mellitus

• Fasting hypoglycaemia;
– Drugs; alcohol binge, insulin, sulfonylureas, quinine, salycylates,
sulfonamide
– Endocrine deficiencies; addison’s disease, pituatary insufficency
– non beta cell tumours,
– endogenous hyperinsulinism; Insulin autoantibodies 3. Insulin
receptor autoantibodies
– insulinomas and primary beta cell disorders
– Critical illness Renal failure Sepsis 5. Falciparum malaria 6.
Congestive heart failure.

• Reactive (Fed) hypoglycaemia

 HYPOGLYCAEMIA IN DIABETES
• Complicates management of DM in patients
on insulin and secretagogues
• Risk of insulin excess occurs when
– Insulin (or oral agent) doses are excessive, ill
timed, or of the wrong type
– The influx of exogenous glucose is reduced
– Insulin-independent glucose utilization is
increased (e.g., during exercise)
– Insulin sensitivity is increased
– Endogenous glucose production is reduced
– Insulin clearance is reduced
 PLASMA GLUCOSE REGULATION IN
DIABETES MELLITIS
• The usual physiologic counter regulatory and
behavioral responses are blunted.
• This is more common in T1DM and it occurs
less frequently T2DM
• It is referred to as Hypoglycaemia-Associated
Autonomic Failure
• It has two components
– Defective glucose counter regulation
– Hypoglycemia Unawareness
Defective Glucose Counter Regulation
• Insulin levels are no longer tightly related to
plasma glucose levels over the first few
months or year due to exogenous insulin.
• Glucagon response to hypoglycaemia is also
lost over the same period. It is a functional
loss, as other stimuli still cause glucagon
production.
• Reduced threshold for epinephrine response
either due to prior antecedent hypoglycaemia
or autonomic neuropathy. At this level there is
a 25x risk of severe hypoglycaemia.
 Hypoglycaemia Unawareness
• Refers to loss of warning symptoms that cause a
behavioral response.
• The first symptoms are neuroglycopaenic when
eating is not possible.
• Increases the risk of severe hypoglycemia 6x for
T1DM and 17x for T2DM
• The syndrome of hypoglycemia unawareness and
the reduced epinephrine component of defective
glucose counter regulation are reversible but
require 2 weeks of strict avoidance of
hypoglycemia. This involves a shift of glycaemic
thresholds back to higher plasma glucose levels
 Reduction of Hypoglycaemia Risk
• Hypoglycaemia unawareness diagnosis can
usually be made from the history.

• The patients plasma glucose log can also give

clues. If it doesn’t show, suspect nocturnal
hypoglycaemia.

• Patient education, frequent self-monitoring of

blood glucose, flexible insulin (and other drug)
regimens, rational glycaemic goals and
professional guidance and support are key.
 Reduction of Hypoglycaemia Risk
• Consider the risk factors and change
medication, lifestyle and diet accordingly

• Nonselective beta blockers may blunt the

recognition of hypoglycemia and they impair
glycogenolysis; a relatively selective 1-
antagonist (e.g., metoprolol or atenolol) is
preferable when a beta blocker is indicated.
 Causes of Fasting Hypoglycaemia
Drugs
• Insulin and sulfonylureas
• Alcohol blocks gluconeogenesis but not glycogenolysis.
Hypoglycaemia develops in the setting of binge
drinking with little eating and is potentially fatal
• Pentamidine used in the treatment of resistant PCP, is
toxic to β cells may produce hypoglycaemia.
Predisposes to DM later.
• Quinine may produce severe hypoglycaemia in the
course of treatment for Falciparum malaria.
• Salicylates may cause hypoglycaemia, usually after
accidental ingestion by children.
• Nonselective - adrenergic antagonists (e.g.,
propranolol) can induce hypoglycaemia in the presence
of strenuous exercise or starvation
 Factitious Hypoglyceamia
• An unusual form of drug induced hypoglycemia.
• Insulin or sulfonylureas taken to intentionally
induce hypoglycemia
• It is most common among health care workers,
patients with diabetes or their relatives, and
people with a history of other factitious illnesses
• If it is from exogenous insulin, c-peptide levels are
low
• If it is from sulfonylureas, C-peptide is high and is
distinguised by measuring drug in plasma or urine
• Critical illness
– Hepatic failure because the liver is the major site for
endogenous glucose production
– In CCF there is weight loss, anorexia, decreased cardiac output,
and mild hepatic dysfunction. Hypoglycaemia is likely due to
decreased delivery of gluconeogenic substrates as a result of
poor appetite and diminished hepatic blood flow.
– Renal failure; there is decreased gluconeogenesis and increased
peripheral utilization due to reduced insulin clearance
– Sepsis; Multifactoral origin. Impaired endogenous glucose
production, perhaps a result of hepatic hypoperfusion and
increased glucose utilization, which is induced by cytokines in
macrophage-rich tissues such as the liver, spleen, and ileum and
in muscle. Nutrition is also often inadequate in the setting of
sepsis
– In malaria, hypoglycaemia is due to increased glucose utilization
by parasitized RBCs. It occurs commonly in severely ill, fasting
patients especially children. May be worsened by Quinine and
sulphonomide treatment
• Endocrine deficiencies;
– Deficiencies of hormones antagonistic to insulin are rare
but well recognized causes of hypoglycaemia.

– These include hypopituitarism, isolated

Adrenocorticotrophic hormone (ACTH) deficiency and
Addison's disease.

– Extended fasting, high rates of glucose utilization (e.g.,

during exercise, pregnancy) and low rates of glucose
production (e.g., following alcohol ingestion) can
precipitate hypoglycemia in adults with hypopituitarism.

– Cortisol and Growth hormone secretion should be

evaluated in patients with fasting hypoglycemia when the
history suggests pituitary or adrenal disease and when
other causes of hypoglycemia are not apparent
• Non β cell tumours
– Those associated with hypoglycaemia are:
• Large mesenchymal tumours (50%)
• Hepatocellular carcinomas (25%)
• Adrenal carcinomas (5–10%)
• Gastrointestinal tumours (5–10%)
• Lymphomas (5–10%)
• Miscellaneous tumours (kidney, lung, anaplastic
carcinomas, carcinoid).
– Production of insulin or insulin like growth factor II
(IGF-II) acting through insulin or IGF-I receptors
may be the cause
• Endogenous hyperinsulinism. Causes are uncommon
and include;
– A primary pancreatic islet cell disorder; insulinoma
sometimes multiple insulinomas or especially in infants or
young children, a functional β cell disorder without an
anatomic correlate
– Secretagogues and theoretically a β cell stimulating
autoantibody
– an autoantibody to insulin and its receptors
– ectopic insulin secretion
• There is hyperinsulinism and increased C peptide in the
presence of hypoglycaemia
• Sulphonylureas give the same picture and are
distinguished by assaying for them in blood or urine
Insulinomas and primary β cell disorders
• Insulinomas are a rare but treatable cause of
potentially fatal hypogycaemia
• 90% are benign and About 5 to 10% of insulinomas are
malignant, as evidenced by the presence of
metastases.
• The yearly incidence is estimated to be 1 in 250,000
• About 60% of cases occur in women
• The median age at presentation is 50 years in sporadic
cases, but it usually presents in the third decade when
associated with Multiple Endocrine Neoplasia Type 1
• Insulinomas arise within the substance of the pancreas
in 99% of cases and are usually small (1 to 2 cm)
• Whipple’s triad is present along with increased C-
peptide and insulin levels and absent insulin antibodies
or plasma/urine sulfonylureas
• Insulin levels are not suppressed by fasting
• Proinsulin constitutes > 20% of insulin. Ratio of insulin
to proinsulin in normal individuals is 6 : 1. Insulinoma;
1 : 1. Sulfonylurea induced hypoglycaemia; 10 : 1.
• 1 mg glucagon after over night fast gives peak insulin
response > 130 μu/ml
• Tumour can be localized by CT, MRI, radionuclear scan
if it is more than 2 cm in size. If the tumour is less than
2 cm in size, pancreatic arteriography and CT with
contrast or Octreotide scans can be used.
• Medical Treatment
– Oral diazoxide 300–1200 mg/day along with a diuretic
(thiazide) to compensate for salt retaining property of
diazoxide
– Octreotide (100–600 mg/day subcutaneously).
– Others; Phenytoin, Chlorpromazine, Propranolol,
Verapamil
– Drug of choice for metastatic islet cell carcinoma is
streptozotocin and doxorubicin or L-asparaginase or
mithramycin.
• Surgical: Surgery is the definitive treatment. Detectable
tumours can be resected. If there is no detectable
tumour, stepwise distal pancreatectomy is done until
frozen section or blood glucose shows that all the
tumour is removed.
 CAUSES OF FED (REACTIVE)
HYPOGLYCAEMIA
• Occurs after meals
• Symptoms are usually adrenergic
• Usually of rapid onset and transient as it is
reversed by normal hormonal responses
• Can be caused by
– Hyperalimentation
– Impaired glucose tolerance
– Idiopathic reactive hypoglycaemia
– Enzymatic defects of carbohydrate metabolism;
Hereditary fructose intolerance , Galactosemia.
 Hyperalimentation
• In the setting of gastric surgery passage of food from
the stomach to the small intestine is rapid
• This causes a rapid postprandial rise in plasma glucose
levels and the release of gut incretins, which induce an
exuberant insulin response and subsequent
hypoglycemia.
• Administration of an α-glucosidase inhibitor, which
delays carbohydrate digestion and thus glucose
absorption from the intestine, can be considered for
treatment of reactive hypoglycemia, although its
efficacy remains to be established in controlled trials.
• A reversed jejunal segment near the gastric outlet
prevents the rapid release of glucose into the
circulation.
• Multiple small feedings may also be useful
 Impaired Glucose Tolerance
• The explanation for late hypoglycaemia occurring
several hours after food is due to the high insulin
level.
• Insulin levels remain high due to decreased
insulin sensitivity
• Lack of influx of enough carbohydrate from the
intestinal tract at the time to buffer the effects of
insulin
• Dietary modifications and treatment with insulin
sensitizers or α-glucosidase inhibitors are
modalities of treatment
Idiopathic Reactive Hypoglycaemia
• The diagnosis of postprandial hypoglycemia
requires documentation of Whipple’s triad after a
typical mixed meal occurring regularly
• The cause of repetitive postprandial symptoms in
certain individuals is unknown, but they may be
particularly sensitive to the normal autonomic
responses that follow ingestion of a meal
• Diet is the mainstay of treatment. Avoidance
simple or refined carbohydrates. Carbohydrate is
reduced to 35–40% of the total calories.
• For obese patients weight reduction is advised
 Enzymatic defects of carbohydrate
metabolism
• In Hereditary fructose intolerance high levels
of fructose-1-phosphate reduce conversion of
glycogen to glucose
• Toxic intermediates may also cause direct
damage to the liver
• Mainstay is dietary modification to remove
offending sugars
 APPROACH TO THE HYPOGLYCAEMIC
PATIENT
• The hypoglycemic patient would present with history
of palpitations, tremor, anxiety, sweating, hunger, and
paraesthesia and Headache, hypothermia, visual
disturbances, mental dullness, behavioral changes,
confusion, fatigue, seizure, loss of consciousness,
amnesia, seizures, coma
• Common signs of hypoglycemia include pallor and
diaphoresis. Heart rate and the systolic blood pressure
are typically raised, but these findings may not be
prominent. The neuroglycopaenic manifestations are
valuable, albeit nonspecific, signs. Transient focal
neurologic deficits occur occasionally.
• Once the suspicion of hypoglycaemia is made, the
random plasma glucose should immediately be
checked
 URGENT TREATMENT
• If the patient is conscious, able and willing to take
orally, glucose containing fluids or tablets are given.
• If neuroglycopaenic symptoms preclude eating,
intravenous glucose at about 20g – 30g is given. 50ml
50% dextrose or 200 – 300mL of 10% dextrose
• Glucagon 1mg IM if no IV access (short duration of
effect so repeat after 20min and follow with oral
carbohydrate). Cannot be used in depleted glycogen
stores
• Recovery is usually prompt.
• Once patient is able to eat, food should be taken to
replenish glycogen stores
• If patient unable to eat glucose infusion should be
continued till when patient can eat to prevent rebound
hypoglycemia
 DIAGNOSIS OF THE HYPOGLYCAEMIC
MECHANISM
• Other points to look out for in the history include;
diabetes on treatment, history of previous
episodes, drug history, recent alcohol ingestion,
history suggestive of other endocrine, renal,
hepatic, cardiac diseases or sepsis and previous
gastric surgeries
• The physical examination may point to the
underlying cause of the hypoglycaemia.
• In the absence of documented spontaneous
hypoglycemia, overnight fasting, or food
deprivation during observation in the outpatient
setting, will sometimes elicit hypoglycemia and
allow diagnostic evaluation
 PREVENTION OF HYPOGLYCAEMIA
• Prevention requires diagnosis of underlying
mechanisms
• Patient counselling and education is of utmost
importance
• Drugs stopped or doses adjusted
• Critical illnesses treated
• Surgical, radio or chemotherapeutic treatment of non
beta cell tumours
• Resection or medical therapy for beta cell tumours
• Replacement of deficient hormones
• The treatment of autoimmune hypoglycemia (e.g., with
a glucocorticoid)is more problematic, but this disorder
is often self-limited. If these fail frequent feedings and
avoidance of fasting may be required. Uncooked
cornstarch at bedtime or an overnight infusion of
intragastric glucose may be necessary in some patients.
 CONCLUSION
• Hypoglycaemia is a biochemical event with
varied etiologies and is potentially fatal

• Prompt recognition and treatment is essential

• Diagnosis of the underlying mechanism and

treating them is key to preventing recurrences
 REFERENCES
Alagapaan, R. (2011). Manual of Practical Medicine (4th ed.). Chennai: Jaypee
Brothers.
Gehlaut, R., Dogbey, G., Schwartz, F., Marling, C., & Shubrook, J. (2015).
Hypoglycemia in Type 2 Diabetes - More Common Than You Think. Journal
Of Diabetes Science And Technology, 9(5), 999-1005. doi:
10.1177/1932296815581052
Gleason, C., & Juul, S. (2018). Avery's Diseases of the Newborn (10th ed.).
London: Elsiever.
Hamdy, O. (2019). Hypoglycemia: Practice Essentials, Background,
Pathophysiology. Retrieved from
https://emedicine.medscape.com/article/122122
Kasper, D. L., & Harrison, T. R. (2005). Harrison's principles of internal
medicine. New York: McGraw-Hill, Medical Pub. Division.
Kumar, P., & Clark, M. (2017). Kumar & Clark's Clinical Medicine (9th ed.).
London: Elsiever.
LONGMORE, M., WILKINSON, I., BALDWIN, A., & WALLIN, E. (2014). Oxford
Handbook of Clinical Medicine (9th ed.). New York: Oxford University
Press.
Martín-Timón, I., & Canizo-Gomez, F. (2015). Mechanisms of hypoglycemia
unawareness and implications in diabetic patients. World Journal Of
Diabetes, 6(7), 912. doi: 10.4239/wjd.v6.i7.912
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