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TRANSCRIPT
Oral Glucose Tolerance Test
Laboratory Exercise Objectives To determine the array of the test that should be
performed on the patient To further identify the particular normal values
that are standard for each test To compare the standard normal values with the
obtained laboratory results To establish expected laboratory values To understand why these laboratory test was
chosen for these specific patient.
Experiment Objective To be familiar with the normal values of
blood sugar in the test To provide the significance of testing OGTT
in patients suspected with diabetes To be acquainted with other diseases that
can cause abnormal glucose tolerance test result
Case 50 year old 122 mg/dL plasma glucose Family history:
Two siblings with Type II Diabetes Mellitus
Sedentary lifestyle and rarely went to the gym
Oral Glucose Tolerance Test Sensitive Lack specificity Defines diabetes chemically Abnormal in many diseases Influenced by diet and other variables
Oral Glucose Tolerance Test Should be administered with in the
standard
Preparation Patient must be ambulatory and free from
illness or trauma Diet containing 150g of CHO for 3 days Advisable to do fasting blood glucose first
For three days prior to the test, the subject had a high carbohydrate diet of 300 gm per day
Eight hours before the test, on the day of the experiment, the subject had nothing by mouth.
Fasting blood sugar was taken using a glucometer.
The subject then ingested 75 gm glucose. Blood sugar was taken at 60 min, 90 min and 120
min after intake of glucose. The results were recorded.
High-Carbohydrate Preparatory Diet
The subject’s maximal ability to metabolize sugar is tested.
The repeated stimulation of postprandial hyperglycemia gradually restores maximal insulin responsiveness and reactivates the processes needed for disposal of glucose by different tissues.
RESULT
Result
105
110
115
120
125
130
135
140
145
60 mins 90 mins 120mins
Glucose level
60 mins= 142
90 mins= 124
120 mins=120
Normal values
AGE
(years)
SLIDING LIMIT
FIXED LIMIT
20 142 148
30 152 163
40 161 178
50 169 193
60 177 208
70 185 224
80 198 239
Proposed Age-Adjusted Normal Limits for Oral Glucose Tolerance Test
Blood sugar(mg/100 cc)
Normal Glucose ToleranceNormal Glucose Tolerance Plasma glucose levels below 140 mg/100cc both fasting and 2 hr after
glucose load
Impaired Glucose TransportImpaired Glucose Transport Requires a two hour plasma glucose level equal to or greater than 140
mg/100 cc but below 200 mg/100 cc and at least one value between 0 time and 2hr equal to or greater than 200 mg/100cc
Definite DiabetesDefinite Diabetes > Require either two fasting plasma glucose values 140 mg/100cc or
more; or a 2 hr plasma glucose level equal to or above 200 mg/100 cc, and at least one value between zero time and 2 hr equal to or greater than 200 mg/100 cc
ENDOCRiNE SYSTEM
PANCREAS
PANCREAS The pancreas is a
elongated organ, light tan or pinkish in color, that lies in close proximity to the duodenum. It is covered with a very thin connective tissue capsule which extends inward as septa, partitioning the gland into lobules.
PANCREAS The bulk of the
pancreas is composed of pancreatic exocrine cells and their associated ducts. Embedded within this exocrine tissue are roughly one million small clusters of cells called the Islets of Langerhans, which are the endocrine cells of the pancreas and secrete insulin, glucagon and several other hormones.
PANCREASPancreatic islets house
three major cell types:
Alpha cells (A cells) secrete the hormone glucagon.
Beta cells (B cells) produce insulin and are the most abundant of the islet cells.
Delta cells (D cells) secrete the hormone somatostatin, which is also produced by a number of other endocrine cells in the body.
INSULINa) stimulates liver, fat, and muscle cells to
take up glucose.
b) stimulates liver and muscles to store glucose as glycogen.
c) promotes buildup of fats and proteins and inhibits their use as an energy source.
INSULIN SYNTHESIS
Insulin gene encodes for preproinsulin.
Preproinsulin contains 4 sequential peptides: N-terminal
signal peptide
B chain C peptide A chain
The N-terminal signal peptide is degraded during the course of completion of the proinsulin molecule.
The proinsulin is folded into a conformation that permits the disulfide linkages between the A and B chains to form.
Converting enzymes cleave off the C peptide.
Insulin synthesis is completed
INSULIN SECRETION
1
34
3
5
7
6
8
2
9
1
2
3 4
5
6
7
REGULATION OF INSULIN SECRETION
REGULATIONGLUCOSE,
AMINO ACIDS,FFA/KETOACIDS,
POTASSIUM
INSULIN
STIMULATES SECRETION
STIMULATES UPTAKE, METABOLISM, STORAGE
Biphasic response:
1. First phase or Immediate pulse or Initial response
1. Rapid release of preformed insulin
– Second phase or Prolonged response1. Rapid release of newly synthesized insulin
2. Slow removal of insulin substrate inhibiting further release
3. Different sensitivity
REGULATION Factors affecting insulin secretion
Stimulators Inhibitors
glucose secretin fasting interleukin-1protein CCK exercise pancreastatin ketoacids vagal activity somatostatin leptinFFA Ach galaninpotassium glucagon endurance trainingcalcium GLP-1 -adrenergic activityGIP diazoxide-Adrenergic activity prostaglandin E2sulfonylurea drugsmeglitinides
INSULIN ACTION INSULIN RECEPTOR
composed of two alpha subunits and two beta subunits linked by disulfide bonds
alpha chains are entirely extracellular and house insulin binding domains
linked beta chains penetrate through the plasma membrane
INSULIN ACTIONInsulin binds to receptorsInsulin binds to receptors
Activates tyrosine kinaseActivates tyrosine kinase
autophosphorilationautophosphorilation
Fully activates tyrosine kinaseFully activates tyrosine kinase
Serine and threonine phosporilationSerine and threonine phosporilation
Activation of phosphatidylinositolGrowth receptor binding protein 2
Generates phosphatidylinositol-3-4 And 3,4,5 phosphates
Activates glycogen synthase,Signals mitogen-activated
Protein (MAP) kinase
2nd messengers2nd messengers
↓ cAMP levels↓ cAMP levels
Activation of glucose transport systemGLUT-4 (for muscle and adipose tissue)
Activation of glucose transport systemGLUT-4 (for muscle and adipose tissue)
Glucose → glycogen → pyruvate → lactate → fatty acids Glucose → glycogen → pyruvate → lactate → fatty acids
INSULIN ACTION
INSULIN ACTION
lipogenesis
lipolysis
glycogenesis
glycolysis
ketogenesis
glycogenolysis
glycogenesis
gluconeogenesis
protein synthesis
proteolysis
Synthesized by the alpha cells of the islets of Langerhans from a preproglucagon precursor when the blood glucose concentration falls
Functions to increase blood glucose concentrations
It is known as a hyperglycemic hormone
It is a primary hormone that regulates hepatic glucose production and ketogenesis
Its activities are affected by glucose concentration and insulin
Liver – major site of glucose degradation
Increased blood glucose inhibits glucagon secretion
• Decreased in blood glucose levels from normal (90 mg/100 ml), increases plasma concentration of glucagon (hypoglycemic)
• Increased blood glucose levels, decreases plasma glucagon (hyperglycemic)
Increased blood amino acids stimulates glucagon secretion
• High conc. of amino acids (esp. alanine & arginine), stimulate secretion of glucagon
• In this instance, glucagon and insulin responses are not opposites
• Glucagon promotes rapid conversion of amino acids to glucose making it more available to tissues
Exercise stimulates glucagon secretion
• Glucagon increases fourfold to fivefold during exhaustive exercise
Fasting for several days stimulates glucagon secretion
Vagal stimulation and acetylcholine release
It can be suppresses or inhibited by:
• glucose
• fatty acids
• GLP-1 and secretin
• somatostatin (inhibits release)
• breakdown of liver glycogen (Glycogenolysis)
• increased Gluconegenesis in the liver
Glucagon
Adenylyl cyclase
cAMP
Protein kinase
Glycogen Phosphorylase A Glycogen Phosphorylase B
Glucose-1-phosphate
(active) (inactive)
Phosphatase activity
Kinase activity
Glucagon phosphorylates
Fructose-6-P
Insulin dephosphorylates
Glucose
Pyruvate
6 Phosphofructokinase
Fructose-6-P
Fructose 2,6-P2
Fructose 1,6 biphosphatase
If increased
If decreased
Fructose 1,6-P2
Glucagon
FFA
Triglyceride Synthesis
Beta oxidation
Malonyl CoA
Carnitine acyltransferase
Acetyl CoA carboxylase
Acetyl CoAIncreases lipolysis and delivery of FFA
to the liver
Beta oxidation
HMG-CoA reductase
Adipose tissue lipase
Decreases cholesterol synthesis
• It is produced by the delta cells of islets of Langerhans
• It inhibits insulin and glucagon secretion
• It is stimulated by:
• increased blood glucose
• increased amino acids
• increased fatty acids
• increased concentrations of several of the GIT hormones
• Inhibitory effects:
• Acts in the islet of Langerhans to depress both insulin and glucagon
• Decreases motility of the stomach, duodenum and gallbladder
• Decreases secretion and absorption in the GIT
• Principal role: it extends the period of time over which the food nutrients are assimilated in the blood
• Decreases the utilization of the absorbed nutrients by the tissues, thus preventing rapid exhaustion of the food and therefore making it available over a longer period of time
It is described as having a blood glucose level that is higher than normal, but not high enough to be classified as diabetes
It is also been referred to as borderline or chemical diabetes or ‘pre-diabetes’
It carries a high risk of progressing to type 2 diabetes
It is combination of impaired secretion of insulin and reduced insulin sensitivity (insulin resistance)
It is also characterized by hyperglycemia
It exists if the fasting plasma glucose level is <140 mg/dl
It exists if the 30-, 60- and 90-minute plasma concentration is >200 mg/dl with a 2-hour plasma glucose level between 140 and 200 mg/dl
People who have a higher risk of developing IGT are:
those overweight
those with a family history of diabetes
women who have had gestational diabetes
those having hypertension or abnormal lipid profile
high LDL-cholesterol (also called "bad" cholesterol)
low HDL-cholesterol (also called "good" cholesterol)
Risks associated with IGT:
•Increased risk of heart attack
•Coronary artery disease, hypertension
•Onset of Type 2 diabetes
Nondiabetic causes
Liver cell disease
Chronic illness, prolonged physical inactivity
Acute stress state
Starvation, malnutrition
Potassium depletion
Diseases of other Endocrine glands
Acromegaly
Islet cell tumors
Pheochromocytoma
Drugs that alter Glucose Tolerance
A. Drugs that raise blood sugar
Chronic glucocorticoid administration
Oral diuretic compounds
Estrogen
Nicotinic acid
B. Drugs that lower blood sugar
Salicylates
Monoamine-Oxidase inhibitors
• following a healthy balanced diet
• weight control
• exercise
• glucose monitoring
• blood pressure monitoring
Fasting Blood Glucose Test
Oral Glucose Tolerance Test
Postprandial Blood Glucose Test
DIABETES MELLITUS
What is it?
- Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels, which result from defects in insulin secretion, or action, or both.
DIABETES MELLITUS
What causes it?
- Insufficient production of insulin (either absolutely or relative to the body's needs), production of defective insulin (which is uncommon), or the inability of cells to use insulin properly and efficiently leads to diabetes.
DIABETES MELLITUS
What are the types?
► Type I DM – insulin dependent
► Type II DM – non-insulin dependent
DIABETES MELLITUS TYPE I DM
- Type IA DM results from beta cell destruction that usually leads to insulin deficiency, while for the Type IB DM lack immunologic markers.
- major susceptibility gene for type IA is located in chromosome 6, HLA region.
- classically occurs in juvenile but can occur at any age
DIABETES MELLITUS Type I DM
- had classic symptoms of diabetes called “ 3 polys” that is associated with weight loss: polyphagia(derire to aet a lot or sugar craving), polydipsia(desire to drink water at all time) and polyuria(have to urinate frequently).
- prone to ketosis due to reduced insulin level, could lead to an increase in lipolysis and release of free fatty acids.
DIABETES MELLITUS Type II DM
- Defect in insulin receptors in insulin targets cells
- Patients are usually obese/overweight- Stronger genetic basis
- Non-ketosis prone - Usually occurs at age 40 or over
DIABETES MELLITUS Type II DM
- 3 pathophysiologic abnormalities: Insulin resistance – decreased ability of insulin
to act effectively on peripheral target tissues. Impaired insulin secretion – endogenous
production continues, but the amount secreted is less than the normal at same plasma glucose concentration.
Increased hepatic glucose production – failure of hyperinsulinemia to suppress gluconeogenesis
Other Laboratory Procedures
For Diabetic screening and diagnosis
Criteria for Diagnosis
Symptoms of diabetes plus random/casual blood glucose concentration greater than or equal to 11.1 mmol/L or 200mg/dL.
Fasting plasma glucose greater than or equal to 7 mmol/L or 126mg/dL.
Two-hour plasma glucose greater than or equal to 11.1 mmol/L or 200 mg/dL during an OGTT.
Criteria for DiagnosisBased on the following premises:
Spectrum of fasting plasma glucose and the response to an oral glucose load varies in normal individuals
DM defined as the level of glycemia at which diabetes-specific cimplications are noted and not the level of tolerance from a population based viewpoint
(reflects new epidemiologic and metabolic evidence as issued by National Diabetes Group and WHO; prevalence of retinopathy in Native Americans begins to increase at FPG >116 mg/dL)
Risk factors for DM type IIFamily history of diabetes (parent or sibling)Obesity (≥ 20% of desired body weight or BMI ≥ 27 kg/m2)Age ≥ 45 yearsRace/ethnicity (African American, Hispanic American, Native American, Asian American, Pacific Islander)History of GDM or delivery of baby over 9 lbs)HypertensionLow HDL cholesterol (≤0.90 mmol/L) levels and/or high triglyceride levels (≥ 2.82 mmol/L)Polycystic ovary syndrome
Diagnosis MethodDiagnosis of diabetes MUST be based on blood glucose estimations Urine glucose must not be the basis for diagnosisTrue blood glucose should be estimated using enzymatic methods (Glucose Oxidase method)Blood glucose estimation should be specified whether it has been carried out on capillary blood, whole venous blood, or on venous plasma OGTT in a known diabetic is not necessaryIn all other persons, an OGTT must be carried out in order to exclude diabetes
Fasting Plasma Glucoseits widespread use as a screening test is strongly encouraged because
(1) a large number of individuals ho meet the current criteria for DM are unaware that they have the disorder
(2) epidemiologic studies suggest that type 2 DM may be present for up to a decade before diagnosis
(3) as many as 50% of individuals with type 2 DM have one or more diabetes-specific complications at the time of their diagnosis
Fasting Plasma Glucoseafter the person has fasted overnight (at least 8 hours), a single sample of blood is drawn and sent to the laboratory for analysis
Venous blood glucoseNORMAL: ≤ 100 mg/dL
IFG: 100 ≥ 110 mg/dL
DIABETIC: ≥ 110 mg/dL
Capillary blood glucoseNORMAL: ≤ 100 mg/dL
IFG: 100 ≥ 110 mg/dL
DIABETIC: ≥ 110 mg/dL
Plasma venous blood glucoseNORMAL: ≤ 110 mg/dL
IFG: 110 ≥ 126 mg/dL
DIABETIC: ≥ 126 mg/dL
Fasting Plasma Glucoseusually preferred: easy to perform, faster, and more convenient for the patientunder-diagnoses the problem: normal FPG, but will have an elevated 2-hour PG first abnormality that occurs is the rise in post-prandial blood glucosefasting levels rise to abnormal values much lateron the basis of FPG alone, complications due to tissue damage might already be present before diagnosis
Random Blood Glucose Test random blood samples (if taken shortly
after eating or drinking) may be used to test for diabetes when symptoms are present
blood glucose level of 200 mg/dl or higher indicates diabetes
must be reconfirmed on another day with a fasting plasma glucose or an OGTT
Intravenous glucose tolerance test given to patients who are unable to tolerate a large carbohydrate load orally or who have altered gastric physiologysame preparation as with OGTT glucose solution is injected within a 3 to 4 minute interval and blood samples are obtained at 5-15 minute intervals over periods varying from 30-90 minutes after the injection glucose values are plotted and from the data, a removal rate constant is obtainedlower values indicate an abnormal tolerance to glucose loadOGTT curves that are flat (no rise greater than 20mg/dL) are observed as the results of various malabsorption syndromes, in this case the test is useful if the additional presence of diabetes is suspected
Urinalysisnot a reliable diagnostic tool but may be used in conjunction with blood glucose estimationpersons with no sugar in their urine, but very high blood sugar levelsless than 0.1% of glucose normally filtered by the glomerulus appears in urine (< 130 mg/24 hr)Glycosuria or Glucosuria
Urinalysiscopper reduction method: Benedict’s test
Highly non-specificCan give false positive results in the presence of other reducing agents
Appearance of reaction Report as Glucose equivalent (mg/dL)
Clear blue to turbid green 0 0-100
Green to yellow precipitate 1+ 100-500
Greenish yellow to yellow 2+ 500-1000
Orange or brown 3+ 1000-2000
Brick red 4+ Over 2000
enzymatic reduction method: Glucose oxidase strips
more specific but can give false negative results
results may be affected by ascorbic acid
PHYSICAL EXAMINATION AND RELATED TESTS
PHYSICAL EXAMINATION INSPECTION PALPITATION PERCUSSION AUSCULTATION LABORATORY TESTS SCREENING FOR DISEASE
WHAT TO CHECK FORVITAL SIGNS GENERAL APPEARANCE
HEENT CARDIOVASCULAR
RESPIRATORY CHEST
GENITOURINARY LYMPHATIC
MUSCULOSKELETAL SKIN
NEUROLOGIC PSYCHIATRIC
SUPPORTIVE TESTS FOR DM
BLOOD PRESSURE PERIPHERAL PULSES
ECG URINALYSIS
RESPIRATION RETINAL EXAMINATION
FOOT EXAMINATION NEUROLOGIC EXAMINATION
BLOOD PRESSURE & PERIPHERAL PULSESORTHOSTATIC Bp increase or decrease by 20mmHG
after standing for one minute against a supine Bp measurement.
LOOK FOR SIGNS OF IRREGULAR HEART BEATS
ECG1. Abnormally fast or irregular heart rhythms. 2. Abnormally slow heart rhythms. 3. Abnormal conduction of cardiac impulses 4. Evidence of the occurrence of a prior heart attack.5. Evidence of an evolving, acute heart attack. 6. Evidence of an acute impairment to blood flow to the heart. 7. Adverse effects on the heart from various heart diseases or
systemic diseases. 8. Adverse effects on the heart from certain lung conditions. 9. Certain congenital heart abnormalities.
Evidence of abnormal blood electrolytes Evidence of inflammation of the heart or its lining
URINALYSISSPECIFIC GRAVITY GLUCONURIA
Ph ANTIBODIES
PROTEINURIA KETONURIA
ELECTROLYTES LEVEL
RESPIRATIONRESPIRATORY RATE
COMPENSATION
HISTORY OF SMOKING
RETINAL EXAMINATIONFLUORECEIN ANGIOGRAPHY
B-SCAN ULTRASOUND
FUNDUS PHOTOGRAPHY
Retinal photograph of a
patient complaining of
decreased vision.
Fluorescein angiogram
indicating fluid leakage within
the retina.
FOOT EXAMINATIONLOSS OF SENSATION
CHANGE IN SHAPE
FOOT ULCERS
NEUROLOGICAL TESTSSENSORY REFLEXES
COORDINATION & GAIT MOTOR
CRANIAL NERVES
MEDICAL HISTORY WEIGHT/BODY MASS INDEX FAMILY HISTORY & COMPLICATIONS CARDIOVASCULAR DISEASE MEDICAL CONDITIONS SMOKING EXERCISE
Genetic Considerations
Type I DM Genetic contributions involve multiple genes Development of the disease require inheritance of a sufficient
complement of genes to confer susceptibility Concordance in identical twins: 30-70%
Additional modifying factors must be present HLA complex polymorphisms – account for 40-50% of genetic
risk Region contain genes for class II MHC proteins (involved in
immune response; present antigen to helper T cells) Ability to present anitgemn dependent on amino acid
composition of the antigen-binding site Aa substitutions may alter the binding affinity of the antigens
Type I DM At least 17 other different genetic loci may
contribute susceptibility Polymorphisms in the promoter region of insulin
account for 10% of predisposition Genetic contributions not very strong component Most individuals with these haplotypes do not
develop diabetes Most individuals with type I DM do not have a first-
degree relative with the disorder
Type II DM Stronger genetic component Polygenic and multi-factorial Various genetic loci contribute to susceptibility Environmental factors further module phenotypic
expression Concordance in identical twins: 70-90% Genetic defect may not manifest itself unless and
environmental even or another genetic defect (obesity) is superimposed
Mutations account for only a small fraction of type II DM