2. HYPOGLYCEMIA
• Introduction
• Definition and classification
• Symptoms and clinical signs
• Physiology of hypoglycemia
• Hypoglycemia in DM
• HAAF(hypoglycemia-associated autonomic failure)
• Hypoglycemia unawareness
• Hypoglycemia without DM
• Approach to patient
• management
3. INTRODUCTION
• India is the capital for DM
• Newer drugs and intensive glycemic control causes
frequent hypoglycemia in DM
• Incresed mortality in DM –severe hypoglycemia
• Need adequate control measures against this life
threatning complication
• Early recognition ,regular self monitoring
,appropriate treatment, educational program
4. DEFINITION
• According to ADA 2018 hypoglycemia defined as blood
glucose < 70mg/dl
• It is a clinical syndrome with diverse causes in which low
plasma glucose concentrations lead to symptoms /signs, and
there is resolution of the symptoms /signs when the plasma
glucose concentration is raised
• The diagnosis of hypoglycemia is not based on an absolute
blood glucose level
• It requires fulfilment of the whipple triad
5.
6. classification
level Glycemic criteria description
Hypoglycemia alert
value
(level 1)
<70mg/dl Needs rx with fast acting
carbohydrate and dose
adjustment of glucose
lowering therapy
Clinically significant
hypoglycemia
(level2)
<54mg/dl Clinically important
hypoglycemia
Severe
hypoglycemia
(level 3)
No specific glucose
thrshold
Associated with severe
cognitive impairment and
need external assistance
for recovery
7.
8. • Reactive hypoglycemia-hypoglycemia after 3-5 hrs
after a rich meal due to inappropriate secretion of
insulin in persons whose fasting sugars were in
normal range
• Post gastrostomy, gastrojejunostomy, pyloroplasty or
vagotomy
• Also called elementary hypoglycemia or elementary
hyper insulinemia.
9. • Relative or pseudo hypoglycemia –occurence
of symptoms of hypoglycemia in persons with
normal blood sugar .
• It is usally due to rapid fall in blood sugar
levels (from 500mg/dl to 150mg/dl)
10. PHYSIOLOGY OF HYPOGLYCEMIA
• Glucose is an obligate metabolic fuel for the brain
under physiologic conditions.
• The brain cannot synthesize glucose or store
more than a few minutes
• and therefore requires a continuous supply of
glucose from the arterial circulation
11. • As the arterial plasma glucose concentration falls
below the physiologic range, blood-to-brain glucose
transport becomes insufficient to support brain
energy metabolism and function.
• multiple integrated glucose counterregulatory
mechanisms normally prevent or rapidly correct
hypoglycemia.
• Hormones involved are insulin ,glucagon,
epinephrin,nor epinephrin,cortisol and GH
12.
13. • Hepatic glycogen stores are usually sufficient to
maintain plasma glucose levels for ~8 h
• This period can be shorter if glucose demand is
increased by exercise or if glycogen stores are
depleted by illness or starvation.
14. INSULIN
• a decrease in insulin secretion is the first
defense against hypoglycemia.
• Glycogenolysis,gluconeogenesis
• Reduce glucose utilization in peripheral tissues
• Lipolysis,proteolysis-gluconeogenic precursors
15. • Glucagone is the second defence against
hypoglycemia
• EPINEPHRINE –glycogenolysis,gluconeogenesis
• Epinephrine becomes critical when glucagon is
deficent
• Epinephrine has similiar hepatic effects as
glucagon
• Epinephrine is the third defence against
hypoglycemia
16. • When hypoglycemia is prolonged beyond 4 h,
cortisol and growth hormone also support glucose
production and restrict glucose utilization to a
limited amount
• As Plasma glucose Levels fall to lower levels
,symptoms prompt the behavioural defense against
hypoglycemia, including ingestion of food
24. • Hypoglycemia activates pro-inflammatory, pro-coagulant and
pro-atherothrombotic responses in T1DM, T2DM, and non-
diabetic individuals.
These responses increase platelet aggregation, reduce
fibrinolytic balance (↑ plasminogen activator inhibitor-1), and
increase intravascular coagulation.
Hypoglycemia also reduces protective nitric oxide-mediated
arterial vasodilator mechanisms in healthy, T1DM, and T2DM
individuals.
25. HYPOGLYCEMIA IN DIABETES
• Hypoglycemia is common in type 1DM especially in patients
receiving intensive therapy - >3fold chance for severe
hypoglycemia
• Hypoglycemia was reported in 38% of pts with type 2 DM with
sulfonylurea or meglitinides
• In contrast to pts with DM ,hypoglycemia is uncommon in
individuals who do not have drug treated DM.
• Insulin, sulfonylureas, or glinides can cause hypoglycemia in T2DM.
• Metformin, thiazolidinediones, α-glucosidase inhibitors, glucagon-
like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase IV
(DPP-IV) inhibitors do not cause hypoglycemia
26. Conventional Risk Factors
1. insulin (or insulin secretagogue) doses are excessive, ill-timed, or of the
wrong type
2. the influx of exogenous glucose is reduced (e.g., during an overnight
fast, periods of temporary fasting, or after missed meals or snacks)
3. insulin-independent glucose utilization is increased (e.g., during
exercise)
4. sensitivity to insulin is increased (e.g., with improved glycemic control,
in the middle of the night, late after exercise, or with increased fitness or
weight loss)
5. endogenous glucose production is reduced (e.g., after alcohol ingestion)
6. insulin clearance is reduced (e.g., in renal failure).
27. • Insulin-the ability to suppress insulin release
cannot occur in pts with absoulute beta cell
failure.there fore ,inhibition of hepatic glucose
production continues.
• Thus the main defence against hypoglycemia is
incresed release of counter regulatory hormones
(glucagon and epinephrine)
28. • Glucagon -normal response at the onset of DM ,
• Is lost in parallel with that of insulin in type 1 DM and
more slowly in type 2 DM
• this may be the result of beta cell failure and
susequent loss of the hypoglycemia induced decline
in intra islet insulin that normally signals increased
glucagon secretion during hypoglycemia
29. • Epinephrine -in the setting of absent insulin and
glucagon responses,pts are dependent upon
epinephrine to protect against hypoglycemia
• The epinephrine response also becomes attenuated
in many patients (recent antecedent hypoglycemia)
30. Hypoglycemia-Associated Autonomic
Failure (HAAF)
• Concept of HAAF in type 1DM and long standing T2
DM ,that recent antecedent iatrogenic hypoglycemia
causes both defective glucose counterregulation and
hypoglycemia un awareness
• Shifting the glycemic threshold for the
sympathoadrenal response to subsequent
hypoglycemia to a lower plasma glucose
concentration.
• Hypoglycemia unawareness by reducing neurogenic
symptom responses
31. Hypoglycemia unawareness
• HU is defined as the onset of neuroglycopenia symptoms
before the appearance of autonomic symptoms
• HU is seen in 40% of T1DM, and is less frequently observed in
T2DM
• HU is more common in
• On tight glycemic control
• Longer duration of DM
• Old age
• History of recent and recurrent hypoglycemic events
• F>M
32. HAAF CAUSES
• Catecholamines -Blunted catecholamine response
• Sleep –sleep is a mediator of HAAF,which is linked with
catecholamine response, significantly decresed epinephrine
response to hypoglycemia during sleep
• Increase in cortisol –reduced sympathoadrenal response to
susequent hypoglycemia
• Up regulation of glucose transport in the brain
• Hypoglycemia induced alteration in hypothalamic functions or
even a cerebral network reduce sympathoadrenal response
to susequent hypoglycemia.
33.
34. additional risk factors for
hypoglycemia in diabetes
• (1) absolute insulin deficiency, indicating that insulin levels will not
decrease and glucagon levels will not increase as plasma glucose levels fall
• (2) a history of severe hypoglycemia or of hypoglycemia unawareness,
implying recent antecedent hypoglycemia, as well as prior exercise or
sleep, indicating that the sympathoadrenal response will be attenuated
• (3) impaired renal function resulting in reduced clearance of exogenous
and endogenous insulin
• (4) classical diabetic autonomic neuropathy
• (5) lower hemoglobin A1C (HBA1C), or lower glycemic goals even at
elevated HBA1C levels (8–10%), as they represent an increased probability
of recent antecedent hypoglycemia.
35. Hypoglycemia Risk Factor Reduction
• The glycemic maintenance goals have been modified to lie
between 140 and 180 mg/dL.
• Pancreatic transplantation (both whole-organ and islet-cell)
has been used in part as a treatment for severe hypoglycemia
• The use of continuous glucose monitors,either alone or in
combination with continuous subcutaneous infusion via a
wearable pump
• a portable wearable “artificial pancreas” incorporating
continuous glucose sensor modulation of either insulin alone
or bi-hormonal delivery of both insulin and glucagon has been
established
36. • stem cell-derived β-cells also offer promise of
novel therapeutic interventions to reduce
hypoglycemia.
• Other interventions to stimulate
counterregulatory responses, such as selective
serotonin-reuptake inhibitors, β-adrenergic
receptor antagonists, opiate receptor antagonists,
and fructose, remain experimental
37. HYPOGLYCEMIA WITHOUT DIABETES
• Drugs-
• Insulin and insulin secretagogues
• Ethanol blocks gluconeogenesis but not
glycogenolysis. Thus, alcohol-induced
hypoglycemia typically occurs after a several-
day ethanol binge during which the person
eats little food, with consequent glycogen
depletion.
40. • Rapid and extensive hepatic destruction (e.g., toxic
hepatitis) causes fasting hypoglycemia because the
liver is the major site of endogenous glucose
production
• Sepsis is a relatively common cause of hypoglycemia.
Increased glucose utilization is induced by cytokine
production in macrophage-rich tissues such as the
liver, spleen, and lung
• Cytokine-induced inhibition of gluconeogenesis in
the setting of nutritional glycogen depletion
• Hypoglycemia can be seen with starvation.
41. • 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.
42. Non-beta-Cell Tumors
• Fasting hypoglycemia, often termed non– islet cell
tumor hypoglycemia, occurs occasionally in patients
with large mesenchymal or epithelial tumors (e.g.,
hepatomas, adrenocortical carcinomas, carcinoids)
• insulin secretion is suppressed appropriately during
hypoglycemia.
• hypoglycemia is due to overproduction of an
incompletely processed form of insulin-like growth
factor II (“big IGF-II”)
• plasma ratios of IGF-II to IGF-I are high, and free IGF-
II levels are elevated
43. • Curative surgery is seldom possible
• but reduction of tumor bulk may ameliorate
hypoglycemia.
• Therapy with a glucocorticoid, growth
hormone, or both has also been reported to
alleviate hypoglycemia.
• Hypoglycemia attributed to ectopic IGF-I
production has been reported but is rare
44. Endogenous Hyperinsulinism
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, among other very rare
mechanisms
45. diagnostic strategy
• To measure plasma glucose, insulin, C-peptide,
proinsulin, and β-hydroxybutyrate concentrations
• And to screen for circulating oral hypoglycemic
agents during an episode of hypoglycemia
• To assess symptoms during the episode and seek
their resolution following correction of
hypoglycemia by IV injection of glucagon (i.e., to
document Whipple’s triad)
46. Diagnostic
• plasma insulin concentration ≥3 μU/mL (≥18
pmol/L)
• a plasma C-peptide concentration ≥0.6 ng/mL
(≥0.2 nmol/L)
• and a plasma proinsulin concentration ≥5.0
pmol/L
• when the plasma glucose concentration is <55
mg/dL (<3.0 mmol/L) with symptoms of
hypoglycemia.
47. • A low plasma β-hydroxybutyrate
concentration (≤2.7 mmol/L)
• and an increment in plasma glucose level of
>25 mg/dL (>1.4 mmol/L)
• after IV administration of glucagon (1.0 mg)
indicate increased insulin (or IGF) actions.
48. Insulinomas
• uncommon with an estimated yearly incidence of 1 in
250,000.
• >90% of insulinomas are benign
• they are a treatable cause of potentially fatal hypoglycemia.
• The median age at presentation is 50 years in sporadic cases,
• but the tumor usually presents in the third decade when it is a
component of multiple endocrine neoplasia type 1
• More than 99% of insulinomas are within the substance of
the pancreas,
• And the tumors are usually small (<2.0 cm in diameter in
90% of cases).
• Therefore, they come to clinical attention because of
hypoglycemia rather than mass effects.
• CT or MRI detects ~70–80% of insulinomas.
49. • metastases in the roughly 10% of patients with a
malignant insulinoma.
• Transabdominal ultrasound often identifies
insulinomas,
• and endoscopic ultrasound has a sensitivity of
~90%.
• Somatostatin receptor scintigraphy is thought to
detect insulinomas in about half of patients.
50. • Surgical resection of a solitary insulinoma is
generally curative.
• Diazoxide, which inhibits insulin secretion, or
the somatostatin analogue octreotide can be
used to treat hypoglycemia in patients with
unresectable tumors;
• everolimus, an mTOR (mammalian target of
rapamycin) inhibitor, is promising.
51. ACCIDENTAL, SURREPTITIOUS, OR
MALICIOUS HYPOGLYCEMIA
• Should be considered when the cause of
hypoglycemic disorder is not apparent
• Can result from medical ,pharmacy,patient
errors
• Malicious hypoglycemia- admn of an insulin
secretogogue or insulin to another person
with the intent to cause hypoglycemia
52. INBORN ERRORS OF METABOLISM
CAUSING HYPOGLYCEMIA
• Cases in adults can be classified into those
resulting in
• fasting hypoglycemia
• postprandial hypoglycemia
• and exercise-induced hypoglycemia
53. fasting hypoglycemia
• glycogen storage disease (GSD) of types 0, I,
III, and IV and Fanconi-Bickel syndrome
• Patients with GSD types I and III
characteristically have high blood lactate
levels before and after meals, respectively.
• Both groups have hypertriglyceridemia, but
ketones are high in GSD type III.
54. • Defects in fatty acid oxidation also result in
fasting hypoglycemia.
• (1) defects in the carnitine cycle
• (2) fatty-acid β-oxidation disorders
• (3) electron transfer disturbances
• (4) ketogenesis disorders.
• Finally, defects in gluconeogenesis (fructose-1, 6-
biphosphatase) have been reported to result in
recurrent hypoglycemia and lactic acidosis.
57. APPROACH TO THE PATIENT
• RECOGNITION AND DOCUMENTATION
• Convincing documentation of hypoglycemia
requires the fulfillment of Whipple’s triad.
• Blood should be drawn, whenever possible,
before the administration of glucose to allow
documentation of a low plasma glucose
concentration.
58. • plasma insulin, C-peptide, proinsulin, and β-
hydroxybutyrate levels
• screening for circulating oral hypoglycemic
agents
• And assessment of symptoms before and after
the plasma glucose concentration is raised.
59. • DIAGNOSIS OF THE HYPOGLYCEMIC
MECHANISM
• hypoglycemic mechanism can often be
deduced from the history, physical
examination, and available laboratory data
60. Management of hypoglycemia
• Acute intervention-to prevent and minimise
neurological damage
• Maintence therapy –to prevent recurrence of
hypoglycemia
• Subsequent measures –to search for and treat
the underlying cause
61. URGENT TREATMENT
• If the patient is able and willing, oral
treatment with glucose tablets or glucose-
containing fluids, candy, or food is
appropriate.
62. Oral Carbohydrates
• Glucose 15-20 g orally – preferred initial
treatment in conscious individual with
hypoglycemia
• Examples of 15 g of carbohydrates:
– 4 ounces of juice
– 8 ounces of skim milk
– 3-4 glucose tablets
– 5-6 Life Savers candies
• After treatment, eat snack with protein/fat to
prevent recurrence
Clinical Diabetes 2012 Jan;30(1):38
63. • If the patient is unable or unwilling (because of
neuroglycopenia) to take carbohydrates orally,
parenteral therapy is necessary.
• IV administration of glucose (25 g) should be
followed by a glucose infusion guided by serial
plasma glucose measurements.
• If the patient has a history of malnutrition or c/c
alcoholic , IV thiamine at a bolus dose of 12mg/kg
should be given before initiating glucose
treatment,to avoid precipitating wernickes
encephalopathy
64. • If IV therapy is not practical, SC or IM glucagon
(1.0 mg in adults) can be used, particularly in
patients with T1DM.
• Because it acts by stimulating glycogenolysis,
• glucagon is ineffective in glycogen-depleted
individuals (e.g., those with alcohol-induced
hypoglycemia)
• Glucagon also stimulates insulin secretion and
is therefore less useful in T2DM.
65. Glucagon
• Dose: 1 mg IV/IM/SQ, may repeat in 15 mins
• IV dextrose should be administered as soon as
it is available; if patient fails to respond to
glucagon, IV dextrose must be given.
• Role: patients without IV access (especially
severe hypoglycemia, unconscious patients
Glucagon Emergency Kit
Glucagon HypoKit
66. • 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.
67. Octreotide
• Somatostatin analogue
– Provides more potent inhibition of growth
hormone, glucagon, and insulin as compared to
endogenous somatostatin
• May reduce recurrent hypoglycemia as with
dextrose-alone therapy
• Should be used with IV dextrose/oral
carbohydrates
• Dose: (ideal dose not well established)
– IV: up to 125 mcg/hour has been used
– SC 50mcg q8h daily
68. Octreotide
• Warnings/precautions:
– Cholelithiasis – may inhibit gallbladder
contractility
– Hypothyroidism – may suppress TSH secretion
– Pancreatitis – may change absorption of fats
• Adverse effects: bradycardia, dizziness,
hyperglycemia, diarrhea, constipation
Sandostatin [prescribing information].
69. Diazoxide
• Antidote for hypoglycemia due to
hyperinsulinemia
• Opens ATP-dependent K+ channels on
pancreatic beta cells hyperpolarization of
the beta cell inhibition of insulin release
• Binds to a different site on the potassium
channel than the sulfonylureas
• Dose: 3-8 mg/kg/day PO in divided doses Q8H
– Starting dose 3 mg/kg/day PO divided in 2-3 doses
70. Diazoxide
• Contraindications: hypersensitivity to diazoxide
or to other thiazides
• Warnings/precautions:
– Heart failure – antidiuretic actions
– Gout – may cause hyperuricemia
– Renal dysfunction
• Adverse effects: hypotension, hyperglycemia
Diazoxide [prescribing information].
71. PREVENTION OF RECURRENT
HYPOGLYCEMIA
• Prevention of recurrent hypoglycemia requires an
understanding of the hypoglycemic mechanism.
• Offending drugs can be discontinued or their doses
reduced.
• Hypoglycemia caused by a sulfonylurea can persist for
hours or even days.
• Underlying critical illnesses can often be treated.
• Cortisol and growth hormone can be replaced if levels
are deficient.
• Surgical, radiotherapeutic, or chemotherapeutic
reduction of a non–islet cell tumor can alleviate
hypoglycemia even if the tumor cannot be cured;
72. • Surgical resection of an insulinoma is curative;
• medical therapy with diazoxide or octreotide
can be used if resection is not possible
• The treatment of autoimmune hypoglycemia
(e.g., with glucocorticoid or
immunosuppressive drugs) is problematic, but
these disorders are sometimes self-limited.
73. • frequent feedings and avoidance of fasting
may be required.
• Administration of uncooked cornstarch at
bedtime
• An overnight intragastric infusion of glucose
may be necessary for some patients
74. Admission criteria
• Any doubt of cause
• Prolonged hypoglycemia.
• Inability to eat and drink
• Treatment has not resulted in prompt sensory
recovery
• Seizures,coma or altered behaviour
• Recurrent hypoglycemia during observation
Insulin
Promotes cellular uptake of glucose
Stimulates glycogen storage in the liver and muscles
Stimulates triglyceride storage in adipose cells
Promotes cellular uptake of amino acids and synthesis of proteins
Glucagon
Stimulates glycogenolysis in the liver
Stimulates gluconeogenesis
Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone-sensitive lipase)
Stimulates lipolysis and ketogenesis
GlucaGen HypoKit (glucagon) [prescribing information]. Princeton, NJ: Novo Nordisk Inc; December 2011.
Glucagon Emergency Kit [prescribing information]. Indianapolis, IN: Eli Lilly and Company; February 18, 2005.
Binds to a different site on the potassium channel than the sulfonylureas so may be helpful for SU overdose
IV form can be used for hypertensive emergency
