METABOLIC CHANGES IN

DIABETES MELLITUS
AND

DIABETIC PREGNANT
WOMAN
DEPARTMENT OF BIOCHEMISTRY

SITI ANNISA DEVI TRUSDA

Humans are able to use a variable

fuel input to meet a variable

metabolic demand

REGULATION OF BLOOD GLUCOSE LEVEL

Disposition of glucose, amino acids, and

fat
by various tissues in the well-fed state

METABOLIC CHANGES IN TYPE-1 DM ( IDDM )

Changes in Carbohydrates
Metabolism
while insulin has 6 roles in carbohydrate
metabolism
1. Increase glucose transport by stimulating
glucose transporter
2. Increase glycolysis pathway
3. Decrease glycogenolysis pathway
4. Increase glycogenesis pathway
5. Decrease gluconeogenesis pathway
6. Increase TCC activity
10

Defect of cells of pancreas absolutely lack of insulin level,

1. Decrease of glucose transports into the cells that

caused by low activity of glucose transporter

11

b). Decrease of glycolysis pathways

activity, that caused by low activity of
three kinds of glycolytic enzymes :
- Glucokinase /Hexokinase
- Phosphofructokinase
- Pyruvate kinase

12

Glucose
Glucokinase /
hexokinase

Glucose-6 P

Fructose-6 P
Phospho fructo
kinase

Insulin

Fructose-1,6 bi P
2 Triose-P

+
2-Phosphoenol pyruvate ( PEP )
Pyruvate kinase
2-Pyruvate
Note : Glycolysis is oxidation of glucose to form pyruvate or lactate
13

c). Increase of glycogenolysis

pathways activity in the liver, that
caused by high activity of
phosphorylase enzymes in the liver

14

Glycogen

Phosphorylase

Glucose-1 P

Insulin

Glucose-6 P
Glucose-6 P-ase

Glucose

15

Glucagon

Insulin

Adenylate
cyclase
ATP

Phospho diesterase
cAMP

5 AMP

+
Glycogenolysis

Note : Glycogenolysis is glycogen breakdown to form glucose

16

d). Decrease of glycogenesis

pathways activity, that caused by
low activity of glycogen synthase
enzymes

17

Glucose
Glucose-6 P
Glucose-1 P
UTP
Insulin
Uridine diphosphate
glucose ( UDPG )
Glycogen
Primer

+
Glycogen
synthase
Glycogen

Note : Glycogenesis is synthesis of glycogen from glucose

18

e). Increase of gluconeogenesis pathways

activity, that caused by high activity of four
kinds of gluconeoneogenetic enzymes :
- Glucose-6 phosphatase
- Fructose-1,6 biphosphatase
- PEP carboxykinase
- Pyruvate carboxylase
Note : Gluconeogenesis is glucose synthesis
from non carbohydrate substrates (lactic
acids, glucogenic amino acids, glycerols
and propionic acids).
19

Glycogen
Glucose

Hexokinase
glucokinase

Glucose-6 P

Glucose-6
phosphatase

Insulin

Phospho
fructokinase

Fructose-6 P

Fructose-1,6
biphosphatase
Fructose-1,6 bi P

Insulin

Insulin

PEP
Pyruvate
kinase

PEP carboxykinase
Oxalo acetate

Pyruvate

Pyruvate
Pyruvate
carboxylase
Oxalo aqcetate
Malate

Malate

TCC

Mitochondrial matrix
20

f). Decrease of TCC activity, may be

caused by decrease of citrate
synthase enzyme activity, or lack of
oxaloacetate

21

Glucose

Lipids
Protein
FFA

Pyruvate
Insulin

Amino acids

+
Acetyl Co A

Citrate
synthase

Oxalo acetate

Malate

citrate

T.C.C

Fumarate
Succianate

Iso citrate

Keto glutarate

22

Decrease of citrate synthase

enzymes activity or lack of
oxaloacetate cause acetyl CoA can
not be oxidized in TCC (decrease of
TCC activity ) in Diabetes Mellitus.
Note :
TCC ( Tricarboxylic acid cycle ) is
oxidation of acetyl CoA to form
CO2, H2O and energy ATP.
23

Change in Lipid
Metabolism
24

Lipid metabolic changes, causing keto acidosis,

hypertriglyceridemias and hypercholesterolemias
* Energy production failure from carbohydrates
(glucoses)
metabolism cause increase of lipolysis from
adipose tissues
Insulin

Hormon sensitive lipase

* Triglycerides
fatty acids

Free

25

Glycerols

Increase of hormon sensitive

lipase enzymes activity in DM type
1, cause increase of lipolysis from
adipose tissues and high blood
level of free fatty acids and would
be taken by the tissues to be
oxidized ( oxidation).

26

FFA
oxidation
Acetyl CoA
TCC
Hydroxy Methyl Glutaryl CoA
( HMG CoA )
HMG CoA
reductase

Cholesterol
(Hypercholesterolemia)

HMG CoA lyase

Keton bodies
(Keto acidosis)

Extra-hepatic tissues
Acetyl CoA
TCC
27

28

FFA (Blood)
Liver
VLDL
Intestine
Chylomicron (TG)

VLDL (TG)

Extra hepatic tissues

Insulin

Lipoprotein lipase

Glycerol
Decrease of lipoprotein lipase enzymes
activity cause hypertriglyceridemia

FFA

29

3. Amino acids metabolic change

Amino acids (glucogenic a.a) from
diet (intestine) and from proteolysis
of protein in the muscle, enter
gluconeogenesis pathways in the
liver to maintain blood glucose
concentration.

30

II. METABOLIC CHANGES IN TYPE-2 DM ( NIDDM )

31

CARBOHYDRATE METABOLIC CHANGES

Insulin level may be normal or slight
increase, but there is insulin resistance.
The insulin receptors can not
fully
respond to insulin, so glucose transporters
become inactive. Glucoses can not enter
into the cells of the tissues especially
muscle tissues and cause hyperglycemia.
Insulin resistance is induced by tumor
necrosis factor (TNF) and a protein called
resistin that produced by adipose tissues.

32

Lipid Metabolic Changes

Lipoprotein lipase enzymes that stimulated
by insulin, also inactive, so TAG content of
VLDL and chylomicrons can not split into
free fatty acid (FFA) and glycerols and cause
hypertriglyceridemia.
Increase of VLDL production in the liver
is
induced
by
hyperglycemia and
hyperinsulinemia.
Ketoacidosis rarely develop, because the
cells of adipose tissues still sensitive to the
insulin effect on lipolysis (insulin inhibits
lipolysis pathways in adipose tissues).
33

Glucagon
epinephrin etc

Insulin

Adenylate cyclase
ATP

Phosphodiesterase
cAMP

5 AMP

+
Lipolysis

34

III. DIABETES MELLITUS AND PREGNANCY

1. Metabolic Changes in Normal Pregnant Woman

35

Pathophysiology
Normal pregnancy is

characterized by:
Mild fasting hypoglycemia
Postprandial

hyperglycemia
Hyperinsulinemia
Due to peripheral insulin

resistance which
ensures an adequate
supply of glucose for the
baby.

Pathophysiology
Human Placental Lactogen (HPL)
Produced by syncytiotrophoblasts of

placenta.
Acts to promote lipolysis increased FFA
and to decrease maternal glucose uptake
and gluconeogenesis. Anti-insulin
Estrogen and Progesterone
Interfere with insulin-glucose relationship.

Insulinase
Placental product that may play a minor

role.

Two reasons that cause metabolic changes in

pregnant woman
a) Changes of hormonal level in pregnancy
especially estrogen and progesteron that
stimulate insulin resistance
b) Fetal needs for energy and
synthesis especially from glucose, and
amino acids that cause maternal
hypoglycemia, also lactate, free fatty acids
and keton bodies

38

Maternal

LDL-cholesterol is
precursor for placental steroids
synthesis (estrogen and progesteron)

Placenta also produce placental

lactogen hormon (peptide) that

stimulates lipolysis in adipose tissues

After feeding, pregnant woman

falls to fasting state rapidly caused

by increase of glucose and amino
acid consumption by the fetus
39

 Blood glucose, amino acids & insulin

level falls rapidly, and on the other
hand glucagon and placental
lactogen increase that cause
increase of lipolysis and ketogenesis
pathways
Changes of steroid hormons and
fuels cause very difficult to control
blood glucose in diabetic pregnant
woman
40

Gestational Diabetes Mellitus

A normal woman before pregnant, can
develop Diabetes mellitus when she is
pregnant, its called gestational DM
Usually she has a diabetic gene that
inherited from her parents
Exessive feeding in pregnancy cause
excessive increase of body weight and
increase of tumor necrosis factor (TNF ),
and a protein called resistin
TNF , resistin, estrogen and progesteron,
induce insulin resistance to develop
Diabetes mellitus in pregnant woman
41
(gestational DM)

 Gestational DM are generally

reversible after pregnancy,
approximately 30 50% of woman
with a history of GDM go on to
develop type-2 DM later in life,
particularly if they are obese.
Although the cellular
mechanisms responsible for the
insulin resistance in GDM are not
fully understood.
42

Diabetes Mellitus that Super Imposed

with Pregnancy
Diabetic pregnant woman, cause
very difficult to control blood
glucose concentration
High level of estrogen and
progesteron will increase insulin
resistance and cause more severe
DM in diabetic pregnant woman
Maternal hyperglycemia, cause
hyperglycemia in the fetus that
transferred via fetal cord

43

Fetal hyperglycemia fetal

hyperinsulinemia synthesis of
triglyceride in adipose tissues
of the fetus and the fetus
become bigger
Insulin like growth factors (IGF)
also increase in the fetus so the
fetus not only bigger, but also
longer. If the fetus weight more
than 4,00 kg, it is called giant
baby
44

 When the giant baby is born,

fetal cord is cut, fetal blood
glucose level decrease rapidly,
causing babys hypoglycemia,
because there is no longer glucose
supply from maternal blood, but
hyperinsulinemia still occur in the
baby
Glucose infuse or lactation must be
given as soon as possible to
increase babys blood glucose
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A Vicious Cycle???

REFERENCE
1. Devlin, T.M. : Textbook of Biochemistry with Clinical
Correlatitions. 6th edition., 2006,
A Wiley

page

875 - 881,

920.

Medical Publication.
2. Harper, H.A. : Illustrated Biochemistry. 27th edition,
2006, page
112 - 230. A Lange Medical Book
3. Lehninger, A.L. : Principles of Biochemistry. 2nd
edition, 1993,
page 400 - 642. Worth Publisher.
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Alhamdulill
ah
THANK YOU

49

QUIZ
Sebutkan enam (6) cara insulin

menurunkan glukosa darah !

Mengapa pada DM tipe 2 jarang
terjadi ketoasidosis?
Apa perbedaan hormon sensitivelipase dengan lipoprotein lipase?
Apa yang menyebabkan resistensi
insulin pada ibu hamil?
Apa yang menyebabkan terjadinya
Giant Baby?