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Hypoglycaemia
1. In the Name of God, Most Gracious, Most Merciful
2. DIABETIC EMERGENCIES
- HYPOGLYCEMIA
- HYPERGLYCEMIC HYPEROSMOLAR
STATE
Dr. Mohammed Sadiq Azam
Dr. D. Sudeepta Rao
II yr. Postgraduates: MD (Gen Med)
Deccan College of Medical Sciences
5. HYPOGLYCEMIA - OUTLINE
• Drugs asso. with hypoglycemia
• Hyperinsulinemic hypoglycemia – D/D
• Endogenous hyperinsulinemia – D/D, and, a word on
insulinoma
• Hypoglycemia in Infancy & Childhood
• Diagnostic approach to an adult with hypoglycemia
• Management – Emergency management & prevention
6. DEFINITION
“Glucose levels <55mg/dl (<3.0mmol/l) with symptoms
that are relieved promptly after the glucose level is
raised document hypoglycemia.”
• 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.
7. GLUCOSE HOMEOSTASIS – Key roles
RESPONSE GLYCEMIC PHYSIOLOGIC EFFECTS ROLE IN GLUCOSE
THRESHOLD REGULATION
(mg/dl)
↓ 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 Prompt behavioral
hypoglycemia defense(food ingestion)
↓ Cognition < 50 ----- Compromises behavioral
defense against hypoglycemia
8. ↓ ARTERIAL GLUCOSE
↓ INSULIN LIVER
PANCREAS ↑ GLUCAGON ↑ GLUCOSE
PRODUCTION
KIDNEY
BRAIN
↑ GLUCONEOGENIC
PRECURSORS
↑ SYM ADR OUTFLOW
PITUITARY MUSCLE FAT
↑GH ↑ ARTERIAL
GLUCOSE
ACTH ↑E
ADR MEDULLA
↓ GLU CLEARANCE INGESTION
ADR CORTEX
↑ NE
↑ CORTISOL Post Gn SymN
SYMPTOMS
↑ Ach
9. CLINICAL FEATURES - Symptoms
• Neurogenic symptoms:
– Sweaty
– Hungry
– Tingly
– Shaky (Tremulous)
– Poundy (Palpitations)
– Nervy (Anxious/Nervous)
• These symptoms are the result of the perception of
physiologic changes caused by the ANS discharge (Adr & Chol)
triggered by hypoglycemia.
10. CLINICAL FEATURES - Symptoms
• Neuroglycopenic symptoms:
– Warm
– Weak
– Confused/Difficulty thinking
– Tired/Drowsy
– Faint
– Dizzy
– Difficulty speaking
– Blurred vision
• These symptoms are the result of direct CNS glucose
deprivation.
11. CLINICAL FEATURES - Signs
• Pallor
• Diaphoresis
• ↑ PR
• ↑ BP
• TIA occasionally (Permanent damage is rare)
“The magnitude of the responses to hypoglycemia is an inverse
function of the nadir plasma glucose concentration rather
than the rate of decrease in plasma glucose.”
(Ref: William’s T. of Endo 10/e)
12. MECHANISMS OF HYPOGLYCEMIA
• Hypoglycemia implies that the rate of glucose efflux from
circulation > rate of glucose influx into circulation.
↑ Efflux ↓ Influx
↑ Utilisation ↑ Losses ↓ Endogenous glucose
production in the
• Exercise • Pregnancy absence of exogenous
• Pregnancy • Renal Glycosuria glucose delivery
• Sepsis – Most Common cause
13. MECHANISMS OF HYPOGLYCEMIA
Defects causing Hypoglycemia
REGULATORY ENZYMATIC SUBSTRATE
↑ Secretion of Insulin Primary Failure to
OR OR mobilize or
↓ Secretion of glucose May result from utilize
counter regulatory hepatic disease gluconeogenic
hormones substrates
14. DIAGNOSIS
1. Whipple’s triad
2. Venous plasma glucose after an overnight fast:
• > 70mg/dl (>3.9 mmol/) : Normal
• 50 - 70 mg/dl (2.8-3.9 mmol/l) : s/o Hypoglycemia
• < 50 mg/dl (<2.8 mmol/l) : => Postabsorptive hypoglycemia
3. Postprandial (=Reactive) hypoglycemia:
– Diagnosis requires documentation of Whipple’s triad
after a mixed meal (low venous plasma concentration
post oral glucose load is not sufficient for diagnosis).
(Ref: William’s T. of Endo 10/e, Harrison’s Principles of Int Med 17/e, 339:2308)
15. CLINICAL CLASSIFICATION
1. Postabsorptive (=Fasting) Hypoglycemia
2. Postprandial (=Reactive) Hypoglycemia
Significance:
– Reproducible hypoglycemia in the postabsorptive state,
implies the presence of disease and requires diagnostic
explanation and treatment.
– It may become apparent during the latter part of any
interdigestive period (NOT necessarily in the fasting state) esp.
post-exercise.
– Postprandial (=reactive) hypoglycemia does not usually imply a
serious underlying disorder.
19. HYPOGLYCEMIA IN DM
IMPACT & FREQUENCY:
• Limiting factor in the glycemic management of DM
1. Causes recurrent morbidity in MOST cases of T1DM and
MANY with T2DM and is sometimes fatal.
2. Precludes maintenance of euglycemia over a lifetime of
diabetes and thus full realization of the benefits of glycemic
control.
3. Causes a vicious cycle of recurrent hypoglycemia by
producing hypoglycemia associated autonomic failure – the
clinical syndromes of defective glucose counterregulation
and of hypoglycemia unawareness.
20. HYPOGLYCEMIA IN DM – The Burden
• T1DM-
– Fact of life
– Average of 2 episodes of symptomatic hypoglycemia per week and at
least one episode of sever, at least temporarily disabling
hypoglycemia each year.
– Estimated 2-4% of people with T1DM die due to hypoglycemia.
• T2DM-
– Less frequent than T1DM.
– Metformin, TZDs, AGIs, GLP-1 analogues, DDP-4 inhibitors should not
cause hypoglycemia, however the risk increases when combined with
insulin/SU.
– As insulin resistance increases and patients require insulin the risk of
hypoglycemia in T2DM approaches that in T1DM.
21. RISK FACTORS – THE PREMISE
“The conventional risk factors for hypoglycemia in diabetes
are based on the premise that relative or absolute insulin
excess is the sole determinant of risk.”
- Harrison’s Principles of Int Med 17/e, 339:2306
“Iatrogenic hypoglycemia in T1DM is the result of the
interplay of therapeutic insulin excess and compromised
glucose counterregulation.”
-William’s T. of Endo 10/e
22. CONVENTIONAL RISK FACTORS
• Absolute/Relative Insulin Excess occurs when:
– Insulin (or secretogogue) doses are excessive, ill-timed or of the
wrong type
– The influx of exogenous glucose is reduced (e.g., overnight fast or
following missed meals/snacks)
– Insulin-independent glucose utilization is increased (e.g., exercise)
– Sensitivity to insulin is increased (e.g., improved glycemic control, in
the middle of the night, late of the exercise, or with increased fitness
or weight loss)
– Endogenous glucose production is reduced (e.g., alcohol ingestion)
– Insulin clearance is reduced (e.g., renal failure)
23. COMPROMISED GLUCOSE COUNTERREGULATION
• Absolute insulin deficiency (C-peptide negativity):
– β cell destruction: No decrease insulin in response to fall
in glucose
– Unknown: No increase glucagon in response to fall in
glucose
• H/O severe hypoglycemia/aggressive treatment per se:
– Lower glucose goals, low HbA1c
– Attenuated autonomic activation & symptoms in response
to fall in glucose.
25. 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 .
No ↓ Insulin
↓ Glucose No ↑ Glucagon ↑ Glucose
No ↑ Epinephrine
26. HYPOGLYCEMIA UNAWARENESS
• Caused by the attenuated 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 ad therefore abort the episode by
ingesting carbohydrates.
• 6x increased risk of severe iatrogenic hypoglycemia during
aggressive treatment .
28. ADDITIONAL RISK FACTORS – T1DM
1. Insulin deficiency that indicates that insulin levels will not
decrease and glucagon levels will not increase as plasma
glucose falls
2. A h/o severe hypoglycemia or of hypoglycemia unawareness,
implying recent antecedent hypoglycemia, that indicates that
the sympathoadrenal response will be attenuated; and
3. Lower HbA1c levels or lower glycemic goals that, all other
factors being equal, increase the probability of recent
antecedent hypoglycemia.
33. ENDOGENOUS HYPERINSULINEMIA
• Hypoglycemia related to endogenous hyperinsulinemia can
be caused by-
– A primary pancreatic islet (β) cell disorder, typically a β cell tumour
(insulinoma), sometimes multiple insulinomas, or, esp. in
infants/young children, a functional β cell disorder with β cell
hyperplasia or without an anatomic correlate.
– A β cell secretogogue, often a SU, theoritically a β cell stimulating
antibody.
– An antibody to insulin
– Ectopic insulin secretion (rare).
34. ENDOGENOUS HYPERINSULINEMIA
• Fundamental pathophysiologic feature of endogenous
hyperinsulinemia caused due to a primary β cell disorder or
an insulin secretogogue is failure of insulin secretion to fall to
very low levels during hypoglycemia.
• Critical diagnostic findings:
– Plasma insulin ≥3 uU/ml
– Plasma C-Peptide concentration ≥ 0.6 ng/ml
– Plasma proinsulin concentration ≥ 5.0 pmol/l, when the plasma
glucose concentration is < 55 mg/dl with symptoms of hypoglycemia.
35. INSULINOMA
• Uncommon, 1/250,000; > 90% benign, treatable cause of
potentially fatal hypoglycemia.
• Median age of presentation – 50 yrs (sporadic cases), third
decade in MEN 1.
• Symptoms:
– Various combinations of diplopia, blurred vision, sweating,
palpitations or weakness: 85%
– Confusion or abnormal behaviour: 80%
– Unconsciousness or amnesia: 53%
– Grand mal seizures: 12%
37. HYPOGLYCEMIA IN INFANCY/CHILDHOOD
3. Enzyme defects:
– CARBOHYDRATE METABOLISM :
• Glycogen storage disease Types I / II/ VI
• Glycogen synthase deficiency
• Fructose 1,6 bis phosphatase deficiency
• Fructose 1-phosphate – aldolase deficiency
• Gal 1-phosphate – uridyl transferase deficiency
38. HYPOGLYCEMIA IN INFANCY/CHILDHOOD
3. Enzyme defects:
– PROTEIN METABOLISM :
• Branched chain α ketoacid dehydrogenase complex deficiency
– FAT METABOLISM :
• FA oxidation defects induding deficiencies in the carnitine
cycle
• β – oxidation spiral defects
• ETC defects
• Ketogenesis sequence defects
39. NEONATAL HYPOGLYCEMIA
Diagnostic Criteria (Cornblath et al):
– < 2.5 mmol/l (<45mg/dl) in infants with clinical
manifestations compatible with hypoglycemia, and,
– <2.0 mmol/l (<30mg/dl) in infants at risk for
hypoglycemia
43. 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.
• Inj.Glucagon 0.1 mg sc/im can be used esp in T1DM. (it has no
role in alcohol induced hypoglycemia)
• Eat ASAP restore glycogen stores.
44. PREVENTION
• Identifying & addressing the cause
• Encouraging SMBG by patient
• Education & empowerment of patient
• Flexible insulin or OAD regimens
• Rational, individual glycemic goals
• Ongoing professional guidance & support
