Sources of Blood Glucose1. Carbohydrate of diet2. Liver glycogen by glycogenolysis3. 10% of Fat of diet by gluconeogenesis4. 58% of Protein of diet by gluconeogenesis5. Lactate from blood & RBCs by gluconeogenesis
Factors Regulating Blood Glucose1.Gastrointestinal factors:• Oral carbohydrate diet stimulates more insulin than intra-venous glucose• This may be due to secretion of glucagon-like substance by intestine which stimulates -cells of pancreas to secrete more insulin
Factors Regulating Blood Glucose2. Hepatic factors (Glucostat organ):A- If blood glucose level increased, liver decreases it by: 1. Oxidation of glucose (Glycolysis & Kreb’s) 2. Glycogenesis 3. LipogenesisB- If blood glucose level decreased, liver increases it by: 1. Glycogenolysis 2. Gluconeogenesis 3. Conversion to fructose and galactose into glucose
Factors Regulating Blood Glucose 3. Renal factors: • Normal Renal Threshold for Glucose = 180 mg/dl • Some patients may have Renal Diabetes, in which Renal Threshold is less than 140 mg/dl
4.Hormonal factors:1. Glucagon: 29 amino acid polypeptide Major target organ: liver Have no receptors on muscle cell Principal hormone for producing a rapid increase in plasma glucose concentration Dominates in Fasting State Metabolism Stimulates production of glucose by glycogenolysis and gluconeogenesis Secretion is suppressed in hyperglycemia
Glucagon Action on Cells Endocrine response to hypoglycemia
2. Epinephrine “fight or flight” A catecholamine secreted by the adrenal medulla Stimulates glucagon secretion and inhibits insulin secretion Stimulates glycogen breakdown (glycogenolysis) and decreases glucose oxidation Physical/emotional stress epinephrine production, releasing glucose for energy
3. Cortisol “Stress Hormone” Only hormone (besides insulin) needed to keep you alive Maintains general functioning of body metabolism and regulates blood pressure Secreted by adrenal cortex in response to ACTH of pituitary gland Cortisol causes breakdown of muscle protein, leading to amino acid release in blood Liver uses amino acids to make glucose (Gluconeogenesis!) Cortisol increases blood sugar!
4. Growth Hormone (GH) Primary function: stimulates growth of soft tissue, bone, and cartilage Secondary function: Effect on plasma glucose: 1. Inhibition of glucose uptake by peripheral cells 2. Stimulation of liver glycogenolysis 3. Acceleration of fatty acid catabolism (Stimulation of gluconeogenesis) Prolonged excess of GH (Acromegaly): Mild hyperglycemia, abnormal Oral Glucose Tolerance Test (OGTT)
5. ACTH ACTH stimulates the production of glucocorticoids Glucocorticoids stimulate gluconeogenesis
6. Thyroxin• It increases the blood glucose level by: 1. Increases the rate of absorption of glucose from intestine 2. Stimulates gluconeogenesis 3. Stimulates glycogenolysis 4. Thyroxine also stimulates glucose oxidation in tissues 5. However the net effect of this hormone is the increase in blood glucose level
7. Glucocorticoids• These hormones are secreted from zona fasiculata• They are hyperglycemic (Insulin antagonistic action)• They produce their effect by: 1. Inhibiting glucokinase 2. Stimulating glucose-6-phosphatase 3. Inhibiting tissue uptake of glucose 4. Stimulating gluconeogenesis On the other hand, Glucocorticoids 5. Stimulating glycogenesis by increasing the activity of glycogen synthase enzyme
8. Insulin First hormone identified (1920’s) by Banting and Best Tied string around pancreatic ducts of dogs or removed ducts. Only thing left were thousands of pancreatic islets, Isolated protein…and discovered insulin! Insulin is a hormone that is needed to convert sugars, starches, and other food into energy needed for daily life
7. Insulin• Circulating insulin rapidly binds to receptors on cell surfaces, increases glucose entry into cells and alters metabolic pathways Fed-state metabolism
Action of glucagon and insulin on theliver, muscle, and adipose tissue.
Phases of Glucose HomeostasisNutritional Gluconeogenic Well-Fed Post-absorptive Prolonged Status (early)Origin of Hepatic Hepatic glycogen, Gluconeo- Blood Exogenous glycogen, Gluconeogenesis genesisGlucose Gluconeogenesis Tissues All except liver. Brain & RBCs; Brain Using All Muscle, adipose Small amount by Slow rate; Glucose diminished rates Muscle RBCs normalMajor Fuel of the Glucose Glucose Glucose Ketone bodies Brain
Fed Post absorptive Gluconeogenic Prolonged 40 Exogenous (glucose from diet) Glucose Used g/hr 30 glucose from gluconeogenesis glucose from (lactate + amino acids) glucose from 20 liver glycogen gluconeogenesis (mostly lactate) 10 0 4 8 12 16 2 7 42 HOURS DAYSSources of blood glucose in the various nutritional states
Summary of Blood Glucose Homeostasis Maintenance of blood glucose concentration depends on insulin and glucagon Brain depends on glucose Prolonged starvation has <25% decline in glucose Hyperglycemia – too little insulin Hypoglycemia – too little intake or too much insulin Under conditions where insulin levels are high, the number of receptors declines and the target tissues become less sensitive, resulting in “down regulation”
22% 45% Glucose Homeostasis
Blood Glucose, What’s “normal”?
Pancreas Pancreas, controls blood glucose levels by secreting hormones into the blood Islet of Langerhans (, , ) 1. -cells (20-30% of islet cells) Glucagon 2. -cells (60-70% of islet cells) Insulin 3. -cells (2-8% of islet cells) Somatostatin
Role ofPancreas inNormalizing Blood Between After high carbohydrate diet Glucose meals Level
Distribution of Glucose After Meal
Distribution of Glucose After Meal Insulin released when glucose is elevated in plasma Insulin increases peripheral tissue uptake, so muscle and fat cells remove glucose from blood Cells breakdown glucose, releasing its energy in the form of ATP (via glycolysis and Kreb’s cycle) Liver and muscle store glucose as glycogen (short- term energy reserve) Adipose tissue stores glucose as fat (long-term energy reserve) Cells use glucose in protein synthesis Insulin is the ONLY hormone that lowers circulating glucose level!
Transcription and Translation of the Insulin Protein First, the DNA coded information (blue helix) in the cell nucleus is copied, or transcribed, to an RNA mirror image (red strand). Second, the ribosome (tan) translates the linear pattern described in the RNA to construct a protein strand. This translation is based on the Genetic Code (background text). Transfer-RNAs (Cross-like shapes) ferry (moving) amino acids to the growing protein chain based on the 3-codon RNA sequence. Finally, the Insulin protein strand folds itself into its active form.
DNA coded information inside the Nucleus Transcribed RNA Insulin moleculeTranscription &Translation of the Insulin Protein mRNA tRNA Ribosome
Preproinsulin 4 (21) 64 Lys31 Arg 65 Arg 132 Arg (24) 2 (30) Aids in transporting insulin through the membrane 3 (35) [Connecting peptide]
Aids in transporting insulin through the membrane PreproinsulinSynthesized in Ribosomes
ProinsulinIn Endoplasmic Reticulum
InsulinIn Golgi Apparatus
Synthesized in Ribosomes Leader (Signal) chain Post-translational Processing of Insulin In Endoplasmic Reticulum A chain 21 amino acidsIn Golgi Apparatus B chain 30 amino acids
Mechanism of Action of Insulin Muscle
Mechanism of Action of Insulin1. Increases peripheral tissue uptake (Fat, RBC’s & Muscle cells)
Mechanism of Action of Insulin5. Inhibits gluconeogenesis (4 enzymes)6. Stimulates Lipogenesis (Supplies Acetyl Co A, -Glycerol phosphate, NADPH & ATP)7. Inhibits lipolysis (1 enzyme)8. Stimulate transamination (Pyruvate to Alanine), (1 enzyme)
Protein synthesis 3 4Lipogenesis Glycogenesis Glycolysis 1 2
Oral Glucose Tolerance Test (OGTT) Collect fasting blood samples for determination of blood glucose and urine samples for detection of glucose in urine Give the patient (1g/Kg body weight, max. 50 g) glucose in half cup of water Every 30 min. collect a blood samples and urine samples, for 2.5 – 4 hr Draw a relation between blood glucose level (mg/dl) against time (hr)
Oral Glucose Tolerance Test (OGTT) Mild Moderate Severe RenalNo Parameter Normal Diabetes Diabetes Diabetes Diabetes Fasting 70 – 110 70 – 140 140 – 180 > 180 mg/dl 70 – 1101 Blood Glucose mg/dl mg/dl mg/dl mg/dl Peak2 Time After 1 hr After 1 hr After 1 hr After 1 hr After 1 hr Peak < 140 < 180 230 – 2703 Value > 270 mg/dl < 140 mg/dl mg/dl mg/dl mg/dl Time of return to 2:30 – 4:00 4:00 – 5:004 Fasting 2:00 hr 2:30 hr 2:00 hr hr hr Level Glucose Present in Present in the Present in the in5 Urine Absent Absent Middle of the all Middle of the Samples Samples Samples Samples
Oral Glucose Tolerance Test (OGTT)
Diabetes Mellitus A medical disorder characterized by hyperglycemia (elevated blood glucose level) especially after eating
“Diabetes“ is a Greek word meaning “passes through, a siphon”, due to polyuria “Mellitus” is a Greek word meaning “sweet” This is due to the diabetic’s urine attracts flies & bees because of its glucose content The Ancient Chinese test for diabetes by observing whether ants were attracted to a person’s urine
Diabetes Disease in which the body: Does not produce insulin, or Does not properly use insulin
Diabetes Warning signs: Extreme thirst (Polydipsia) Frequent urination (Polyuria) Unusual fatigue or drowsiness Unexplained weight loss Blurry vision from time to time Diabetes is the leading cause of kidney failure, blindness, and amputation in adults, and can also lead to heart disease
Main Types of Diabetes Mellitus (D.M.) Type I (IDDM) Type II (NIDDM)Insulin Dependent Non-Insulin Diabetes Mellitus Dependent Diabetes Mellitus
Other Types of Diabetes Mellitus (D.M.) (Non Type 1 – Non type 2)• Type 3:• Type 3A: Genetic defect in β-cell function• Type 3B: Genetic defect in insulin action• Type 3C: Diseases of the exocrine pancreas• Type 3D: Caused by hormonal defects (Endocrinopathies)• Type 3E: Caused by chemicals or drugs
Other Types of Diabetes Mellitus (D.M.)• Type 4: Gestational D.M. It appears in 2 – 5% of all pregnancies It is temporary & fully treatable under medical supervision About 20 – 50% go on to develop type II diabetes
Other Classes of D. M.5. Diabetes insipidus: due to deficiency of Vasopressin (ADH) polyuria
Other Classes of D. M.6. Renal diabetes: due to congenital defect in renal threshold for glucose (140 mg/dl or less)7. Stress diabetes (Emotional diabetes): due to secretion of catecholamines
8. Bronze diabetes: due to excessive absorption & deposition of iron in pancreas: a) Hyperglycemia D.M. b) Skin Bronze in color, c) Liver Cirrhosis9. Steroid diabetes: due to secretion or prolonged administration of glucocorticoids10. Pituitary diabetes: due to over-secretion of Growth hormone (Acromegaly)
7. Experimental diabetes: a) Alloxan diabetes Uncontrolled diabetes b) Streptozotocin diabetes Controlled diabetes c) Surgical diabetes: i. Total pancreatectomy ii. Partial pancreatectomy8. Drug-induced diabetes: large doses of dehydroascorbic acid
Causes of Diabetes Mellitus Insufficient production of Insulin Increased production of anti-insulin hormones, e.g.: 1. Cushings syndrome ( Cortisone) 2. Hyperthyroidism ( Thyroid Hormone) 3. Acromegaly ( Growth Hormone)
Risk Factors for Diabetes Mellitus2 1
4 23 1
9 107 85 6
High-Tech increases Body Weight Cellular phones and remote controls deprive us from walking! 20 times daily x 20 m = 400 m Walking distance lost/year 400x365 = 146,000 m 146 km = 25 h of walking 1 h of walking = 113-226 kcal Energy saved =2800-6000 kcal 0.4-0.8 kg adipose tissueRössner, 2002
Increased Time at Computer/TV/Video Decreases Time for Leisure-Time Physical Activity >
New Remote ControlCan Be Operated byRemote• No more leaning forward to get remote from coffee table means greater convenience for TV viewers• Television watching became even more convenient with Sony’s introduction of a new remote-controlled remote control
Eat to Live to Eat! Live!
“EAT TO LIVE”Intake = Expenditure Weight Stable “LIVE TO EAT”Intake > Expenditure Obese
reveals itself in childhood.can be made worse from excessive lifestyle.
Type I (IDDM) Insulin Dependent Diabetes It is caused by the destruction of insulin-producing cells (-cells of islets of Langerhans of pancreas) IDDM may be due to: 1. -cell destruction may be due to: a) -cell lesions (trauma or tumor) b) Viral infection c) Chemical toxins (rat poison) 2. Autoimmune mediated disorder 3. Idiopathic (Unknown cause)
Type I (IDDM) It is an autoimmune disorder, so confused with type II Known by misleading names: Juvenile (Childhood) onset diabetes (under 20–30 years) Usually accompanied with loss of body weight Characterized by Diabetic Ketoacidosis (DKA) Diabetic Coma
Type I IDDM Lipid metabolism Fatty acid production Ketone formation Decreased glucose uptake & Protein metabolism GlycogenolysisGluconeogenesisDecreased glucose uptake
Symptoms of Type 1 Diabetes Increased thirst Increased hunger (especially after eating) Dry mouth Frequent urination (polyuria) Unexplained weight loss (even though you are eating and feel hungry) Fatigue (weak, tired feeling) Blurred vision Labored respiration (heavy breathing, ٌ ُ َتن َ ّفس ُ ذي ّ ِ ْ( )جهKussmaul respirations) Loss of consciousness (rare)
Type II (NIDDM) Non-Insulin Dependent Diabetes In this case, the pancreas continues to manufacture insulin. However, this production may be inadequate or normal For some unknown reason, the body develops resistance to insulin, thus resulting in a relative insulin deficiency
Type II (NIDDM) NIDDM may range from:1. Insulin resistance with relative insulin deficiency, to:2. Insulin secretary defect with insulin resistance Insulin resistance may be due to: a) Decreased number of insulin receptors, or b) Insensitivity of insulin receptors to insulin
DIABETES TYPE 2:INSULIN RESISTANCE
Type II (NIDDM) This is a more complex problem than type I, but is sometimes easier to treat Known by misleading names: “Adult onset diabetes” (over 40 years), “Obesity-related diabetes” due to gain of body weight, or “Insulin-resistant diabetes” Chronic obesity leads to increased insulin resistance that can develop diabetes
Type II Diabetes Mellitus Decreased glucose uptake with any amount of insulin Insulin resistance
Insulin Resistant Cell
Insulin Shock People who accidentally take too much insulin may be victims of insulin shock The symptoms of insulin shock include: Agitation الهياج Trembling اإلرتِعاد Sweating ال َعَ ُق ت ّر Pallor الشحوب Speech difficulty صعوبة الكالم Unconsciousness فقذ الوعي
Insulin Shock Someone suffering from the preliminary symptoms is given sugar in the form of sweets or fruit An unconscious patient is given an injection of adrenaline into muscle, or glucose solution into a vein
Symptoms of Type 2 Diabetes Slow-healing sores or cuts Itching of the skin (usually in the vaginal or groin area) Yeast infections Recent weight gain Numbness ( ) َمَل ؛ اِخْ ِرارor tingling ذ ن ( )نَخْزof the hands and feet Impotence or erectile dysfunction
Bases of Treatment of Diabetes Mellitus
Type I (IDDM) Diabetes Mellitus It is treated with: 1. Insulin injections, human insulin is often preferred in initiating insulin treatment because it is less antigenic than animal-derived varieties 2. lifestyle adjustment 3. Monitoring of blood glucose levels 4. Experimental replacement of -cells (-cells Transplant) may become clinically available in future 5. Patient may requires immuno-suppressor drug, e.g.: “Cyclosporine”
Basis of Treatment of Type II (NIDDM) Type II may go unnoticed for years in patients before diagnosis, due to milder symptoms (No ketoacidosis) and can be sporadic1. Patient must reduces body weight (Diet) or Lifestyle Modification, which can restore insulin sensitivity2. Patient requires muscular exercise3. Patient may require an oral antidiabetic drugs4. When these failed, insulin therapy may be necessary
Diagnosis of Diabetes Mellitus Type I diabetes is usually prompted by recent symptoms of: Excessive urination (Polyuria) Excessive thirst (Polydipsia) Weight loss Diabetic ketoacidosis (DKA) The diagnosis of other types of diabetes is made by: Health screening Detection of hyperglycemia Signs & symptoms of D.M.
Criteria for Diagnosis of Diabetes Mellitus 1. Two fasting plasma glucose level above 125 mg/dl 2. Plasma glucose above 200 mg/dl two hours after a 50 g glucose load 3. Symptoms of D.M. and a random glucose above 200 mg/dl 4. Elevated glycosylated or glycated hemoglobin (glucose bound to Hb, HbA1C) of 6.0 or higher
Hypoglycemia Hypoglycemia may occur because of: An error in insulin dosage A small or missed meal Unplanned exercise Hypoglycemia, usually respond rapidly to the ingestion of sugar All diabetics should carry candy, lumps of sugar, or glucose tablets
An identification card, indicating that the patient is an insulin-treated diabetic, aids in recognizing hypoglycemia in emergencies Close family members should be instructed to administer glucagon with an easy-to-use injection device Emergency medical personnel, after confirming the hypoglycemia with a glucostick, should initiate therapy with a rapid bolus injection of 25 ml of 50% glucose solution followed by a continuous IV infusion of glucose
Manifestation & Complication of Diabetes 1- Carbohydrate Disturbances Hyperglycemia Glucosuria Hyperphagia (eating too much)
Diabetic Patients• Diabetic Patients must examine feet thoroughly, looking for blisters (,)بثور cuts ( )تخفيضاتand bruises ()كدمات
Dont miss a spot Diabetes can damage nerves (neuropathy), reducing the abilityIf youre unable to to feel pain in your feet. Thatsee some parts of means you may not notice ayour feet, use a small cut or blister until itmirror. becomes a large sore.
• Athletes foot isLook for infection a common fungal infection
Serious Complications of Chronic hyperglycemia
Chronic hyperglycemia Gangrene of toes
Chronic hyperglycemia Ophthalmoscope Normal Diabetic retinopathy
Continuous Glucose Monitor & Insulin Pump
GLUCOSE MONITORING DEVICES A device is now available for continuous glucose measurement and continuous insulin administration (i.e., a true artificial pancreas). The MiniMed Continuous Glucose Monitoring System (CGMS) measures glucose level every five minutes for seventy-two hours and records it in its internal memory.
GLUCOSE MONITORING DEVICES
GLUCOSE MONITORING DEVICES
GLUCOSE MONITORING DEVICES
GLUCOSE MONITORING DEVICES
Insulin pen injectors
Insulin jet injectorAn insulin jet injector uses high-pressure air to send a finespray of insulin under your skin. This device may be anoption if you cant use needles....
INSULIN DELIVERY DEVICES
Site of Insulin InjectionInsulin is best injected into any area of the body where fatty tissue is present and where large blood vessels, nervesand bones are not close to the surface .