This document defines hypoglycemia and describes its causes and clinical manifestations. It discusses hypoglycemia in diabetes, including its epidemiology, risk factors like insulin excess, and complications like hypoglycemia unawareness. It also covers hypoglycemia without diabetes, caused by drugs, critical illness, hormone deficiencies, tumors, and inborn errors of metabolism. The approach to patients involves recognition, diagnosis of the hypoglycemic mechanism through tests, and urgent/definitive treatment depending on the underlying etiology.

1. HYPOGLYCEMIA
Dr. Anup Bhatta
Dhulikhel Hospital

2. DEFINITION
• Glucose levels <55mg/dL (<3.0mmol/L) with
symptoms that are relieved promptly after the
glucose level is raised document hypoglycemia.

3. DEFINITION
• Hypoglycemia is most convincingly documented by,
Whipple’s triad, i.e:
– Symptoms consistent with hypoglycemia
– Low plasma glucose concentration (measured with a
precise method)
– Relief of symptoms when plasma glucose concentration is
increased.

4. • Glucose levels <3.5mmol/L (63mg/dL).

5. SYSTEMIC GLUCOSE BALANCE AND GLUCOSE
COUNTERREGULATION

6. PHYSIOLOGIC RESPONSES TO DECREASING PlASMA
GLUCOSE CONCENTRATIONS
RESPONSE GLYCEMIC
THRESHOLD
(mg/dl)
PHYSIOLOGIC EFFECTS ROLE IN GLUCOSE
REGULATION
↓ Insulin 80-85 ↑ Ra (↓ Rd) 1st line of defense (Primary
glucose regulatory factor)
↑ Glucagon 65-70 ↑ Ra 2nd line of defense (Primary
glucose counterreg. factor)
↑ Epinephrine 65-70 ↑ Ra ↓ Rc 3rd line of defense (critical
when glucagon ↓)
↑ Cortisol & GH 65-70 ↑ Ra ↓ Rc Defense against prolonged
hypoglycemia, not critical
Symptoms 50-55 Recognition of
hypoglycemia
Prompt behavioral
defense(food ingestion)
↓ Cognition < 50 ----- Compromises behavioral
defense against hypoglycemia

7. • However, these thresholds are dynamic.
• They shift to higher-than normal glucose levels in people with
poorly controlled diabetes, who can experience symptoms of
hypoglycemia when their glucose levels decline toward the
normal range (pseudohypoglycemia).
• On the other hand, thresholds shift to lower-than-normal
glucose levels in people with recurrent hypoglycemia;

8. Causes of Hypoglycemia in Adults
• Ill or medicated individual
1. Drugs
Insulin or insulin secretagogue
Alcohol
others
2. Critical illness
Hepatic, renal or cardiac failure
Sepsis
3. Hormone deficiency
Cortisol
Glucagon and epinephrine (in insulin-deficient diabetes)
4. Non–islet cell tumor

9. Seemingly well individual
5. Endogenous hyperinsulinism
Insulinoma
Functional beta-cell disorders (nesidioblastosis)
Noninsulinoma pancreatogenous hypoglycemia
Post–gastric bypass hypoglycemia
Insulin autoimmune hypoglycemia
Antibody to insulin
Antibody to insulin receptor
Insulin secretagogue
6. Accidental, surreptitious or malicious hypoglycemia

10. Clinical manifestations
• COMMON SYMPTOMS OF HYPOGLYCAEMIA
Autonomic
• Sweating
• Trembling
• Pounding heart
• Hunger
• Anxiety
Neuroglycopenic
• confusion
• Drowsiness
• Speech difficulty
• Inability to concentrate Incoordination
Non-specific
• Nausea Tiredness Headache

12. signs
• Pallor
• Diaphoresis
• ↑ Heart rate
• ↑ systolic BP
( But may not be raised in an individual who has experienced
repeated, recent episodes of hypoglycemia.)

13. HYPOGLYCEMIA IN DIABETES
• Hypoglycemia is most commonly a result of the treatment of
diabetes.
• it is the limiting factor in the glycemic management of
diabetes mellitus
• it causes recurrent morbidity in most people with type 1
diabetes (T1DM) and in many with advanced type 2 diabetes
(T2DM), and it is sometimes fatal.
• it causes a vicious cycle of recurrent hypoglycemia by
producing hypoglycemia-associated autonomic failure—i.e.,
the clinical syndromes of defective glucose counterregulation
and of hypoglycemia unawareness

14. Epidemiology
They suffer an average of two episodes of symptomatic
hypoglycemia per week,
thousands of such episodes over a lifetime of diabetes,
and
one episode of severe, at least temporarily disabling
hypoglycemia per year.
•An estimated 6–10% of people with T1DM die as a
result of hypoglycemia.

15. Conventional Risk Factors
Relative or absolute insulin excess is the sole determinant of
risk.it occurs when:
(1) insulin (or insulin secretagogue) doses are excessive, ill-
timed, or of the wrong type
(2) the influx of exogenous glucose is reduced
(3) insulin-independent glucose utilization is increased (e.g.,
during exercise);
(4) sensitivity to insulin is increased
(5) endogenous glucose production is reduced ( following
alcohol ingestion)
(6) insulin clearance is reduced (e.g., in renal failure).

16. Nocturnal hypoglycaemia:
• Nocturnal hypoglycaemia in patients with type 1 diabetes
is probably common and under-recognised.
• As hypoglycaemia does not usually waken a person who is
asleep and the usual warning symptoms are not perceived,
it is often undetected.
• However, on direct questioning, patients may admit to
poor quality of sleep, morning headaches, ‘hangover’,
chronic fatigue and vivid dreams or nightmares.
• Sometimes a partner may observe profuse sweating,
restlessness, twitching or even seizures.
• The only reliable way to identify this problem is to
measure the blood glucose during the night.

17. Exercise-induced hypoglycaemia
• Exercise-induced hypoglycaemia occurs in people with
well-controlled, insulin-treated diabetes because of
hyperinsulinaemia and the absence of the capacity to
suppress secretion of endogenous insulin, a key factor in
the normal adaptation to exercise.

18. MORBIDITY OF SEVERE HYPOGLYCAEMIA IN
DIABETIC PATIENTS
CNS
• Impaired cognitive function
• Coma
• Convulsions
• Transient ischaemic attack, stroke
• Intellectual decline
• Brain damage (rare)
• Focal neurological lesions (rare)
Heart
• Cardiac arrhythmias
• Myocardial ischaemia

19. Eye
• Vitreous haemorrhage
• ? Worsening of retinopathy
Other
• Hypothermia
• Accidents (including road traffic accidents) with
injury

20. HYPOGLYCEMIA ASSOCIATED
AUTONOMIC FAILURE
• The concept of HAAF in diabetes posits that recent
antecedent iatrogenic hypoglycemia (or sleep or prior
exercise) causes both defective glucose counterregulation
and hypoglycemia unawareness .
 Defective glucose counterregulation compromises
physiologic defense, and hypoglycemia unawareness
compromises behavioral defense.

21. DEFECTIVE GLUCOSE COUNTERREGULATION
• Failure of All 3 lines of defense.
• Result of antecedent iatrogenic hypoglycemia
• Glycemic threshold is shifted to lower plasma glucose
concentrations.
• 25x or more risk of sever iatrogenic hypoglycemia during
aggressive glycemic therapy .
↓ Glucose
No ↓ Insulin
No ↑ Glucagon
No ↑ Epinephrine
↑ Glucose

22. HYPOGLYCEMIA UNAWARENESS
• Caused by the reduced sympathoadrenal response (largely
the ↓ sympathetic neural response) to hypoglycemia.
• Characterised by the loss of warning adrenergic & cholinergic
symptoms that previously allowed the patient to recognise
developing hypoglycemia and therefore abort the episode by
ingesting carbohydrates.
• 6x increased risk of severe iatrogenic hypoglycemia during
aggressive treatment .

23. • These impaired responses create a vicious cycle of recurrent
iatrogenic hypoglycemia.

25. • HYPOGLYCEMIA WITHOUT DIABETES

26. Drugs
• Insulin
• Sulfonylureas
• Quinine
• Pentamidine
• Salicylates
• Sulfonamides
• indomethacin
• Ethanol
• Haloperidol
• ACE inhibitors
• others

27. Critical illness
• renal, hepatic, or cardiac failure, sepsis.
• are second only to drugs as causes of hypoglycemia.

28. Hormone deficiencies
• hypoglycemia can occur with prolonged fasting in
patients with primary adrenocortical failure
(Addison's disease) or hypopituitarism.
• Growth hormone deficiency can cause hypoglycemia
in young children.

29. Non–Beta-Cell Tumors
• occurs occasionally in patients with large
mesenchymal or epithelial tumors (e.g., hepatomas,
adrenocortical carcinomas, carcinoids)

30. Endogenous Hyperinsulinism
• Hypoglycemia due to endogenous hyperinsulinism can be
caused by
• (1) a primary β-cell disorder—typically a β-cell tumor
(insulinoma), sometimes multiple insulinomas, or a
functional β-cell disorder with β-cell hypertrophy or
hyperplasia
• (2) an antibody to insulin or to the insulin receptor;
• (3) a β-cell secretagogue such as a sulfonylurea;
• (4) ectopic insulin secretion,

31. INBORN ERRORS OF METABOLISM
CAUSING HYPOGLYCEMIA
those resulting in-
1.Fasting Hypoglycemia:
disorders of glycogenolysis. These disorders include
glycogen storage disease (GSD) of types 0, I, III, and IV
and Fanconi-Bickel syndrome
• Defects in fatty acid oxidation also result in fasting
hypoglycemia. These defects can include (1) defects in
the carnitine cycle (2) fatty-acid β-oxidation disorders;
(3) electron transfer disturbances; and (4) ketogenesis
disorders

32. 2.Postprandial Hypoglycemia:
These errors include (1) glucokinase and potassium channel
mutations; (2) congenital disorders of glycosylation; and (3)
inherited fructose intolerance.
3. Exercise-Induced Hypoglycemia:
It results in hyperinsulinemia caused by increased activity of
monocarboxylate transporter 1 in β cells.

33. Approach to the patient with
Hypoglycemia
• RECOGNITION AND DOCUMENTATION
 Symptoms and signs
 Whipple’s triad

34. • DIAGNOSIS OF THE HYPOGLYCEMIC
MECHANISM
 history,
 physical examination,
 investigation

35. Laboratory tests
1) Glucose
2) CBC
3) Insulin
4) C-peptide
5) Beta-hydroxybutyrate
6) Proinsulin
7) Antibodies for insulin and its receptors
8) Sulfonylurea and meglitinide screen
9) Electrolytes, BUN/Cr, UA
10) liver function tests, cortisol and thyroid levels , growth
hormone level
11) Other tests: CT and MRI

36. Urgent Treatment
• Oral treatment with glucose tablets or glucose containing fluids,
candy or food is appropriate if the patient is able & willing to take
these.
• Initial dose = 20 g of glucose
• Unable to take oral foods  parenteral therapy
• IV glucose 25 g bolus followed by infusion guided by serial plasma
glucose measurements. Or,
• Inj.Glucagon 1.0 mg sc/im can be used esp in T1DM. (it has no role
in alcohol induced hypoglycemia)

37. • The somatostatin analogue octreotide can be used to
suppress insulin secretion in sulfonylurea-induced
hypoglycemia.
• These treatments raise plasma glucose concentrations only
transiently, and patients should therefore be urged to eat as
soon as is practical to replete glycogen stores.

38. • Non-diabetic hypoglycemia definitive management depends
on the underlying etiology.
• Offending drugs can be discontinued or their doses reduced.
• Underlying critical illnesses should be treated.
• Cortisol and growth hormone can be replaced if levels are
deficient.
• Surgical, radiotherapeutic, or chemotherapeutic reduction of
a non–islet cell tumor .
• Surgical resection of an insulinoma is curative; medical
therapy with diazoxide or octreotide can be used if resection
is not possible and in patients with a nontumor β-cell
disorder.

39. PREVENTION OF HYPOGLYCEMIA
• Identifying & addressing the cause
• Encouraging Self-monitoring of blood glucose by patient
• Education & empowerment of patient
• Flexible insulin or Oral anti-diabetic regimens
• Rational, individual glycemic goals
• Ongoing professional guidance & support

40. References;
• Harrison's Principles of Internal Medicine, 18th
Ed
• Davidson's Principles & Practice of Medicine
21th ed,