CHAPTER 1 INTRODUCTION

Hypoglycemia means the blood glucose level is below normal range.`1` It poses a major
barrier in the treatment of diabetes mellitus.`1`,`2`,`3`,``,`!` "he goal in the treatment of
diabetes mellitus is to control blood glucose level to prevent long term complications, but
in the other hand we have to avoid hypoglycemia, or recogni#e and treat it as soon as
possible if it occurs.`3`
"he main factor causing hypoglycemia is very important to be recogni#ed is
because of the dependence of neural tissue, especially brain, to continuous glucose
supply.`1`,`2`,`!` It is because glucose is an obligate metabolic fuel for the brain, and
brain cannot synthesi#e or store it for more than a few minutes supply as glycogen. If
plasma glucose level is maintained within physiological range, the glucose transport
across blood brain barrier e$ceeds brain%s need. &ut if arterial plasma glucose falls below
normal range, within a few minutes it could disturb brain metabolism, function, and
finally survival.`2`
'everal physiologic mechanisms have been evolved to maintain the plasma
glucose level. In healthy individuals, hypoglycemia that could cause cognitive
impairment rarely occurs, because of the effective glucose homeostasis mechanism. In
patients with diabetes mellitus or receiving hypoglycemic therapy, this homeostasis
mechanism is disturbed and causing clinically important hypoglycemia.`1`
1
CHAPTER 2 LITERATURE REVIEW
2.1 Definition
Hypoglycemia is defined by blood glucose level below normal range. (ccording to some
resources, it is mar)ed plasma glucose level *+, mg-d..`/`,`0`
2.1 Epidemiology
'ome studies show that in type 2 diabetes, severe hypoglycemia appears to be much less
common. &ut when patients with type 2 diabetes receive insulin therapy, they may
become as susceptible to hypoglycemia as patients with type 1 diabetes. 'ome studies
reported the following incidence rates of severe hypoglycemia 1episodes per 1,, patient2
years34`3`
2 In patients with type 1 diabetes511.!
2 In patients with type 2 diabetes treated with insulin511.0
2 In patients with type 2 diabetes treated with oral hypoglycemic drugs5,.,!.
2.1 Py!iology of "l#$o!e Homeo!t%!i!
6any evidences showed that main physiological response to hypoglycemia is produced
by ventromedial hypothalamus 176H3 neurons.`1`,`3` "here is also evidence that carotid
bodies`+` and liver`3` plays their own role in sensing hypoglycemia. (ctivation of these
sensors initiates cascade of responses to raise blood glucose. "hese responses are
suppression of insulin release by pancreas, secretion of contra2regulatory hormones,
stimulation of autonomic nervous system, and generation of warning symptoms to warn
the individual.`1`,`2`,`3`,``,`!`,`+`
&#pp'e!ion of in!#lin 'ele%!e. "he insulin release is decreased as plasma glucose
level is decreased. In normal beta cell, the mean plasma glucose level threshold for
insulin suppression is around 01202 mg-d..`3`,``
2
Epinep'ine %nd gl#$%gon is released at glycemic threshold around +!2/,
mg-d..`3`,`` "he glucagon only wor)s in liver, where it increases glycogenolysis and
latter induces gluconeogenesis. 8pinephrine, other than increasing glycogenolysis and
gluconeogenesis in liver, is also causing lipolysis in fat cells and glycogenolysis and
proteolysis in muscle cells.`1` It could also increases gluconeogenesis in )idneys and
decreases glucose utili#ation in insulin2sensitive cells.`1`,`2` 9licerol, the result of
lipolysis, and amino acids are the substrates for gluconeogenesis in liver.`1` 8pinephrine
and glucagon appear to have same :uantitative effect on glucose production, and defect
in one hormone alone doesn%t impair glucose counterregulation,`3` but other resource
said that if the glucagon secretion is prevented after insulin2induced hypoglycemia, the
normali#ation of glucose level is decreased by ,;.`1`
Co'ti!ol %nd g'o(t f%$to'! are other counter2regulatory hormones that wor)
slower, and are less critical in the first +, minutes. "hey ta)e role in a longer lasting
hypoglycemia, by decreasing peripheral glucose use and increasing
gluconeogenesis.`1`,`3` <eficiency in these hormones could cause hypoglycemia, which
is usually mild.`1`
Ne#'ogeni$ 'e!pon!e %nd ne#'ogly$openi$ !ymptom! occur at lower glycemic
threshold, around !,2!! mg-d.. "he autonomic neurogenic responses include increased
heart rate, cardiac output and blood pressure.`+` It produces symptoms li)e tremor,
perspiration, palpitations, irritability, nervousness, headache, hunger, tachycardia, pallor,
and alerting the individual.`3` "he neuroglycopenic symptoms, the direct result of
glucose deprivation from brain neurons, are fatigue, a sensation of warmth 1despite
observable pallor and diaphoresis3, drop in body temperature, difficulty thin)ing and
spea)ing, and behavioral changes. (t slightly lower glucose levels, cognitive function is
impaired. =rolonged severe hypoglycemia can cause a sei#ure, coma, permanent brain
impairment, or even death.`2`,`3`,``,`+`
2.2 Hypogly$emi% in Type 2 Di%)ete!
Hypoglycemia cases in type 2 diabetes are much lower than in type 1 diabetes, even in
type 2 diabetes patients with aggressive insulin therapy.`2`,`3`,``,`!` In type 1 diabetes,
3
the counter2regulatory mechanism is disturbed. "he insulin is not suppressed, because it
is e$ogenous, glucagon secretion is impaired, maybe because of signaling defect, and
epinephrine releases become disturbed because the glycemic threshold is shifted to lower
plasma level.`3` In type 2 diabetes without insulin therapy, the mechanism is intact and
the glycemic threshold even shifted to higher plasma level. However, in type 2 diabetes
patients with aggressive insulin therapy, their glucagon secretions are also impaired and
glycemic threshold shifted to lower level.`2`,``,`!` "he rates of severe hypoglycemia in
type 2 diabetes is the same with type 1 diabetes matched for duration of insulin
therapy.`2`
Hypogly$emi%*%!!o$i%ted %#tonomi$ f%il#'e +HAA,-. H((> concept is that
recent antecedent hypoglycemia causes both defective glucose counter2regulation 1by
reducing the epinephrine response in the setting of an absent glucagon response3 and
hypoglycemia unawareness 1by reducing the autonomic response and thus the neurogenic
symptom response3. "he mediator and mechanism of H((> still have to be studied.`2`
"he hypoglycemia unawareness is a common problem in diabetic patients who
receive insulin therapy. (bout 2!; of patients that denies having hypoglycemia
unawareness failed to recogni#e hypoglycemia in a test. If this condition happened, the
ris) of severe hypoglycemia increases by +2/ times.`1`
2.. Ri!/ ,%$to'!
>actors that related with hypoglycemia 4
D'#g!. <rugs, mainly insulin secretagogues are associated with episodes of
hypoglycemia. 6etformin and thia#olidindiones also associated with hypoglycemia,
usually if they are consumed with other agents. (lpha2glucosidase inhibitors are not
associated with hypoglycemia.`3`
In!#lin. "he inappropriate insulin level is the main cause of hypoglycemia. "his
is because e$ogenous insulin cannot perfectly mimic physiological insulin secretion
pattern i.e. high level in high glucose plasma level and low in low glucose plasma level.
"he hypoglycemia is usually associated with mista)es of doctors, pharmacists, and
patients themselves, changes in lifestyle, increase of insulin bioavailability 1by e$ercise,

)idney failure, etc3 and increasing insulin sensitivity 1by weight loss, e$ercise, post
partum, menstrual cycle, etc3.`1`
Le!! $%')oyd'%te int%/e. Hypoglycemia is also associated with delayed or
forgotten meals, diets, anore$ia, vomiting, etc.
Ote'!. (lcohol and some drugs li)e salicylates, sulfonamides, non selective
beta2bloc)ers, and pentamidine are also associated with hypoglycemia.`1` ?ther factors
are children, old age, antecedent hypoglycemia, and critical illness such as sepsis, )idney,
liver, or cardiac failure.`3`
2.0 &ign %nd &ymptom!
"he symptoms and signs of hypoglycemia could be divided into autonomic and
neuroglycopenic symptoms.`1`,`3`,`/`,`0`
A#tonomi$ 'e!pon!e! include diaphoresis, tremor, perspiration, palpitations,
irritability, nervousness, headache, hunger, tachycardia, pallor, and increased heart rate
and systolic blood pressure.`1`,`3`,``,`/`,`0` In newly diagnosed patients, these
symptoms usually preceding neuroglycopenic symptoms, but in advanced stage these
signs and symptoms may be reduced or gone, due to H((>.`1`
Ne#'ogly$openi$ !ymptom! include confusion, sleepiness, uncoordinated speech
and movement, drop in body temperature, behavioral changes, blurred visions,
hallucinations, hemiparesis, convulsions, and coma.`1`,`3`,`/`,`0` =ermanent brain
damage is rare.``
2.0 Di%gno!i! %nd Cl%!!ifi$%tion
(ccording to =(=<I, diagnose of hypoglycemia in the conte$t of diabetes is made
if plasma glucose level is same or less than +3 mg;.`1` In the other resources, it is
defined by blood glucose level lower than +, mg-d..`/`,`0` "he most convincing method
of diagnosing hypoglycemia is by @hipple%s triad, that are symptoms compatible with
hypoglycemia, a low plasma or blood glucose concentration, and resolution of those
symptoms after the glucose concentration is raised to normal.`1`,``
!
(cute hypoglycemia could be clinically classified into three4 mild, medium, or
severe. It is mild if symptomatic, but can be treated by the patient him-herself and no
daily activity disturbance. 6edium is the same with mild, e$cept the patient has clear
daily activity disturbance. Hypoglycemia is severe is the patient cannot treat the
hypoglycemia him-herself, usually because of cognitive impairmet.`1`
2.1 T'e%tment
O'%l gl#$o!e. ?nce the diagnosis of hypoglycemia was made, 1,22, g oral glucose has to
be given.`1`,`/`,`0` It could be given in the form of gel, jelly, tablets, or 1!,22,, ml of
sweet non2diet drin)s.`1`
Int'%m#!$#l%' gl#$%gon. 1 mg of intramuscular glucagon could be given by
nonprofessional careta)er.`1` It is given in severe cases or failure of oral glucose.`/`,`0`
"he result could be seen in 1, minutes, the same with intravenous glucose. If the patient
is conscious, it have to be continued with 2, g of oral glucose and , g of carbohydrates.
9lucagon may not be effective in long starving or alcohol usage,`1`
Int'%2eno#! gl#$o!e. It could be given by 12.!22! g bolus or infusion.`1`,`0`
Infusion of !,; glucose is too to$ic to the tissue, /!21,, ml of 2,; glucose or 1!,22,,
ml of 1,; glucose is preferable.`1` Intravenous glucose is usually given in unconscious
patients.`/`
2!2!, mg ephedrine injection is also could be used.
+
CHAPTER . &U33AR4
Hypoglycemia is a major barrier in treatment of type 2 diabetes mellitus. "he ris)
factors are usage of hypoglycemic drugs, insulin, less carbohidrate inta)e, and others.
Aormal glucose homeostasis that prevents hypoglycemia in healthy individuals is
impaired in advanced diabetes cases, especially in those receiving insulin therapy. 'ome
signs and symptoms could be seen because of the autonomic response and
neurogycopenia, but they are often reduced or even gone, therefore causing
hypoglycemia unawareness and increase ris) of severe hypoglycemia.
"he diagnosis is made if blood glucose level below +, mg-d., or more
convincingly by @hipple%s triad. ?nce diagnosis is made, treatment should be started
immediately, either by oral glucose, intramuscular glucagon, intravenous glucose, or
sometimes ephedrine.
/
RE,ERENCE&
1. (ru @', &ambang ', Idrus (, 6arcellus 'B, 'iti '. &u)u (jar Ilmu =enya)it <alam.

th
ed Ca)arta4 =usat =enerbitan Ilmu =enya)it <alam >a)ultas Bedo)teran Dniersitas
IndonesiaE 2,,+. p.10/,23.
2. =hillip 8F. Hypoglycemia2associated autonomic failure in diabetes. (m C =hysiol
8ndocrinol 6etab. 2,,1E 2014111!221.
3. Ilan 9, Harry '. Hypoglycemia in diabetes 4 common, often unrecogni#ed. Fleve Flin
C 6ed. 2,,E/11343!22.
. =hillip 8F, 'tephen A<, Harry '. Hypoglycemia in diabetes. <iabetes Fare.
2,,3E2+1+341G,2212.
!. Aicola AH, &rian 6>. Hypoglycemia in type 2 diabetes. <iabetes Fare.
2,,!E20112342G02+1.
+. 6ar) @C'. =hysiological responses to hypoglycaemia I not all Jjust in the head%. C
=hysiol. 2,,/E!021234/!2+.
/. =er)umpulan 8ndo)rinologi Indonesia. Bonsensus =engelolaan dan =encegahan
<iabetes 6ellitus "ipe 2 di Indonesia 2,,+. =er)umpulan 8ndo)rinologi IndonesiaE
2,,+. p. 2/20.
0. I6 &a)ta, IB 'wasti)a. 9awat <arurat di &idang =enya)it <alam. 1
st
ed Ca)arta4
=enerbit &u)u Bedo)teran 89FE 1GGG. p.11,23,.
0