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METABOLISM of

CARBOHYDRATE
2013

LOO HIAN DAO


DEPARTEMEN of BIOCHEMISTRY
UNIVERSITY of WIJAYA KUSUMA
SURABAYA
Glycolysis
Glycolysis, the major pathway
for glucose metabolism, occurs
in the cytosol of all cells, it can
function either aerobically or
anaerobically.
Enolase is inhibited by
fluoride. To prevent glycolysis
in the estimation of glucose,
blood is collected in tubes
containing fluoride.
Tissues That Function Under
Hypoxic Circumstances Tend to
Produce Lactate:
* skeletal muscle
(whitefiber)
* erythrocytes (lack
mitochondria).
Glycolysis Is Regulated at
Three Steps: hexokinase (and
glucokinase),
phosphofructokinase, and
pyruvate kinase.
HEXOKINASE AND GLUCOKINASE
• Hexokinase has a high affinity (low Km ) for glucose, and in the
liver it is saturated under normal conditions, and so acts at a
constant rate to provide glucose 6-phosphate to meet the cell's
need.
• Liver cells also contain an isoenzyme of hexokinase,
glucokinase, which has a K m very much higher than the
normal intracellular concentration of glucose.
• The function of glucokinase in the liver is to remove glucose
from the blood following a meal, providing glucose 6-phosphate
in excess of requirements for glycolysis, which is used for
glycogen synthesis and lipogenesis.
2,3 Bisphosphoglycerate pathway

This alternative pathway


involves no net yield of ATP from
glycolysis. However, it does
serve to provide 2,3 bisphospho
glycerate, which binds to
hemoglobin, decreasing its
affinity for oxygen and so
making oxygen more readily
available to tissues.
NADH = 2,5 ATP
FADH2= 1,5 ATP

2 2 28
Covalent modification

Feedback regulation
5

7
5
5
5

3
5
25
32
ASIDOSIS LAKTAT
• Penimbunan asam laktat didalam darah sampai kadar yg secara bermakna mempengaruhi pH,
terjadi akibat pembentukan laktat yg berlebihan.
• Kadar laktat > 5 mM & pH darah <7,2.
• Penyebab :
a. Gangguan oksidasi piruvat yg dikatalisa oleh piruvat dehidrogenase
& gangguan pada siklus TCA, biasanya berhubungan dengan
ketidakmampuan melakukan reoksidasi NADH dalam rantai respirasi
dengan kecepatan yg adekuat.
b. Pembentukan NADH yg berlebihan, misalnya intoksikasi etanol.
c. Defisiensi piruvat karboksilase.
d. Defisiensi tiamin yg parah misalnya pada peminum alkohol.
e. Intoleransi fruktosa herediter yg menimbulkan inhibisi penggunaan laktat
untuk glukoneogenesis.
f. Defisiensi glukosa 6-fosfatase yg menimbulkan peningkatan glikolisis.
g. Ion arsen/merkuri yg berikatan dengan gugus- SH dari asam lipoat sehingga
menghambat kerja piruvat dehidrogenase.
h. Defek genetik pada salah satu komponen dari kompleks piruvat
dehidrogenase.
i. Fisiologis : Akibat glikolisis anaerob yg meningkat selama olah raga.
METABOLISM OF GLYCOGEN
 “Glycogen
storage
disease” is a
generic term
to describe a
group of
inherited
disorders
characterized
by deposition
of an
abnormal
type or
quantity of
glycogen in
the tissues.
PENTOSA PHOSPHAT PATHWAY
HMP
SHUNT vs GLIKOLISIS

AKSEPTOR
NADP+ ELEKTRON NAD+

CO2
(+) (-)

ATP
(-) (+)

RIBOSA
(+) FOSFAT (-)
• 3 molecules of glucose
6-phosphate →3 CO2 +
3 molecules C5 sugars.
• 3 molecules C5 sugars
→ 2 molecules glucose
6-phosphate + 1
molecule glycolytic
intermediate,
glyceraldehyde 3-
phosphate.
• FASE OXIDATIVE NON-
REVERSIBLE :
GLUKOSA 6-
P→RIBULOSA 5-P
MELIBATKAN
DEHIDROGENASE &
DEKARBOKSILASE→NA
DPH
• FASE NON-OXIDATIVE
REVERSIBLE :
RIBULOSA 5-
P→GLUKOSA 6-P
MELIBATKAN 2 GROUP
ENZIM :
TRANSKETOLASE &
TRANSADOLASE→RIBO
SA
Genetic deficiency of glucose 6-phosphate dehydrogenase,the first enzyme of the pentose
phosphate pathway, is a major cause of hemolysis of red blood cells, resulting in hemolytic
anemia.
(*Not found in liver) • Fructose undergoes more
rapid glycolysis, because it
bypasses the regulatory
step catalyzed by
phosphofructokinase.
• Fructokinase activity is not
affected by fasting or by
insulin.

METABOLISME FRUKTOSA
Aldolase A is found in all tissues,
whereas aldolase B is the predominant
form in liver.
• In contrast, under hyperglycemic
(*Not found in liver) conditions, hexokinase is
saturated, and there is increased
flux of glucose into the polyol
pathway. Aldose reductase,
which catalyzes the reduction of
glucose to sorbitol, is the rate-
limiting enzyme in this pathway.
• Sorbitol is subsequently reduced
by sorbitol dehydrogenase to
fructose. Sorbitol is degraded
slowly and does not readily
diffuse across the cell
membrane. The intracellular
accumulation of sorbitol results
in osmotic changes that
potentially lead to cell damage,
may lead to compensatory
depletion of the endoneurial
osmolytes taurine and myo-
METABOLISME FRUKTOSA inositol in order to maintain
Aldolase A is found in all tissues, whereas osmotic balance.
aldolase B is the predominant form in liver.
FRUKTOSA LOADING

 Pembebanan hepar dengan fruktosa seperti pada diit tinggi


fruktosa atau pemberian infus fruktosa akan meningkatkan
sintesa TG serta sekresi VLDL. Hal ini menimbulkan
Hipertrigliseridemia yg juga menyebabkan kenaikan kadar
LDL-kolesterol yg dianggap potensial utk menimbulkan
aterosklerosis.
 Fruktosa loading juga menimbulkan sekuestrasi fosfat
anorganik dalam senyawa fruktosa 1-fosfat & mengurangi
sintesa ATP. Hal ini mengakibatkan inhibisi sintesa purin oleh
ATP dihilangkan & sintesa asam urat dipercepat sehingga
timbul hiperurisemia yg menimbulkan penyakit gout.
GALACTOSEMIA
NON KLASIK
• In liver, the uronic acid
pathway catalyzes the
conversion of glucose to
glucuronic acid, ascorbic
acid, and pentoses.
• In humans and other
primates as well as guinea
pigs, ascorbic acid cannot
be synthesized because of
the absence of L-
gulonolactone oxidase.
URONIC ACID PATHWAYS
Hexosamine pathway
 A relatively minor branch of
glycolysis.
 Fructose 6-phosphate is
converted to glucosamine
6-phosphate, catalyzed by
the first and rate-limiting
enzyme glutamine:fructose-
6-phosphate
amidotransferase (GFAT).
 The major end product is
UDP-N-acetylglucosamine
(UDP-GlcNAc).
Hexosamine pathway
 Subsequent steps
metabolize glucosamine 6-
phosphate to UDP-N-
acetylglucosamine (UDP-
GlcNAc), UDP-N-
acetylgalactosamine (UDP-
GalNAc), and CMP-syalic acid,
essential building blocks of the
glycosyl side chains of
glycoproteins, glycolipids,
proteoglycans, and gangliosides.
A simplified schematic representation of the hexosamine biosynthetic
pathway.

©2006
Buse MbyGAmerican Physiological
Am J Physiol Society Metab 2006;290:E1-E8
Endocrinol
DIIT GLYCOGENOLYSIS

- +
BLOOD
GLUCOSE
LEVEL GLUCAGON
CATECHOLAMINES
- GH
CORTISOL

GLUCONEOGENESIS +
FASTING
HIGH CARBOHYDRATE
DIIT BLOOD GLUCOSE
GLUCOSE LEVEL INCREASE
LEVEL
(80-100 mg/dl) 30 MINUTE – 1 HOUR (120-140 mg/dl)

2 HOUR POST PRANDIAL


TISSUE UTILITATION
INTAKE ENDOGENOUS PRODUCTION GLYCOLYSIS
GLUCOSE ABSORPTION GLYCOGENOLYSIS PENTOSE PHOSPHATE PATHWAY
FROM THE GUT GLUCONEOGENESIS TCA CYCLE
GLYCOGEN SYNTHESIS

PLASMA
GLUCOSE
CONCENTRATION
Diagnosis of diabetes mellitus & glucose intolerance
condition Diagnostic criteria (mg/dl) comments
Normal fasting plasma glucose < 110

Impaired fasting glucose (IFG) Equal or >110 but <126

Impaired glucose tolerance Plasma glucose 2h after 75 g load Diagnosed during


(IGT) ≥140,but <200 OGTT

Diabetes mellitus *
Criterion 1 Random plasma glucose ≥ 200 ** Using a method that is
NGSP certified and
Criterion 2 Fasting plasma glucose ≥126
standardized to the
Criterion 3 2 h value during OGTT ≥ 200 DCCT assay (A1C)
Criterion 4 A1C 6,5%
* If one of the criteria is fulfilled, diagnosis is provisional.
** if accompanied by symptoms (polyuria, polydypsia, unexplained weight loss .
CLASSIFICATION of DIABETES
SYNDROME COMMENTS

Type 1 Autoimmune destruction of ß -cells

Type 2 ß-cell failure and insulin resistance

Other types Genetic defects of ß-cells (e.g.mutation of glucokinase gene).Rare of


insulin resistance syndromes. Disease of exocrine pancreas. Endocrine
disease (acromegaly, Cushing’s syndrome). Drugs and chemical-induced
diabetes. Infections (e.g. mumps). Rare syndromes with the presence of
antireceptor antibodies.
Diabetes accompanying other genetics diseases (e.g. Down syndrome)

Gestational diabetes Any degree of glucose intolerance diagnosed in pregnancy.


COMPARISON of TYPE 1 and TYPE 2 DIABETES MELLITUS
TYPE 1 TYPE 2
ONSET USUALLY <20 YEARS of AGE USUALLY >40 YEARS of AGE

INSULIN SYNTHESIS Absent, immune destruction of ß- Preserved,combination of impaired


cells ß -cell function & insulin

PLASMA INSULIN Low or absent Low,normal or high


CONCENTRATION
GENETIC Yes,inheritance associated with Not associated with HLA,
SUSCEPTIBILITY HLA antigens important polygenic inheritance

ISLET CELL ANTIBODIES yes no


at DIAGNOSIS

OBESITY uncommon common

KETOACIDOSIS yes Possible after major stress


Hyperglycemia-induced production of superoxide by
the mitochondrial electron transport chain.

Hyper glycemia
blocked

Brownlee M Diabetes 2005;54:1615-1625


ROS-induced DNA damage activates PARP and modifies
GAPDH.

NA= Nicotinic acid, ADPR= ADP- Ribose


Brownlee M Diabetes 2005;54:1615-1625
The unifying mechanism of hyperglycemia-induced
cellular damage.

PARP inhibitors

Copyright ©M2011
Brownlee American
Diabetes Diabetes Association, Inc.
2005;54:1615-1625
results in the depletion of NADPH, a decrease in
cellular reduced glutathione levels, and increased
oxidative stress. Sorbitol↑→osmotic stress ↑→
cataract diabetic

alter gene expression and protein function led to


insulin resistance and increase NFB

transketolase activators
(benfotiamine)

glycolytic intermediates to pentose


phosphates pathway

GAPDH, glyceraldehyde-3-phosphate dehydrogenase


 Advanced glycation end products (AGEs) are heterogeneous group of non-enzymatic
malliard reaction products of aldose sugar with proteins and lipids.
 In diabetic patients, AGE formation occurs in large scale and manifests with clinical
symptoms such as cataract, atherosclerosis, nephropathy and neuropathy.
McCants Pathophysiology 4th ed.
excessive

Somogyi Effect
 Rebound hyperglycemia
 Counterregulatory hormones activate
gluconeogenesis and glycogenolysis
 Hormones supress insulin 12-48 hours
 Also influenced by excessive carb intake
Dawn Effect
 Dawn effect is defined as an increase in the blood sugar in the morning
and is typically invoked in the context of diabetes. It is different from
Chronic Somogyi rebound in that dawn effect is not associated with
nocturnal hypoglycemia.
 It is possible that dawn effect is caused by the release of counterregulatory
hormones such as cortisol, glucagon, epinephrine, all of which can signal
the liver to release glucose. In most of the cases, there is no need to change
insulin dosing of patients who encounter dawn effect.
 The dawn phenomenon is more common than the Somogyi effect.
 To diagnose these phenomena, it is useful to measure plasma glucose levels
for several nights between 3 a.m. and 5 a.m. or use a continuous glucose
monitoring system.
Dawn Effect vs Somogyi Effect

(Continuous Glucose Monitors)