CHO METABOLISM
BY Dr. Naglaa Ibrahim Azab
Assistant professor of medical
biochemistry
What is glucose homeostasis???
It is the maintenance of blood
glucose level within the normal
range
Normal blood glucose level (mg/dl)
Fasting
(6-12 h after meals)
70-110(126)
1 h after CHO meals
130-150
2 h after CHO meals
70-110(126)
Starvation
(prolonged fasting)
60-70
Importance of glucose homeostasis
Maintain a continuous supply of sufficient
blood glucose to the
brain and CNS
Sudden hypoglycemia (< 40 mg/dl)
lead to????
Coma and even death
Glycogenolysis
(Liver glycogen)
Source
during
early fasting
(12- 18 hrs)
Diet
by digestion
and absorption
mostly
Gluconeogenesis
(mainly from amino
acids)
Main source
during
prolonged
starvation
(> 18 hrs)
Blood glucose
Uptake by
Tissues
as muscles,
adipose tissue &
brain
Oxidation glycogenesis lipogenesis
How to maintain the balance between
addition and removal of glucose???
(What are the factors important for
maintaining glucose homeostasis
What are the factors that regulate blood
glucose level????
tissues
hormones
Tissues regulating blood glucose level
GIT
Liver
Muscles and
adipose
tissues
Kidney
GIT
Maximum rate of glucose absorption is 1 gm
glucose/Kg body weight / hour → prevents sudden
hyperglycemia after meal.
Glucose
\
/
↑ enterogastrone
hormone from duodenum
\
- - - gastric evacuation
\
↑intestinal factors
\
stimulate insulin secretion
from pancreas
Fasting
Liver
(Blood glucostat)
After CHO diet
Uptake
Glycogenolysis
Glucose
Gluconeogenesis
Oxidation
Glycogenesis
LIPOGENESIS
Blood
glucose
Blood
glucose
Fasting
Muscle &Adipose
tissue
After CHO diet
Gluconeogenesis
Muscle: Release
alanine to liver
Adipose tissue:by
lipolysis release
glycerol and f.as
Blood
glucose
\
Uptake
Glucose
Oxidation
Glycogenesis
in muscle
Lipogenesis
In adipose
tissue
Blood
glucose
Kidneys
Renal threshold for
glucose is 180 mg/dl
Hormones
Glycogenolysis
\
Glucose
Oxidation
Glycogenesis
Gluconeogenesis
\
LIPOGENESIS
Lipolysis
Blood
glucose
\
Insulin
Uptake (except
brain,
liver,RBCs- non
dependant)
Glucagon and adrenaline
Uptake
Glycogenolysis
Glucose
Oxidation
Glycogenesis
\
Gluconeogenesis
\
LIPOGENESIS
Lipolysis
Blood
glucose
\
Clucocorticoids and G.H.
Gluconeogenesis
\
Uptake
\
Glucose
\
Oxidation
a.as
( glucocorticoids)
\
Lipolysis ( G.H)
Blood
glucose
\
Thyroid hormones
Uptake
Absorption
Glycogenolysis
Glucose
Oxidation
Glycogenesis
Gluconeogenesis
LIPOGENESIS
Blood
glucose
\
\
Presence of detectable amounts
of glucose in urine (> 0.5 g/day,
normally < 150 mg/day).
Causes:
1)
2)
-
I. Hyperglycemic glucosuria:
Diabetes mellitus glucosuria
Adrenaline glucosuria
Pheochromocytoma.
Emotions.
Stress (oral examination).
Hypotension
Injection
3)
Alimentary glucosuria: It is due to intake
of large amounts of glucose after prolonged
carbohydrate deprivation.
Causes:
II. Renal glucosuria (plasma glucose < 180 mg/dl):
1)
Congenital glucosuria : = renal diabetes =
Diabetes innocence = benign glucosuria.
2)
Pregnancy glucosuria : Occurs in about
20% of normal pregnancies.
3)
Nephritis & Nephrosis : Only some cases
show glucosuria.
4)
Phlorrhizin Glucosuria : Phlorrhizin inhibits
renal tubular reabsorption of glucose.
DM
hyperglycemia
\
syndrome
glucosuria
\
polyuria
\
\
polydepsia
\
polyphagia
Loss of weight
Causes
↓insulin level
or insulin
resistance
↑anti-insulin
hormones
(glucagon, adrenalin )
Types
Type I:
Insulin dependent DM
=IDDM
= Juvenile diabetes.
Type II:
Non Insulin dependent DM
=NIDDM
= Maturity onset DM
Metabolic changes in DM
1-Disturbed Carbohydrates metabolism:
hyperglycemia due to
Decreased glucose uptake and utilization by
tissues.
Decreased glycogenesis &lipogenesis.
Increased glycogenolysis &gluconeogenesis.
2-Disturbed lipid metabolism:
hyperlipidemia and hypercholesterolemia due to
Increased lipolysis and plasma FFA
Increased ketogenesis: which may cause
ketoacidosis
Metabolic changes in DM
3-Disturbed protein metabolism:
Negative nitrogen balance ,wasting ,weakness of muscle
and delayed healing of wounds due to
Decreased protein anabolism.
Increased protein catabolism.
4-Disturbed water and electrolyte balance:
- Glucosuria → osmotic dieresis → polyuria → dehydration
→ polydepsia
- Increased loss of Na+ & K + in urine.
• Points of
differences
• Insulin-dependent
diabetes mellitus (IDDM)
• Type I; juvenile-onset
• diabetes
• Usually during childhood
or puberty
• Other name
• Age of onset
• Nutritional status • Frequently undernourished
at time of onset of
the disease
• Prevalence
• Genetic
predisposition
• Defect or deficiency
• Ketosis
• Plasma insulin
• Acute
complications
• Oral hypoglycemic
drugs
• Treatment
insulin
with
• 10-20% of diagnosed
diabetics
• Moderate
• b-cells destroyed,
eliminating production of
insulin
• Non-insulin-dependent
diabetes mellitus (NIDDM)
• Type II; adult-onset diabetes
• Frequently after age 35
Obesity usually present •
• 80-90% of diagnosed diabetics
• Very strong
• Inability of b–cells to produce
appropriate quantities of insulin,
insulin resistance
• Common
• Low or absent
• Ketoacidosis
• Rare
• Normal or high
• Hyperglycemia
• Unresponsive
• Responsive
• Always necessary
• Usually not required
Complications of DM
1-Macrovascular complications of DM:
(atherosclerosis, hypertension, myocardial infarction and
renal failure).
• Most of these complications are due to damage of the
large blood vessels by glycosylation of protein
molecules in the wall of blood vessels secondary to
hyperglycemia.
• The presence of hypercholesterolemia and
hyperlipoproteinemia increase the risk for the
development of atherosclerosis and its complications.
2- Microvascular complications:
They affect the small blood capillaries and lead to :
Diabetic retinopathy and neuropathy .
These are due to vascular damage caused by protein
glycation and sorbitol (the alcohol of glucose )
accumulation.
Complications of DM
3- Diabetic cataract :
It usually occurs in young age .
It is due to accumulation of sorbitol in the eye lens, which
leads to osmotic accumulation of fluid in the lens lead to
its opacity.
4-Diabetic coma:
Coma is loss of consciousness. There are many types of
coma.
Differences between hyperglycemic and hypoglycemic coma
Points of
differences
Diabetic Coma
Hyperglycemic coma
Hypoglycemic Coma
Cause
Severe uncontrolled DM.
Insulin overdose
Mouth
Odor of acetone
Absent
Respiration
Hyperventilation (acidosis)
Normal
Pulse
Rapid & weak (dehydrated)
Skin
Dry (dehydrated)
Rapid & strong
(increased sympathetic
activity)
Sweating
Blood Glucose
Hyperglycemia
Hypoglycemia
Urine Glucose
Present
Absent
Urine Acetone
Present
Absent
Treatment of coma
hyperglycemic coma treated by
• insulin and glucose intravenous to avoid
sever drop of blood glucose
• correction of electrolyte imbalance
resulting from acidosis and polyuria .
hypoglycemic coma treated by
• glucose infusion.
Diagnosis of DM
1- By measuring the blood glucose level in
fasting( 8-12 h) state and two-hour postprandial
blood glucose level.
a)
Normally:
Fasting blood sugar = 70 – 110 mg/dl.
2-hours postprandial = up to 140 mg/dl.
b)
In Diabetics:
Fasting blood glucose = > 140 mg/dl.
2-hours postprandial = > 200 mg/dl.
Diagnosis of DM
2- Oral glucose tolerance test (OGTT):
- After fasting 8-12 hours, the patient is given 70 gm Dglucose (1 g/Kg body weight) in a cup of water
Blood and urine samples are taken fasting, ½, 1,
1½, 2, 2½ hours.
Samples are analyzed for glucose.
A blood sugar curve is plotted.
Diagnosis of DM
Diagnosis of DM
Comments on normal & abnormal oral glucose tolerance curves
Time
0 time
Fasting
½
hour
Normal
Minimum
curve
80 mg/dl
90 mg/dl
Normal
Maximum
curve
120 mg/dl 135 mg/dl 160 mg/dl 140 mg/dl 120 mg/dl 120 mg/dl
Blood
Glucose
Curve with
mild diabetes
Curve with
severe
diabetes
an 1 hour
1 ½ hour 2 hours
105 mg/dl 105 mg/dl 90 mg/dl
2½ hours
80 mg/dl
115 mg/dl 145 mg/dl 180 mg/dl 160 mg/dl 160 mg/dl 130 mg/dl
200 mg /dl 235 mg/dl 265 mg/dl 280 mg/dl 290 mg/dl 300 mg/dl
Diagnosis of DM
- In normal persons:
• fasting 70 – 120 it increases after 1 hour and returns
back to fasting after 2 hours:
•
The blood glucose never exceeds 170 mg/dl.
•
No glucosuria.
- In Diabetes mellitus:
• the fasting is more than normal ( > 110 mg/dl or more
) and the curve takes 3 hours or more to return back
to fasting level.
• One or more samples exceed 180 mg/dl.
• There is glucosuria.
Diagnosis of DM
3-Measurement of glycosylated –Hb (HbA1C)
• Glycosylated Hb (HbA1c) results from non enzymatic
binding of glucose with Hemoglobin .The process is
irreversible and continues during the half life of RBCs.
• Normal subjects and controlled cases of DM have 48% glycosylated –Hb .
• The increase in the percent of HbA1c is related to the
blood glucose level.
• The test is used for follow up of diabetic patients.
• Not affected by fasting or feeding or any factor that
affect blood glucose immediately so it gives an idea
about the glycemic control of the patient throughout
the life span of RBCs ( 120 days ).Also it gives an idea
about the efficiency of the drugs used in treatment
and adjustment of proper dose.
Other types of DM
1Diabetes insipidus: Deficiency of antiduretic hormone
(ADH). Urine volume > 10 L/day, watery specific gravity 1003.
2Steroid diabetes: Long term treatment with
glucocorticoids which cause hyperglycemia. Prolonged
hyperglycemia causes exhaustion of β-cell of pancreas.
3Stress diabetes : Due to increased adrenaline in
emotional states.
4•
•
•
•
Experimental diabetes; could be caused by :
Alloxan
Streptozotocin
Dehydroascorbic acid
Surgically by removal of pancreas
Other types of DM
Differences between diabetes mellitus and diabetes
insipidus
Points of
differences
Cause
Diabetes Mellitus
Diabetes
Insipidus
Decreased ratio of
Insulin / Anti-insulin
Decreased
ADH
< 10 L/ day
15 – 25 L/ day
>1030
<1030
Urine volume
Urine
gravity
specific
Present
Glucose in urine
Absent
It is the decrease of blood glucose
level to less than 50 mg /dl.
Importance
The CNS is very dependent on a
continuous supply of blood
glucose as a fuel for energy.
Symptoms
Adrenergic
symptoms
mediated by
epinephrine
release
\
•
Anxiety
• Palpitation
• Tremors
• sweating
Neuroglycopenic symptoms
(neuroglycopenia)
Mediated by impaired delivery
of glucose to the brain
\
impairment of brain functions
causing headache, confusion
,slurred speech, seizures,
coma and even death
Overdose
of insulin
(most
common
cause)
Causes
Fasting
hypoglycemia
\
Liver cell failure
(no glycogenolysis
or gluconeogenesis)
Chronic Alcoholism
Adrenocortical
insufficiency
(Addison's
disease).
(glucocorticoids)
due to excessive
alcohol intake with
decreased food intake
(no gluconeogenesis)
Glycogen storage
diseases (Von
Gierke's disease)
G-6-p can not leave liver
(no G-6-phosphatase
Postprandia
l hypoglycemia:
\
Alimentary hypoglycemia
due to exaggerated insulin release
following a carbohydrates meal or
after gastrectomy
Hereditary fructose
intolerance : Ingestion of
sucrose causes hypoglycemia due to
accumulation of fructose -1-P which
inhibits glycogenolysis by allosteric
inhibition of liver phosphorylase
enzyme.
CH3-CH2OH → CH3-CHO  CH3-COOH →ACTIVE
ACETATE - - Phosphofructokinase enzyme
Gluconeogenesis
Fructose-6-P
PFK-2
Phosphofructokinase-1
(PFK-1)
Glycolysis
Fructose-2,6-BP
Fructose-1,6-BP
Fructose-1,6Bisphosphatase