Abnormal Carbohydrate Metabolism
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Abnormal Carbohydrate MetabolismChemistry of CHO
1 -Monosaccharides : It is an aldehyde or keto compounds
with multilpe OH groups (hydrated carbon ,Cn(H2O)
Hexoses are alcohol reducing sugars
Ex: Glucose, Fructose ,Galactose
2 -Disaccharides:
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 1 -Hyperglycemia
2 -HypoglycemiaHyperglycemia :Sustained elevation of the blood glucose level.
(Etiology of the hyperglycemia)1 -Over production of glucose
2 -under peripheral utilization of glucose3 -Abnormal insulin production (defect in insulin synthesis
production ,release( 4 -Abnormal insulin utilization (insulin resistance)
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 categories1 -Primary DM : A- Type one IDD B- Type Two IND
2 -Secondary DM due to other disease when treated DM will be 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
1-There is no insulin ,there are either:
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 groupsType 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)1-There is generally enough insulin but the cells are not normally sensitive to its action,(Insulin
resistance)due to I- low No. of receptots ,or the
presence of II.inactive receptors
2 -Appear at majority
In type I)DKA diabeyic Ketoacidosis(1 -Insulin therapy is essential
2-The onset is most commonly during childhood3 -Ketoacidosis
4 -Inherited disorderIn Type II)NKHS Non ketotic hyperosmolar state(
1 -Insulin therapy is not essential , some times may be needed
2 -Onset during adult most patients acquired the disease after the age 40 but it may occur in younger people
3 -There is not develop ketoacidosis4 -Obesity is commonly associated &weight loss improve
the hyperglycemia
In type II ,patients required:
1 -Dietary manipulation
2 -Oral hypoglycemic agents or insulin to control
hyperglycemia
Other specific types of diabetes:
1 -Gestational DM
2-Impared Glucose Tolerance
3-Impared Fasting Glucose
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:
1 -Patients with a Fasting plasma venous glucose concentration
Between (5.5 -&7.8 mmmol/l , 100- 180 mg/dl)
2 -Plasma glucose concentration between
) 7.8-11.1 mmol/l , 140 -200 mg/dl (at two 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:1 -Measuring serum insulin
2 -Random blood glucose level ≥ 200 mg/dl accompanied by a classic symptoms ( polyurea ,polydipsia ,weight
loss 3-OGTT still a valid mechanism for diagnosis DM4 -HbA1Cuse as a diagnostic test for diagnosis DM
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
1 -Fasting blood glucose level (FBG) : No food
intake for at least 6 hours or more.
2 -Random blood glucose(RBG) : Any time after
the meal.
3 -Post prandial blood glucose level : Two hours
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( :
1-Different techniques in collection of the blood
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.
2 -The presence or absence of the preservative,like
NaF inhibit the glycolysis enzymes
3-Storage of the sample.
4 -The time of the sample collection ,evening or
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.
5 -Sera separated from the RBC at least ½ an hour
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
1 -Glucooxidase method
2 -Hexokinse method
Hyperglycemia lab.finding:
1-Increase glucose in the urine &plasma
2 -Increase ketone –bodies in the urine & plasma
3-Increae urine specific gravity
4 -Increase urine & serum osmolality
5 -Decrease the PH of the urine & blood (acidosis)
6 -Electrolyte imbalance
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:1 -Lowest the blood glucose level by stimulate glucose entry
into the cells. Except : Brain ,RBC & Intestinal mucosaGlucose enter to these cells with out the need of insulin.
2-Inhibit lipolysis3-Inhibit gluconeogenesis
4-Inhibit proteolysis5 -Promot glycogen synthesis
The normal response to hyperglycemia depend on:1-Adequate insulin secretion
2 -Normal insulin receptor3 -Normal post –Receptor Events (lipolysis,gluconeogenesis
&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:
1 -Stimulate the hepatic gluconeogenesis (Synthesis of glucose from non CHO source
2 -Stimulate the hepatic glycogenolysis ( glycogen 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: 1 -DM
2 -IV infusion of glucose3 -Sever stress
4-After cerebrovascular accidentDiabetes 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
2-Can not synthesize glucose (gluconeogenesis)
3-Can not metabolized substrates other than glucose & ketone bodies.
Under normal physiological condition the concentration of plasma ketone bodies are very low & are of little importance as an energy source.
Chronic Complication1 -Vascular Complication
2-Non-Vascular ComplicationVascular complication
1-Macrovascular : Coronary artery Disease ) CAD ,(peripheral vascular disease ,
Cerebrovascular disease 2 -Microvascular:
Retinopathy lead to blindnessNephropathy lead to renal damageNeuropathy lead to the CNS damade
Non –Vascular complication:
1-Sextual dysfunction
2-Gastrpparesis
3-Skin change
Mechanism of Complication
There are three major theories
First hypothesis1 -Increase intracellular Glucose lead to the formation of
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 HypothesisIncrease 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
1 -Altered potential Redox
2 -Reduced myoinositol
These are lead to cellular dysfunction
Third hypothesisIncrease 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 complicationActivation 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
1-Diabetic Ketoacidosis )DKA( Type I
2-Non Ketotic HyperOsmolar State)NKHS( Type II
DKA
1-Diabetic Ketoacidosis )DKA( Type INausea ,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:
1 -deficiency of insulin
2 -Combined with Excess of counterregulartory
hormones (glucagon ,GH,Cortisol
, Catecholamine(
Hyperglycemia in DKA result from
1 -Increase hepatic production of glucose
) Gluconeogenesis ,glycogenolysis(
2 -Impaired glucose peripheral utilization
3-Insulin / Glucogon ratio ,this ratio is decreased
lead to increase production of ketone bodies in
the liver
4 -Increase substrate delivary from fat of the
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:
1 -Ketone- bodies exist as a keto acid which are neutrilized by HCO3 (Bicarbonate) ,as bicarbonate store are deleted metabolic acidosis occur (ensues).
2 -Lactic acid production increase also contribute to acidosis
In DKA ,due to deficiency of insulin:
1 -Increase lipolysis ,increase FFa production ,increase TAG ,VLDL in the liver.
2 -The clearance of VLDL is also reduced due to 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
1 -Hyperglycemia2 -Ketosis
3 -Metabolic acidosis ( increase anion gap)4 -S.HCO3 < 10 mmol /l
5 -Arterial PH (6.8 – 7.3 ) depend on the severity of the acidosis.
6 -Total body stores of Na ,Cl ,PO4 ,Mg are also reduced (because of osmotic diuresis effect of glucose)
7 -Increase S.urea & S.creatinine due to osmotic diuresis ,effect of glucose ,cause volume depletion &
haemoconstration
8 -Hyper Triglyceridemia
9 -Hyperlipoproteinemia
10 -Hyperamylasemia may suggest diagnosis of
pancreatitis ,especially when accompanied by
abdominal pain.
However in DKA the amylase is usually of salivary origin & thus is not diagnostic of pancreatitis
2 -Non – Ketotic Hyper Osmolar State Type II 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)
1 -Polyuria (dehydration )
2 -Hyperosmolality
3 -Volume depletion ( Osmotic diuresis)
4 -Hypotension
5 -Tachycardia6 -Myocardial Infarction
7 -StrokePathophysiology of NKHSInsulin deficiency lead to increase
Hepatic gluconeogenesis Hepatic Glycogenolysis
1 -Lead to increase glucose production2 -Decreased the glucose utilization,
) decrease glucose uptake due to insulin deficiency(
1-Hyperglycemia
2 -Osmotic Diuresis
3-Volume depletion
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
1 -Hyperglycemia > 55.5 mmol /l
2 -Hyperosmolality >350 mosmol /l
3 -Na /Normal or slightly low What about 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
4 -Acidosis / Absent
5 -Ketonuria / Absent
6 -Metabolic acidosis /may be present secondary to increase lactic acid.
Factors Affecting Glucose Tolerance Test
1-CHO intake: Prepare patients at least three days before the test ,100-300 gm/day ,if there is CHO restricted diet ,we get abnormal GTT
2-Any stress or fever cause pseudo diabetic.3-Obsity show impaired GTT
4-Age:Blood glucose increase 1mg/dl in each year after 50yr.5-Diurinal variation :GTT decrease I evening
6-Active person show GTT near to the diabetic person than normal person
7-Drugs;Steroid,oral contraceptive ,thiazide &diuretics may impair GTT
8-No smoke during the test .
Glucose Tolerance Test
1 -The person should be fasted for 10-16 hours
2 -75-100 gm glucose dissolved in 300 ml of water ,this solution should be drunk slowly over about 4 minutes.
3-Blood should drawn every half hour for three hours
½hr ,1hr , 1.5hr ,2 hr , 2 .5 hr ,3 hr
4 -Urine specimen should be collected after 0 ,1hr & 2 hr measured urine glucose &urine ketone bodies
5-After two hours of ingestion glucose the peak of blood 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 DefinitionHypoglycemia 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 &InfantsNeonatal blood glucose concentrations are much lower than adult (mean= 35 mg /dl) . The more common cause of
hypoglycemia in the neonate period include:
1-Prematurity
2-Maternal diabetes
3-Respiratory Disress Syndrome
4-Toxemia of pregnancy
These are transient hypoglycemia
Fasting Hypoglycemia
Hypoglycemia result from a 1-Decreased rate of hepatic glucose production
2-Increased rate of glucose use or utilization
Causes of Hypoglycemia :) Adult(1-Medications(insulin,oral hypoglycemic agents)
2-Toxins (alcohol )3-Severe hepatic dysfunction
4-Deficiency of hormones (glucocorticoid ,GH)5-Insulin –producing pancreatic tumors (Insulinoma)
6-Insulin Antibodies
7-Nonpancreatic Neoplasms
8 -Septicemia
9-Chronic Renal Failure
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 .
1-These include over medicating with manufactured
insulin,
2Missing or delaying a meal, eating too little food for the amount of insulin taken,
3 -Exercising too strenuously ,
4-Drinking too much alcohol ,
5-or any combination of these factors
Ideopathic or reactive hypoglycemiaIdeopathic 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 hypoglycemiaFasting hypoglycemia sometimes occurs after long periods
without food, but it also happens occasionally following strenuous exercise, such as running in a marathon.
Causes and symptomsWhen carbohydrates are eaten, they are converted to glucose that goes into the bloodstream and is distributed throughout the body .The chemical regulators include
1)-Insulin, glucagon, epinephrine )adrenalin(, and norepinephrine.Any abnormalities in the effectiveness of any one of the regulators can reduce or increase the body's level of glucose.
2)- Gastrointestinal enzymes such as amylase and lactase 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.
3 )-Cell sensitivity to these regulators can be changed in many ways .
1-Person's stress level, 2-Exercise patterns ,
3-Advancing age ,4-Dietary habits influence cellular sensitivity.
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.
TreatmentTreatment 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
1-Alcohol ,
2-Caffeine, and
3- Cigarette smoke,
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.
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