Abnormal Carbohydrate Metabolism

Chemistry of CHO
Monosaccharides : It is an aldehyde or keto compounds- 1
(with multilpe OH groups (hydrated carbon ,Cn(H2O
Hexoses are alcohol reducing sugars
Ex: Glucose, Fructose ,Galactose

:Disaccharides- 2
Ex: lactose (glactose +glucose( ,Reducing sugar
Maltose(glucose +glucose( ,Reducing sugar
Sucrose(fructose +glucose( ,Non – Reducing
. sugar,No free carbonyl group
There are two abnormalities
Hyperglycemia- 1
Hypoglycemia- 2
.Hyperglycemia :Sustained elevation of the blood glucose level

(Etiology of the hyperglycemia)

Over production of glucose- 1
under peripheral utilization of glucose- 2
Abnormal insulin production (defect in insulin synthesis- 3
(production ,release
(Abnormal insulin utilization (insulin resistance- 4
a- Inactive receptors
b- Low No. of receptors
Definitions of Diabetes mellitus
It is a chronic condition ,it is a group of metabolic
disorder of CHO metabolism in which the glucose
is under used producing hyperglycemia

TheWHO classify DM into the following categories

Primary DM : A- Type one IDD B- Type Two IND- 1
Secondary DM due to other disease when treated DM will be- 2
disappear )acromegaly increase GH ,Cushing syndrome increase
cortisol ,increase glucocorticoid secretion due to adminstration of
the thiazid
A-In type 1 )IDD()Insulin dependent diabetes (
)Juvenile ( Diabetic Keto Acidosis DKA
Appearance at early stage
(Abnormal Insulin production)
Deficiency of insulin caused by loss of pancreatic islet ß
cell this is outoimmuno process ,most patients have Ab
.pancreatic exocrine disease when the majority of the
. pancreatic islet are destroyed
The patients depend on the insulin to sustain the life and
prevent ketosis
:There is no insulin ,there are either-1
A- Defect in synthesis ,deficiency in synthesis
B- Defect in production
.C- Defect in release of insulin
Type I It is divided into two sub groups
:Type IA

Result from outoimmune ß cell destruction which usually

lead to insulin deficiency
:Type IB
It is also characterized by insulin deficiency as well as
tendency to develop ketosis .lack of the immunological
markers ,absolute insulin deficiency due to pancreatic
diseases
I- Chronic pancreatitis
II- Cystic fibrosis
(III- Haemochromatosis (Deposite of iron in soft tissue
B- In type Two)INDD()Insulin non dependent
diabetes ) Non ketotic hyperosmolar State
( NKHS
(Abnormal Insulin Utilization)
There is generally enough insulin but the cells-1
are not normally sensitive to its action,(Insulin
resistance(due to
I- low No. of receptots ,or the
presence of
II.inactive receptors

Appear at majority- 2
(In type I)DKA diabeyic Ketoacidosis
Insulin therapy is essential- 1
The onset is most commonly during childhood-2
Ketoacidosis- 3
Inherited disorder- 4
(In Type II)NKHS Non ketotic hyperosmolar state
Insulin therapy is not essential , some times may be- 1
needed
Onset during adult most patients acquired the disease- 2
after the age 40 but it may occur in younger people
There is not develop ketoacidosis- 3
Obesity is commonly associated &weight loss improve- 4
the hyperglycemia
 :In type II ,patients required
Dietary manipulation- 1
Oral hypoglycemic agents or insulin to control- 2
hyperglycemia
:Other specific types of diabetes
Gestational DM- 1
Impared Glucose Tolerance-2
Impared Fasting Glucose-3
:Gestational DM
Insulin resistance related to the metabolic changes
.of late pregnancy
Excessive secretion of hormones that antagonize
.The action of the insulin
Diabetic women who become pregnant are not
.include in this category
:Impaired Glucose Tolerance Test
(Oral GTT between normal and DM(
IGT is diagnosed in people who have FBS
concentration less than those required for a
diagnosis of DM.Patiens have an increased
prevalence of atherosclerosis and mortality
.from cardiovascular disease
Microvascular disease is quite rare in this group
and patients usually do not experience the renal
or retinal complications of diabetes
 :Impaired Glucose Tolerance
The WHO definition of impaired glucose
:tolerance includes
Patients with a Fasting plasma venous glucose- 1
concentration
(Between (5.5 -&7.8 mmmol/l , 100- 180 mg/dl
Plasma glucose concentration between- 2
mmol/l , 140 -200 mg/dl( at two 7.8-11.1 (
(hours after taking standard glucose load (GTT
:Impaired Fasting Glucose
This new category is analog to IGT ,but is diagnosed
by a fasting glucose value between that of normal
and diabetic individuals .IGT,&IFG are risk
factors for developing diabetes & cardiovascular
.diseases
:Diagnosis of Diabetes
Measuring serum insulin- 1
Random blood glucose level ≥ 200 mg/dl accompanied- 2
by a classic symptoms ( polyurea ,polydipsia ,weight
loss
OGTT still a valid mechanism for diagnosis DM-3
HbA1Cuse as a diagnostic test for diagnosis DM- 4
Measuring blood glucose level which is
considered the best index because
It gives the net result of the change in the
hormonal activity.High insulin activity does not mean that there is
No Diabetes due to the high glucagon that has insulin opposite
.action
In the Diagnosis of the diabetes by measuring blood
glucose level either using
Fasting blood glucose level (FBG( : No food- 1
.intake for at least 6 hours or more
Random blood glucose(RBG( : Any time after- 2
.the meal
Post prandial blood glucose level : Two hours- 3
.after a normal meal
FBG: > 120 mg /dl
RBG : >160 mg/dl
 Renal Threshold : The concentration of the blood
glucose above which it appears in the
.urine

( : Different Result from one lab to the another) the causes

Different techniques in collection of the blood-1
sample (venous sample is a standard clinical
specimen for glucose, artery blood contains more
glucose ,but at fasting there is the same
.concentration of glucose
The presence or absence of the preservative,like- 2
NaF inhibit the glycolysis enzymes
.Storage of the sample-3
The time of the sample collection ,evening or- 4
morning. Due to the level of the cortisol,its
concentration is high at the morning,cortosol is
glucogenic hormones ,so the blood glucose level
.at morning is higher than at the evening
Sera separated from the RBC at least ½ an hour- 5
after coagulation due to the presence of the
glycolytic enzymes.If the sample does not done
immediately ,we have to collect the sample in
NaF non- specific inhibitor of the glycolytic
&enzymes,prevent the glycolysis of glucose
keep the concentration of glucose constant..if
% there is no NaF the blood losses about 8%-10
of its glucose every hour
 Method used for the measuring the blood
:glucose level
Coloremetric method :which is depend on the
reducing property of the glucose ,so any
substances has reducing property will interfere
with the result such as
Vitamin C .glutathion ,aspirin , uric acid
,creatinine
( paracetol ,INH ( structure related compound
 Enzymatic Method : Specific method
Glucooxidase method- 1
Hexokinse method- 2
:Hyperglycemia lab.finding
Increase glucose in the urine &plasma-1
Increase ketone –bodies in the urine & plasma- 2
Increae urine specific gravity-3
Increase urine & serum osmolality- 4
(Decrease the PH of the urine & blood (acidosis- 5
Electrolyte imbalance- 6
:Hormonal Regulation
Hormones keep the blood glucose level with in
the normal range .any disturbance in hormonal
activity ,lead either to make blood glucose
.level above or below the normal range
:Action of Insulin
Lowest the blood glucose level by stimulate glucose entry into the cells- 1
.
Except : Brain ,RBC & Intestinal mucosa
.Glucose enter to these cells with out the need of insulin
Inhibit lipolysis-2
Inhibit gluconeogenesis-3
Inhibit proteolysis-4
Promot glycogen synthesis- 5
:The normal response to hyperglycemia depend on
Adequate insulin secretion-1
Normal insulin receptor- 2
Normal post –Receptor Events (lipolysis,gluconeogenesis- 3
(&proteolysis
.C-peptide :is probably of little physiological importance
But its measurement may help in the differential diagnosis of
. hypoglycemia
Insulin is the most important hormone controlling the
.metabolic path way controlling the blood glucose level
Beta cell of pancreatic islets produce proinsulin
Proinsulin (51aa insulin + 33aa C-peptide( ,proteolysis of
.proinsulin releases insulin
Both ( insulin & C-peptide are stored in islet cells & released
into plasma in equimolar amounts ,mainly in response to
rising plasma glucose level
:Glucagon
:Glucagon maintains the blood glucose level by
Stimulate the hepatic gluconeogenesis (Synthesis of glucose- 1
from non CHO source
Stimulate the hepatic glycogenolysis ( glycogen- 2
breakdown(,so it is glucogenic hormone or hyperglycemic
hormone
Glucagon is a single polypeptide chain of 29 aa secreted by
the alpha islet cell of pancreas in response to the low blood
glucose level (hypoglycemia(.Elevated level of glucagon is
.associated with fasted state ,it is a catabolic hormone
(Hyperglycemia &Diabetes Mellitus )DM
:Hyperglycemia may be due to
DM- 1
IV infusion of glucose- 2
Sever stress- 3
After cerebrovascular accident-4
:Diabetes Mellitus
It is caused due to absolute or relative insulin
deficiency. It has been defined by (WHO( World Health
:Organization ,on the basis of laboratory findings
(Fasting venous concentration : > 140 mg/dl (7.8 mmol / L
(Two hours after CHO meals :> 200mg/dl (11mmol /L
Two hours after oral ingestion of the 75 gm of glucose :>200
even the fasting conc. is normal
:Physiology
The importance of extra cellular (EC( glucose concentration
The brain cells are very dependent on EC glu conc.for
.their energy supply
Hypoglycemia (Low blood glucose level(:is likely to impair
the cerebral function.This is because the brain cells can
not : 1- Store the glucose in significant amount
(Can not synthesize glucose (gluconeogenesis-2
Can not metabolized substrates other than glucose -3
. & ketone bodies
Under normal physiological condition the concentration of
plasma ketone bodies are very low & are of little
.importance as an energy source
Chronic Complication
Vascular Complication- 1
Non-Vascular Complication-2
Vascular complication
Macrovascular : Coronary artery Disease-1
, CAD(, peripheral vascular disease (
Cerebrovascular disease
:Microvascular- 2
Retinopathy lead to blindness
Nephropathy lead to renal damage
Neuropathy lead to the CNS damade
:Non –Vascular complication
Sextual dysfunction-1
Gastrpparesis-2
Skin change-3
Mechanism of Complication
There are three major theories
First hypothesis
Increase intracellular Glucose lead to the formation of- 1
Advanced glycocylation end products )AGEs( via non-
Enzymatic glycosylation of cellular protein result from the
interaction of glucose with amino group of the protein
AGEs have been shown to cross linked proteins eg
collagen , Extracellular matrix protein
AGEs accelerate atherosclerosis & promote
glomerular dysfunction ,induce endothelial
dysfunction
Ulter the Extraxcellulat matriux composition &
.structure
The serum level of AGEs correlate with the level of
. glycemia
AGEs accumulate & GFR reduced
Second Hypothesis
Increase glucose metabolism via sorbitol pathway
Intracellular glucose is predominantly metabolized
.by phosphorylation &subsequent glycolysis
But when intracellular glucose increased ,some
glucose is converted to sorbitol by Aldolase
.Reductase
Increase concentration ofd the sorbitol affect
several aspects of cellular physiology
Altered potential Redox- 1
Reduced myoinositol- 2
These are lead to cellular dysfunction
Third hypothesis
Increase hyperglycemia → lead to increase the
→formation of the DAG Di-acyl glycerol
That lead to activation of the protein kinase c
→that affect variety of the cellular events → DM
complication
Activation of the protein kinase c by glucose
Alter the transcription of genes for collagen
contractile protein ,fibrinonectin
typeIV,Extracellular matrix protein in
endothelial cell neuron
Increased in diabetes oxidative stress and free radical
generation ,as a consequence of the hyperglycemia may
.also promote the development of complication
The renal complications may partly be due to the
increase in glycosylation of structural proteins within the
. arterial wall of the glomerular basement membrane

Similar vascular change (Glycosylation( in the retina may

account for the high incidence of diabetic retinopathy
Glycosylation of protein in the lense may cause
. Cataract
Complication of the DM
Diabetic Ketoacidosis )DKA( Type I-1
Non Ketotic HyperOsmolar State)NKHS(-2
Type II
DKA
Diabetic Ketoacidosis )DKA( Type I-1
Nausea ,vomiting ,abdominal pain may be severe & some
.times suggest acute pancreatitis
(Hyperglycemia →Osmotic diuresis (glucosuria
Volume depletion
Hypotension
Tachycardia
Acetone odor on the patients breath
secondary to the metabolic acidosis
CNS depression &coma Note: The
extracellular hyperosmolarity cause severe cellular
dehydration &loss of water from cerebral cell & is probably
.the reason for the confusion &coma
Pathophysiology of DKA
:Result from the
deficiency of insulin- 1
Combined with Excess of counterregulartory- 2
hormones (glucagon ,GH,Cortisol
(Catecholamine ,
Hyperglycemia in DKA result from
Increase hepatic production of glucose- 1
(Gluconeogenesis ,glycogenolysis (
Impaired glucose peripheral utilization- 2
 Insulin / Glucogon ratio ,this ratio is decreased-3
lead to increase production of ketone bodies in
the liver
Increase substrate delivary from fat of the- 4
.adipose tissue & muscle (FFA,AA( to the liver
Due to deficiency of insulin lead to increase (
(lipolysis & protein breakdown
Ketosis
Result from marked increase of lipolysis & increase
FFA release from adipose tissue & shift toward
the formation of the Ketone –bodies
Due to the deficiency of insulin , increase
gluconeogenesis OAA through this process lead
to the formation of the glucose ,So there is no
OAA to react with Acetyl CoA to form citrate
through TCA cycle acid cycle ,for this reason
AcetylCoA react with other molecule of acetyl
,CoA & lead to Ketone –bodies formation
Normally Increase the level of Free fatty acid due
to increase lipolysis FFA converted to TAG
,VLDL in the liver
FFA → TAG ,VLDL ( in normal condition in the
(liver
But in DKA due to hyperglucagonemia (increase
level of glucagon( alter hepatic metabolism
toward the formation of the Ketone-bodies
Through the activation of the enzyme (Carnitine
Palmitoyl Transferase enzyme(,thisenzyme is
crucial for regulating fatty acid transport into
mitochondria which Beta oxidation & conversion
.to ketone – bodies occur
:At physiological PH
Ketone- bodies exist as a keto acid which are- 1
neutrilized by HCO3 (Bicarbonate( ,as
bicarbonate store are deleted metabolic acidosis
(.occur (ensues
Lactic acid production increase also contribute to- 2
acidosis
 :In DKA ,due to deficiency of insulin
Increase lipolysis ,increase FFa production- 1
.,increase TAG ,VLDL in the liver
The clearance of VLDL is also reduced due to- 2
the activity of the enzyme insulin sensitive
lipoprotein lipase is decreased lead to
HyperTriglyceridemia may be severe enough to
cause pancreatitis (the most constituent of the
(VLDL is TAG
Laboratory Abnormalities in DKA

Hyperglycemia- 1
Ketosis- 2
(Metabolic acidosis ( increase anion gap- 3
S.HCO3 < 10 mmol /l- 4
Arterial PH (6.8 – 7.3 ( depend on the severity of the- 5
.acidosis
Total body stores of Na ,Cl ,PO4 ,Mg are also reduced - 6
( (because of osmotic diuresis effect of glucose
Increase S.urea & S.creatinine due to osmotic diuresis- 7
& ,effect of glucose ,cause volume depletion
haemoconstration
Hyper Triglyceridemia- 8
Hyperlipoproteinemia- 9
Hyperamylasemia may suggest diagnosis of- 10
pancreatitis ,especially when accompanied by
.abdominal pain
However in DKA the amylase is usually of salivary
origin & thus is not diagnostic of pancreatitis
Non – Ketotic Hyper Osmolar State Type II- 2
:DM
It is most commonly seen in elderly patients
Polyurea ,weigh loss ,orthostatic hypotension
( ,Cause by standing(
Neurological symptoms (lethargy ,altered mental
(status seizure & possible coma
(Polyuria (dehydration- 1
Hyperosmolality- 2
(Volume depletion ( Osmotic diuresis- 3
Hypotension- 4
Tachycardia- 5
Myocardial Infarction- 6
Stroke- 7
Pathophysiology of NKHS
Insulin deficiency lead to increase
Hepatic gluconeogenesis
Hepatic Glycogenolysis
Lead to increase glucose production- 1
,Decreased the glucose utilization- 2
decrease glucose uptake due to insulin (
(deficiency
Hyperglycemia-1
Osmotic Diuresis- 2
Volume depletion-3
Relative deficiency of insulin & lower level of
counterregulatory hormones lead to increase
.FFA
Insulin /Glucagon ratio this ratio is not enough to
favor ketogenesis
Laboratory Abnormalities of NKHS Type II DM

Hyperglycemia > 55.5 mmol /l- 1

Hyperosmolality >350 mosmol /l- 2
Na /Normal or slightly low What about- 3
?plasma Na concentration
The plasma Na concentration is either Low or below the
normal value because of osmotic effect of high
extracellular concentration of glucose which draws water
(.from the cells (Haemodilution
When there is hyperlipidaemia there is possibility of
pseudo hyponatraemia )Dillution
Acidosis / Absent- 4
Ketonuria / Absent- 5
Metabolic acidosis /may be present secondary- 6
.to increase lactic acid
 Factors Affecting Glucose Tolerance Test
CHO intake: Prepare patients at least three days before the-1
test ,100-300 gm/day ,if there is CHO restricted diet ,we
get abnormal GTT
.Any stress or fever cause pseudo diabetic-2
Obsity show impaired GTT-3
.Age:Blood glucose increase 1mg/dl in each year after 50yr-4
Diurinal variation :GTT decrease I evening-5
Active person show GTT near to the diabetic person than -6
normal person
Drugs;Steroid,oral contraceptive ,thiazide &diuretics may-7
impair GTT
. No smoke during the test-8
 Glucose Tolerance Test
The person should be fasted for 10-16 hours- 1
gm glucose dissolved in 300 ml of water ,this 75-100- 2
.solution should be drunk slowly over about 4 minutes
Blood should drawn every half hour for three hours-3
hr ,1hr , 1.5hr ,2 hr , 2 .5 hr ,3 hr½
Urine specimen should be collected after 0 ,1hr & 2 hr- 4
measured urine glucose &urine ketone bodies
After two hours of ingestion glucose the peak of blood-5
glucose level should be less than 140 mg/dl
Hypoglycemia
Carbohydrates are the main dietary source of the
glucose that is manufactured in the liver and
absorbed into the bloodstream to fuel the body's
. cells and organs
Glucose concentration is controlled by hormones,
primarily insulin and glucagon. Glucose
concentration also is controlled by epinephrine
)adrenalin( and norepinephrine, as well as
.growth hormone
If these regulators are not working properly, levels
of blood sugar can become either excessive (as in
hyperglycemia( or inadequate (as in
hypoglycemia(. If a person has a blood sugar
level of 50 mg/dl or less, he or she is considered
hypoglycemic, although glucose levels vary
.widely from one person to another
.Hypoglycemia can occur in several ways
Hypoglycemia Definition
Hypoglycemia is a blood glucose concentration below the fasting
value .The most widely suggested cutoff is 50 mg/dl. The
concentrations fall below a level necessary to properly support the
body's need for energy and stability throughout its cells

Symptoms of hypoglycemia vary among individuals and non is

specific.The classic signs & symptoms of hypoglycemia ,namely
sweating,nausea,rapid pulse,hunger, ,and ,epigastric discomfort
,headache , confusion, blurred vision ,and dizziness , loss of
.consciousness ,and even death
These autonomic (neurogenic( symptoms are
nonspecific and may also be noted in other
conditions such as
Hyperthyroidism
. Anxiety
During prolonged fasting
In hypoglycemia ,ketones may be used as an
energy source
Hypoglycemia in neonates &Infants
Neonatal blood glucose concentrations are much lower than
adult (mean= 35 mg /dl( . The more common cause of
:hypoglycemia in the neonate period include
Prematurity-1
Maternal diabetes-2
Respiratory Disress Syndrome-3
Toxemia of pregnancy-4
These are transient hypoglycemia
Fasting Hypoglycemia
Hypoglycemia result from a
Decreased rate of hepatic glucose production-1
Increased rate of glucose use or utilization-2

(Causes of Hypoglycemia :) Adult

(Medications(insulin,oral hypoglycemic agents-1
(Toxins (alcohol-2
Severe hepatic dysfunction-3
(Deficiency of hormones (glucocorticoid ,GH-4
(Insulin –producing pancreatic tumors (Insulinoma-5
Insulin Antibodies-6
Nonpancreatic Neoplasms-7
Septicemia- 8
Chronic Renal Failure-9
Ethanol produce hypoglycemia
by inhibiting gluconeogenesis ,and this is aggravated by
.malnutrition
( Hepatic failure ( viral hepatitis ,toxins
.Decreased glucose production by impaired gluconeogenesis
Glycogen storage disease may result in
.hypoglycemia
 Drug-induced hypoglycemia
Hypoglycemia occurs most often in diabetics who
must inject insulin periodically to lower their blood
.sugar
Unless recognized and treated immediately, severe
hypoglycemia in the insulin-dependent diabetic can
lead to generalized convulsions followed by
amnesia and unconsciousness. Death, though rare, is
.a possible outcome
.
:In insulin-dependent diabetics
hypoglycemia known as an insulin reaction or
. insulin shock can be caused by several factors
These include over medicating with-1
manufactured
,insulin
2Missing or delaying a meal, eating too little food
,for the amount of insulin taken
, Exercising too strenuously- 3
, Drinking too much alcohol-4
or any combination of these factors-5
 Ideopathic or reactive hypoglycemia
Ideopathic or reactive hypoglycemia (also called
postprandial hypoglycemia( occurs when some
people eat. A number of reasons for this reaction have
.been proposed, but no single cause has been identified
In some cases, this form of hypoglycemia appears to be
associated with malfunctions or diseases of the,
. pituitary, adrenals, liver, or pancreas
Children intolerant of a natural sugar (fructose( or who
have inherited defects that affect digestion also may
. experience hypoglycemic attacks
It sometimes occurs among people with an intolerance to
(.the sugar found in milk )galactose
Fasting hypoglycemia
hypoglycemia sometimes occurs after long periods Fasting
without food, but it also happens occasionally following
.strenuous exercise, such as running in a marathon
Causes and symptoms
When carbohydrates are eaten, they are converted to glucose
that goes into the bloodstream and is distributed throughout
. the body
The chemical regulators include
Insulin, glucagon, epinephrine )adrenalin(, and-(1
.norepinephrine
Any abnormalities in the effectiveness of any one of the
regulators can reduce or increase the body's level of
.glucose
Gastrointestinal enzymes such as amylase and lactase -(2
that break down carbohydrates may not be functioning
.properly
These abnormalities may produce hyperglycemia or
hypoglycemia, and can be detected when the level of
.glucose in the blood is measured
 Cell sensitivity to these regulators-( 3
. can be changed in many ways
,Person's stress level-1
, Exercise patterns-2
, Advancing age-3
.Dietary habits influence cellular sensitivity-4
For example, a diet rich in carbohydrates increases insulin
.requirements over time
Eventually, cells can become less receptive to the effects of
the regulating chemicals, which can lead to glucose
.intolerance
:Symptoms of hypoglycemia include
Extreme tiredness. Patients first lose their muscle
strength and coordination. Sometimes the patient
. will actually fall asleep
Additional symptoms of reactive hypoglycemia
include headaches, double vision, inability to
walk, abdominal distress, premenstrual tension,
chronic colitis, allergies, ringing in the ears,
unusual patterns in the frequency of urination,
skin eruptions and inflammations, pain in the
neck and shoulder muscles, memory problems,
.and sudden and excessive sweating
Treatment
Treatment of the immediate symptoms of
hypoglycemia can include eating sugar., drink
milk, or drink fruit juice.. Patients usually are
encouraged to eat small, but frequent meals
. throughout the day
Those patients with severe hypoglycemia may require
fast-acting glucagon injections that can stabilize
.their blood sugar within approximately 15 minutes
 Hypoglycemics should avoid
, Alcohol-1
Caffeine, and-2
,Cigarette smoke -3
since these substances can cause significant swings in
.blood sugar levels
:Hypoglycemia occurs in
endocrinopathies Hypopituitarism ,Addison's
,disease
Islet cell tumors
,Hepatic disease, glycogen storage disease
Gastrectomy
Drug –related (eg, sulfonylureas, oral hypoglycemics–
agents, chlorpropamide, tolbutamide, alcohol,
.aspirin, phenformin, insulin