Approach to

Hypoglycemia

Diabetics and NonNon-Diabetics

Incidence

In (DCCT), 10
10--30
30%
% of type 1 diabetics per year

Of those,10
those,10%
% require 3rd party Intervention

In the (UKPDS),(30
(UKPDS),(30--35
35%
%)of type 2 diabetics on Insulin
require 3rd party Intervention

Causes
Drugs

Insulin- most common cause,

InsulinTiming, dose, type
clearance of insulin (eg, renal failure);
altered counter regulation
Sulfonylureas
Metformin does not cause hypoglycemia
High dose salicylates, b blockers, quinine,quinolones

Renal failure

Second gluconeogenic organ

decreased clearance of renally excreted drugs or their metabolites
(eg, insulin, chlorpropamide, metabolite of glyburide)

Hepatic Failure

Decreased glycogenolysis
Decresed gluconeogenesis
Large functional reserve,( 20%
20% func required to prevent
hypoglycemia)
Genetic defects in glycometabolic pathways
Finally, compromised drug metabolism (tolbutamide, glyburide,
glipizide )

Endocrinopathies

Adrenal (glucocorticoid) insufficiency

Growth hormone deficiency

Glucagon deficiency

Pituitary disease ( decreased combined corticotropin and GH

deficiecy)

Poisoning
(ethanol, propanolol, salicylates)

Ethanol inhibits gluconeogenesis

Ethanol--induced hypoglycemia occurs 12

Ethanol
12--72 hrs after ingestion

Neoplasm

Nonislet
Non
islet--cell tumors
Mesenchymal tumors,
hepatocellular carcinoma,
adrenocortical tumors,
carcinoid tumors,
leukemia, and lymphomas

Most of these tumors secrete IGF II molecule

Some also secrete GlucagonGlucagon- like peptide(GLPpeptide(GLP-1) and Somatostatin

Insulinoma
Pancreatic -cell tumors that secrete Insulin
Small,solitary, benign( < 10%
10% malignant)
Inability of insulinoma cells to suppress insulin secretion during low
levels of circulating glucose, leading to severe hypoglycemia

Diagnosis and Tumor Localization

Very high Insulin levels
spiral CT, arteriography, ultrasonography
Treatment of Choice
Enucleation
Recurrence at 10 yrs is 6% and 20 yrs is 10
10%
%

Islet Hyperplasia

Also called nesidioblastosis or diffuse islet hyperplasia

or the syndrome of noninsulinoma pancreatogenous hyperinsulinism

Represent hyperplastic processes and budding of islet cells from

ducts (nesidioblastosis). Now interpreted as precursor to MEN 1,
with molecular evidence.
Heterozygous knockout of the MEN
MEN1
1 gene in the mouse show
multiple giant hyperplastic islets that precede insulinoma.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), these

infants have an identifiable genetic mutations in sulfonylurea
receptor 1 (SUR1
(SUR1) ,potassium channel Kir6
Kir6.2, glucokinase.

Autoimmune causes

Anti--insulin receptor antibody

Anti

Rarely, hypoglycemia is caused by autoantibodies that bind the

insulin receptor and mimic the biologic action of insulin
Most patients have elevated ESR, +ve ANA

Anti--insulin antibody
Anti

autoantibodies against insulin bind free circulating plasma insulin

when its concentration is high and release insulin when the
concentration of free plasma insulin drops.

Release of insulin at inappropriate times can cause hypoglycemia

hypoglycemia..

Symptoms
Adrenergic Symptoms
usually seen early with a rapid decline in blood glucose and include
tachycardia, tachypnea, vomiting, and diaphoresis

Neuroglycopenic

usually associated with slower or prolonged hypoglycemia, include

poor feeding, altered mental status, lethargy, and seizures

Classification of Hypoglycemia
Fasting hypoglycemia occurs in the postabsorptive period
(ie, hours after a meal)

Reactive (postprandial
(postprandial)) hypoglycemia
hypoglycemia..

Reactive hypoglycemia is controversial

low postprandial plasma glucose levels alone are not

sufficient

10% to 30
10%
30%
% of normal individuals undergoing oral GTT
have plasma glucose <50
<50 mg/Dl, with no symptoms

Only patients with severe (eg, loss of consciousness,

traumatic injury or accident) attributed to postprandial
hypoglycemia require further workup.

Dumping Syndrome/ Alimentary Hypolycemia

Alimentary hypoglycemia presents 2 hrs after a meal

Pathophysiology
disruption of controlled gastric emptying
decreased transit time
rapid elevation in plasma glucose that triggers
exaggerated insulin response.
abnormal insulin then causes a precipitous drop in blood
glucose

Pathophysiology of Hypoglycemia
Responses to Hypoglycemia is our ability to suppress insulin in
response to hypoglycemia

In Diabetics,
Diabetics, it does not occur as Insulin is supplied exogenously

Main defense is increased release of counterregulatory hormones, as

Glucagon, Epinephrine, Cortisol, and Growth hormone

Glucagon stimulates both glycogenolysis and gluconeogenesis

Epinephrine acts via -adrenergic receptors and stimulates

glycogenoalysis and gluconeogenesis
Also acts on alphaalpha-2-receptors to inhibit insulin secretion

Cortisol and Growth hormone contribute only after prolonged

hypoglycemia by limiting peripheral uitilization of glucose.

Counterregulatory effects of Epinephrine during Hypoglycemia

Glucagon and epinephrine secretion rises when plasma

glucose concentrations fall below 65 to 70 mg/dL (3
(3.6 to
3.9 mmol/L)

Growth hormone secretion increases when plasma

glucose concentrations fall below 60 to 65 mg/dL (3
(3.3 to
3.6 mmol/L)

Cortisol secretion increases when plasma glucose

concentrations fall below 60 mg/dL (3
(3.3 mmol/L).

Hypoglycemia Unawareness
50%
50
% of type 1 patients undergo diminution in their epinephrine response
to hypoglycemia,
Further patients lose the autonomic warning symptoms of hypoglycemia
and may recognize (or even fail to recognize) the condition only when
somatic neurologic function becomes impaired.
Usually associated with duration of diabetes and autonomic neuropathy
May also occur when patients are switched to intensive insulin regimens.
The introduction of intensified treatment regimens can lower the glucose
level that triggers epinephrine release and adrenergic symptoms.
The DCCT trial showed that even brief periods of antecedent
hypoglycemia can suppress countercounter-regulatory responses during
subsequent hypoglycemic episodes.

Diagnosis
Establishing the cause

History (liver failure, sepsis, autoimmune disease, neoplasm, alcohol,

drugs)

Establishing fasting hypoglycemia

Supervised 72 hour fast test

In hospital setting to lower risk to the patient
Usually hypoglycemia develops in first 48 hours of the fast in 95
95%
% of
cases

72-HOUR FAST
72Protocol
Date the onset of the fast as the time of the last intake of calories
Discontinue all non essential medications
Allow the patient to drink calorie-free and caffeine-free beverages
Collect blood specimens for measurement of plasma glucose, insulin,
C-peptide, and proinsulin every six hours until the plasma glucose
concentration is below 60 mg/dL (3.3 mmol/L) at this point, the
frequency of sampling should be increased to every one to two hours.

Test end points and duration

the plasma glucose concentration is 45

45 mg/dL (2
(2.5
mmol/L)
the patient has symptoms or signs of hypoglycemia,
72 hours have elapsed,
or when the plasma glucose concentration is less than
55 mg/dL (3
(3 mmol/L) if Whipple's triad is present
Plasma betabeta-hydroxybutyrate and sulfonylurea levels are
measured
1 mg of glucagon is given intravenously and the plasma
glucose measured 10
10,, 20,
20, and 30 minutes later.

In normal subjects, the following thresholds have been identified in

graded glucose reductions

Insulin secretion decreases,(BG < 80),

80), followed by increase in
Glucagon and Epinephrine, growth hormone( BG <65
<65)) and Cortisol
(BG<60
(BG<
60)respectively
)respectively

Normal subjects do not have symptomatic hypoglycemia after a

prolonged fast because

Gluconeogenesis accounts for approximately 50 percent of glucose

production after an overnight fast and for almost all glucose
production after 42 hours or more of fasting

Interpretation of values after 72 hour test

 ].

Relation of Plasma Glucose and Proinsulin

Hypoglycemia Pathway

Principles of Treatment
Principles of therapy

Priority in treating hypoglycemia to maintain plasma glucose geater

than 50 mg/dl, either snacks vs IV dextrose

The second priority is to address the underlying cause. removal or

adjustment of the offending drug, appropriate hormone replacement
for patients with deficiency, resection of the tumor in Insulioma.

Patients with autoantibodies against the insulin receptor can be

treated with highhigh-dose glucocorticoid (prednisone, 60 mg/d) to
prevent hypoglycemia

Most episodes of asymptomatic hypoglycemia and mild to moderate

symptomatic hypoglycemia are effectively selfself-treated by ingestion
of glucose tablets or carbohydrate in the form of juices, soft drinks,
milk, crackers, candy, or a meal.

A commonly recommended dose of glucose is 1616-20 g of oral

glucose.

However, the glycemic response to oral glucose is transient, usually

less than 2 hours in insulin
insulin--induced hypoglycemia

Parenteral treatment is necessary when a hypoglycemic patient is

unable or unwilling (because of neuroglycopenia) to take
carbohydrate orally.

Most common 1 amp of D50

D50,(?glucose)
,(?glucose)

Glucagon is commonly injected subcutaneously or intramuscularly

standard dose, 1 mg .
less useful in T2
T2DM than it is in T1
T1DM as stimulates insulin secretion

Hypoglycemia related to endogenous hyperinsulinism is often curable

by the surgical removal of an insulinoma.

If this is not possible because of multiple or metastatic tumors,

Diazoxide can be used, (100
(100--800 mg/day) raises the plasma glucose
concentration by suppressing insulin secretion.

Side effects include hypotension,brain edema,, gastrointestinal side

effects

Other treatments include octreotide or calcium channel antagonists

Sort term treatment of hypoglycemia associated with non

nonbeta cell
tumors involves shortshort-term measures pending effective medical,
surgical, or radiotherapeutic treatment can be done by glucocorticoid
or growth hormone

Remissions of autoimmune hypoglycemias have been associated with

immunosuppressive therapy, including glucocorticoids, but controlled
trials are lacking.

The treatment of hypoglycemia related to hepatic or renal disease,

cardiac failure, or sepsis includes shortshort-term measures and, treatment
or management of the underlying disease process.

Hypoglycemic Coma
Recovery from hypoglycemia may be delayed, because of cerebral
edema. Unconsciousness lasting more than 30 minutes after plasma
glucose is corrected is called posthypoglycemic coma, IV mannitol (40
(40
g as a 20%
20% solution over 20 minutes) or glucocorticoids (e.g.,
dexamethasone, 10 mg), or both can be used along with maintenance
of normal plasma glucose levels

CASE 1 A 39
39--yearyear-old man was referred for evaluation of repeated episodes of
sweating, slurred speech, and confusion during the last four years that could
be aborted by eating. On two occasions, he drove his car off the side of the
road; both times he was found to be confused, his serum glucose
concentrations ranged from 30 to 40 mg/dL (1
(1.7 to 2.2 mmol/L), and he
improved after intravenous glucose administration.
After fasting for 12 hours, he began to sweat and became confused and
combative. Serum values at that time were as follows:
Glucose - 22 mg/dL
Insulin - 110 microU/mL (660
(660 pmol/L)
C-peptide - 3200 pmol/L (0
(0.03
03--1 nmol/L)
Proinsulin - 800 pmol/L (2
(2-31 pmol/L)
2.2 mmol/L)
Glucose increase after glucagon - 39 mg/dL ((2
Sulfonylurea negative
What is the nost likely Diagnosis?
A) Surreptious Insulin use
B) Antibodies to Insulin receptor
C) Insulinoma
D) None of the above

Comment This is a classic case of insulinoma. The patient was healthy but had episodes of
neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low serum glucose concentrations at the
same time, and relief of symptoms by glucose administration) was satisfied. That the hypoglycemia was
caused by endogenous insulin was confirmed by the high serum insulin, CC-peptide and proinsulin
concentrations, and supported by the low serum betabeta-hydroxybutyrate concentration and the small rise in
serum glucose after intravenous glucagon administration.

CASE 2 A 27
27--yearyear-old man was referred by his local physician for evaluation of
hypoglycemia found incidentally during a workwork-up for peptic ulcer disease.
Past medical history included gastric by pass surgery for morbid obesity 2
years ago. During the last four months, he had several episodes of weakness
and feeling "shaky inside" late in the evening. During the night he would
periodically drink soda. When symptomatic, reflectance meter blood glucose
values measured by the patient using equipment purchased for his sevenseven-year
year-old daughter (diagnosed with type 1 diabetes one year earlier) had been in the
range of 40 to 50 mg/dL ((2
2.2 to 2.8 mmol/L). Serum values after an overnight
fast were:
Glucose - 36 mg/dL ((2
2.0 mmol/L)
Insulin - 140 microU/mL (840
(840 pmol/L)
C-peptide - <33 pmol/L(
pmol/L(0
0.03
03--1nmol/L)
Proinsulin - 0.9 pmol/L(
pmol/L(2
2-31 pmol/L)
What is he most likely diagnosis?
A) Insulinoma
B) Insulin antibodies
C) Exogenous Insulin administration
D) Alimentary hypoglycemia
The low serum CC-peptide and proinsulin values indicate that the hyperinsulinemia
(140 microU/mL ((840
840 pmol/L)) was due to exogenous insulin administration.

Thanks.

CASE 8 A 7676-yearyear-old woman was referred for the evaluation of postprandial adrenergic
symptoms with occasional visual changes. There was one episode of confusion while on a
telephone call to her daughter. During an episode of light headedness, sweating, weakness and
irritability two hours after breakfast (which occurred while under observation), serum values were
as follows:
Glucose
51 mg/dl (2
(2.8 mmol/L)
Insulin
6.4 microU/mL (45
(45..9 pmol/L)
C-peptide
2.6 ng/mL (858 pmol/L)
Betahydroxybutyrate
0.1 mmol/L
Glucose increase after glucagon 46 mg/dL (2
(2.6 mmol/L)
Sulfonylurea
negative
A mixed meal test was performed because of the presence of postprandial symptoms
accompanied by biochemical evidence of insulininsulin-mediated hypoglycemia. Biochemical testing 180
minutes after a mixed meal revealed the following:
Glucose
43 mg/dl (2
(2.4 mmol/L)
Insulin
22..0 microU/ml (157
22
(157..8 pmol/L)
C-peptide
4.7 ng/ml (1551
(1551 pmol/L)
The biochemical tests confirmed insulininsulin-mediated hypoglycemia. The differential diagnosis
included noninsulinoma pancreatogenous hypoglycemia (Islet cell hypertrophy/nesidioblastosis),
which is associated with postprandial hypoglycemia, insulin autoimmune hypoglycemia
(postprandial or fasting hypoglycemia), or insulinoma, which more commonly presents as fasting
hypoglycemia. (See
(See "Noninsulinoma pancreatogenous hypoglycemia" and see "Insulinoma").
"Insulinoma").