Abnormal Carbohydrate Metabolism

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.