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
. 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 Lowest the blood glucose level by stimulate glucose entry into the cells- 1

.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 nonEnzymatic 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

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