H YPOGLYCEMIA

Dharma Lindarto

Divisi Endokrin-Metabolik
Departemen Ilmu Penyakit Dalam FK USU/
RSUP H Adam Malik Medan.
 What is Hypoglycemia?
• Hypoglycemia is “an abnormally low
plasma glucose level that leads to
symptoms of sympathetic NS stimulation or
of CNS dysfunction.”

The Merck Manual of Diagnosis and Therapy

Seventeenth Edition (1999)
Review of Blood Glucose control
• Normal BG 60-100 mg/dL
• Hypoglycemia: BG <50 mg/dL in men; <45
mg/dL in women
• Important hormones:
– Insulin, glucagon, epinephrine, cortisol, growth
hormone
 PHYSIOLOGY OF GLUCOSE
COUNTERREGULATION
Characteristic sequence:

1.  insulin secretion as glucose concentrations decline within the

physiological range (72–108 mg/dl /4.0–6.0 mmol/l).

2.  glucagon and epinephrine secretion, glucose concentrations fall

just below the physiological range (65–70 mg/dl (3.6–3.9 mmol/l).

3. Neurogenic and neuroglycopenic symptoms, and cognitive

impairments in range (50–55 mg/dl (2.8– 3.0 mmol/l).
 Hypoglycemia Risk Factors

• Missed or delayed meal

• Eating less food at a meal than planned
• Vigorous exercise without carbohydrate compensation
• Taking too much diabetes medicine (e.g., insulin,
insulin secretagogues, and meglitinides)
• Drinking alcohol
 Causes…
• Fasting hypoglycemia
• Result of a serious medical condition
– Insulinomas (most are benign)*
• Pancreatic tumors-secrete insulin
– Other tumors (breast, cervix, adrenal glands)*
• Secrete insulin-like growth factors (IGF)
• Glucose production by liver inhibited; increased uptake in
peripheral tissues
– Extensive liver disease
*Le Roith, Derek. (1999). Tumor-induced hypoglycemia. The New England Journal of Medicine,
341, 10.
 Causes…
• Postprandial (reactive)
• 2-5 hrs after eating
• Early insulin release with excess secretion in response to the
hyperglycemia
– Alimentary
• In patients w/GI procedures (gastrectomy, pyloroplasty,
gastrojejunostomy)
– Idiopathic alimentary
• RARE; over-diagnosed
• Healthy young-adults
• 2-4 hrs after meal or after a missed meal
 Various Causes
• Alcoholic hypoglycemia
– Ingestion of alcohol after a long fast

• Factitious hypoglycemia
– Insulin & sulfonylureas
– Primarily in health care worker and relatives of
diabetics
– Distribution of incorrect drugs to patients*

*Robinson, Irving, et. Al. (1994) Closet Hypoglycemia. Journal of Family

Practice, 38, 1.
 Hormones in the response to hypoglycemia:
(counterregulatory hormone)

1. Glucagon (glycogenolysis and gluconeogenesis).

2. Epinephrine (glycogenolysis and gluconeogenesis and limits
glucose utilization)
3. growth hormone (reduce glucose utilization and support its
production).
4. Cortisol (reduce glucose utilization and support its production)

play less important roles in the control of glucose flux during

normal physiologic circumstances, except in critically ill
Counter Regulation Respons to Hypoglycemia
 Symptoms
BG level at which symptoms develop varies from person to person

• Adrenergic
– Sweating, trembling, anxiety, nausea, pallor, faintness,
palpitations, hunger

• Neuroglycopenic (CNS manifestations)

– Confusion, fatigue, difficulty speaking, headache, dizziness,
inability to concentrate, inappropriate behavior, stupor, coma
 SYMPTOMS OF HYPOGLYCEMIA
Neurogenic (autonomic) Neuroglycopenic
trembling difficulty concentrating
palpitations confusion
sweating weakness
anxiety drowsiness
hunger vision changes
nausea difficulty speaking
tingling headache
dizziness
tiredness
 Requirements for Diagnosis
• Whipple’s Triad
– Symptoms of hypoglycemia
– Blood glucose levels <50 mg/dL in men or <45
mg/dL in women
– Alleviation of symptoms after correction of the
low BG levels (ingestion of sugar)
 Management of Hypoglycemia
• Lifestyle:
– 5-6 small meals/day (CHO, PRO, FAT)
– Spread out intake of CHO evenly (2-4/meal)
– Avoid foods w/large amounts of CHO
– Restrict/avoid coffee & alcohol
– Decrease fat intake (moderate intake <30% of total kcal)
– Moderate (upper range) PRO intake
 Treatment

• Two components:
– Relief of symptoms by restoring blood glucose levels
within normal ranges
– Correcting the underlying cause
• Immediate:
– Eat foods/beverages containing CHO
– IV glucose may be required
 TREATMENT
GOALS:
• To detect and treat a low blood glucose level and provides a rapid
rise is blood glucose to a safe level
• eliminating the risk of injury, and relieving symptoms quickly.
 15 g of glucose will usually increase blood glucose by 2.1
mmol/L within 20 minutes with adequate symptom relief for
most people.
 20 g will usually increase blood glucose by 3.6 mmol/L within
45 minutes.
 TREATMENT

Mild to moderate hypoglycemia

 15 g of oral carbohydrate (CHO), preferably as glucose or sucrose tablets or
solution. Retest blood glucose in 15 minutes; repeat treatment if BG still < 4.0
mmol/L

Severe hypoglycemia, conscious

 20 g of oral CHO (glucose tablets or equivalent); retest in 15 minutes, repeat
treatment if BG still < 4.0 mmol/L

Severe hypoglycemia, unconscious adult

 1 mg glucagon subcutaneously or intramuscularly or 10 to 25 g of glucose
intravenously (20 – 50 cc of D50W)
 Preventing Hypoglycemia
• If blood glucose is < 70 mg/dl, give 15–20 g of quick-acting
carbohydrate (1–2 teaspoons of sugar or honey, 1/2 cup of regular
soda, 5–6 pieces of hard candy, glucose gel or tablets as directed,
or 1 cup of milk).

• Test blood glucose 15 minutes after treatment. If it is still < 70

mg/dl, re-treat with 15 g of additional carbohydrate.

• If blood glucose is not < 70 mg/dl but it is > 1 hour until the next
meal, have a snack with starch and protein (crackers and peanut
butter, crackers and cheese, half of a sandwich, or crackers and a
cup of milk).
 HYPOGLYCEMIA
- RECOMMENDATIONS
 In hospitalized patients, efforts must be made to ensure that
patients using insulin have ready access to an appropriate form
of glucose at all times, particularly when NPO or during
diagnostic procedures [Grade D, Consensus].
 In adults, mild to moderate hypoglycemia should be treated by
the oral ingestion of 15 g of carbohydrate, preferably as
glucose or sucrose tablets or solution. These are preferable to
orange juice and glucose gels [Grade B, Level 2].
To wait 15 minutes, retest BG and retreat with another 15 g of
carbohydrate if BG level remains < 4.0 mmol/L. In smaller
children (< 5 years of age or < 20 kg), 10 g of carbohydrate
may be used initially [Grade D, Consensus].
 HYPOGLYCEMIA
- RECOMMENDATIONS
 Severe hypoglycemia in a conscious adult, should be treated by
the oral ingestion of 20 g of carbohydrate, preferably as glucose
tablets or equivalent. Patients should be encourage to wait 15
minutes, retest BG and retreat with another 15 g of glucose if the
BG level remains < 4.0 mmol/L [Grade D, Consensus].
 Severe hypoglycemia in an unconscious individual  5 years of
age, in the home situation, should be treated with 1 mg of
glucagon subcutaneously or intramuscularly. In children < 5
years of age, a dose of 0.5 mg of glucagon should be given.
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].
 HYPOGLYCEMIA
- RECOMMENDATIONS

 In the home situation, support persons should be taught

how to administer glucagon by injection [Grade D,
Consensus].
 For severe hypoglycemia with unconsciousness in adults,
when intravenous (IV) access is available, glucose 10 to
25 g (20 to 50 cc of D50W) should be given over 1 to 3
minutes. The pediatric dose of glucose for IV treatment is
0.5 to 1 g/kg [Grade D, Consensus].
 HYPOGLYCEMIA
- RECOMMENDATIONS
 In hospitalized patients, a PRN order for glucagon should be
considered for any patient at risk for severe hypoglycemia (i.e.
requiring insulin and hospitalized for concurrent illness) when
IV access is not readily available [Grade D, Consensus].

 To prevent repeated hypoglycemia, once the hypoglycemia has

been reversed, the person should have the usual meal or snack
that is due at that time of day. If a meal is > 1 hour away, a
snack (including 15 g of carbohydrate and a protein source) is
recommended in the absence of complicating factors [Grade D,
Consensus].
 Conclusions
• Hypoglycemia is rare—should not automatically
suspect it on basis of reported symptoms
• Due to past over-diagnosis, Whipple’s Triad most
important determinant of hypoglycemia
• In those with diagnosed hypoglycemia, serious
underlying medical conditions must be considered
• Testing for medications in blood important in
ruling out insulinomas
HYPOGLYCEMIA IN DIABETES
CLINICAL RISK FACTORS FOR HYPOGLYCEMIA
IN DIABETES

Absolute or relative insulin excess occurs when

1.  doses Insulin (or insulin secretagogue or sensitizer)

2.  Exogenous glucose delivery.
3.  Endogenous glucose production
4.  Glucose utilization
5.  Sensitivity to insulin
6.  Insulin clearance
Sulfonylureas : hypoglycemic risk

RR

Tolbutamide 1
Gliclazide 1 - 2(2)
Repaglinide 1-2
Glipizide 2(1)
Glimepiride 3 - 4(3)
Glibenclamide 5(1)

1) Ferner 1988
(2) Teisse, Diab Med,1994
(3) Dills, Horm Metab Res,1996
 Hypoglycemic risk

• Glibenclamide has greatest risk for hypoglycemia (less so when

given 2-3 times a day in smaller portions)

• Repaglinide (3 times a day) seems to have smallest risk, but needs

more confirmation on its efficacy in severe DM.
Although different receptor-binding explains this difference, the
small doses used is crucial.
HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE

(1)  counterregulatory hormone responses (type 1 diabetes)

- insulin levels do not decline as glucose levels fall (first
defense lost)
- glucagon response diminishes (the second defense lost)
- the epinephrine response reduced (third defense lost)

(2) hypoglycemia unawareness.

• a loss of the warning symptoms
• the first manifestation of hypoglycemia
 Interventions
• Mild
– carbohydrate 10-15 gram
• Moderate
– 20-30 gram of carbs
– Glucagon, 1 mg SC or IM

• Severe
– 50% dextrose 25 g IV
– Glucagon 1 mg IM or IV
 Somogyi Effect
• Rebound hyperglycemia
– Counterregulatory hormones activate
gluconeogenesis and glycogenolysis
– Hormones supress insulin 12-48 hours
– Also influenced by excessive carb intake
Somogyi Effect
 Common Prescription Medications
• Oral agents
– Sulfonylureas - insulin secretion, may result in significant
hypoglycemia
• Glipizide, glyburide, glucagon,acetohexamide, chlorpropamide,
tolazamide, tolbutamide, glimepiride
– Α-glucosidase inhibitors - ↓ carb absorption
• Acarbose, miglitol
– Biguanides - ↓ hepatic production and absorption of
glucose
• Metformin (glucophage)
– Thiazolidinediones – increase effect of insulin
• Avandia, actos
 Common Prescription Medications

• Insulin
– Rapid acting (onset 15 min – 1 hr)
• Regular, NovolinR, HumulinR, Lispro, Semilente
– Intermediate (onset 1 – 2.5 hr)
• NPH, HumulinN, NovolinN, Lente
– Long acting (onset 4 – 8 hr)
• Ultralente