METABOLIC CHANGES

IN DIABETES MELLITUS
&
DIABETIC PREGNANT WOMAN

DEPARTMENT OF BIOCHEMISTRY
Siti Annisa Devi Trusda

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Humans are able to use a variable fuel input to meet a
variable metabolic demand

Variable fuel input

storage fuels
O2
ADP + Pi Variable
metab
demand
ATP

CO 2 + H 2 O + urea

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Disposition of glucose, amino acids, and fat
by various tissues in the well-fed state

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I. METABOLIC CHANGES IN TYPE-1 DM ( IDDM )

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1. Carbohydrates metabolic changes, that cause hyperglycemia
Defect of cells of pancreas, cause absolutely lack of insulin

level
a). Decrease of glucose transports into the cells that caused

Glucose
by low activity of glucose transporter

Insulin
Insulin
receptor Glucose transporters

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b). Decrease of glycolysis pathways activity, that caused by
low activity of three kinds of glycolytic enzymes :

- glucokinase /Hexokinase
- Phosphofructokinase
- Pyruvate kinase

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Glucose
Glucokinase /
hexokinase

Glucose-6 P
+
Fructose-6 P
+
Phospho fructo Insulin
kinase

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 8

c). Increase of glycogenolysis pathways activity in the
liver, that caused by high activity of phosphorylase
enzymes in the liver

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Glycogen
-
Phosphorylase

Glucose-1 P Insulin

Glucose-6 P

Glucose-6 P-ase
-
Glucose

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 Glucagon Insulin

+ +

Adenylate Phospho di-

cyclase esterase
ATP cAMP 5 AMP

Glycogenolysis

Note : Glycogenolysis is glycogen breakdown to form glucose

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d). Decrease of glycogenesis pathways activity, that
caused by low activity of glycogen synthase enzymes

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 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

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 e). Increase of gluconeogenesis pathways activity, that
caused by high activity of four kinds of gluconeo-
neogenetic enzymes :
- Glucose-6 phosphatase
- Fructose-1,6 biphosphatase
- PEP carboxykinase
- Pyruvate carboxylase

Note : Gluconeogenesis is glucose synthesis from non carbo-

hydrate substrates ( lactic acids, glucogenic amino
acids, glycerols and propionic acids ).

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 Glycogen

Glucose
Hexokinase Glucose-6
+ glucokinase phosphatase
Glucose-6 P
Insulin

+ Phospho
Fructose-6 P
Fructose-1,6
fructokinase biphosphatase
Fructose-1,6 bi P

Insulin Insulin

PEP
+
PEP car- Pyruvate
boxykinase kinase

Oxalo acetate Pyruvate

Pyruvate
Pyruvate
carboxylase
Oxalo aqcetate

Malate Malate TCC 15

 f). Decrease of TCC activity, may be caused by decrease
of citrate synthase enzyme activity, or lack of
oxaloacetate

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 Glucose
Lipids
Protein

Pyruvate FFA Amino acids

Insulin
+
Citrate Acetyl Co A
synthase

Oxalo acetate citrate

Malate T.C.C Iso citrate

Fumarate
Keto glutarate
Succianate

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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.

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2. Lipids metabolic changes, that cause keto acidosis, hyper-
triglyceridemias and hypercholesterolemias
* Energy production failure from carbohydrates ( glucoses )

metabolism cause increase of lipolysis from adipose tissues

Insulin

Hormon sensitive lipase

* Triglycerides Free fatty acids

Glycerols 19
Increase of hormon sensitive lipase enzymes activity in
IDDM, 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 ).

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

Cholesterol Keton bodies

(Hypercholesterolemia) (Keto acidosis)

Extra-hepatic tissues

Acetyl CoA

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TCC
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 FFA (Blood)
Liver

VLDL
Intestine

Chylomicron (TG)
VLDL (TG)

Extra hepatic tissues

+
Insulin Lipoprotein lipase

Glycerol FFA

Decrease of lipoprotein lipase enzymes

activity cause hypertriglyceridemia 23
3. Amino acids metabolic change
Amino acids ( glucogenic a.a. ) from diet ( intestine ) and
from proteolysis of protein in the muscle, enter gluconeo-
genesis pathways in the liver to maintain blood glucose
concentration.

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

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 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 new protein called resistin that produced by adipose
tissues.

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 Lipid Metabolic Changes

* Lipoprotein lipase enzymes that stimulated by insulin, also in

active, 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 ).

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 Glucagon Insulin
epinephrin etc

+ +

Adenylate cyclase Phosphodiesterase

ATP cAMP 5 AMP
+

Lipolysis

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III. DIABETES MELLITUS AND PREGNANCY

1. Metabolic Changes in Normal Pregnant Woman

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 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
* 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
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* 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

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2. 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 new protein called resistin
* TNF , resistin, estrogen and progesteron, induce insulin
resistance to develop Diabetes mellitus in pregnant woman
(gestational DM)

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* 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.

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3. 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
* Fetal hyperglycemia, stimulate fetal hyperinsulinemia that
stimulate 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
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* When the giant baby is born, fetal cord is cutted, fetal
blood glucose level decrease rapidly, cause babys
hypoglycemia, because there is no 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 Correlati-

tions. 6th edition., 2006, page 875 - 881, 920. A Wiley
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 41
 QUIZ
Enzim-enzim apa saja dalam jalur glikolisis
yang dipengaruhi oleh insulin?(3)
Enzim-enzim apa saja dalam jalur
glukoneogenesis yang dipengaruhi oleh insulin?
(4)
Apa perbedaan hormon sensitive-lipase dengan
lipoprotein lipase?
Apa yang menyebabkan resistensi insulin pada
ibu hamil?
Apa yang menyebabkan terjadinya Giant Baby?