Blood Glucose Regulation PDF

Regulation of Blood Glucose  The maintenance of glucose level in blood within narrow limits is a very finely and efficiently regulated system. This is important, because it is essential to have continuous supply of glucose to the brain.  Although brain can utilize ketone bodies to some extent...

Regulation of Blood Glucose  The maintenance of glucose level in blood within narrow limits is a very finely and efficiently regulated system. This is important, because it is essential to have continuous supply of glucose to the brain.  Although brain can utilize ketone bodies to some extent, but it has an obligatory requirement for glucose.  RBC and renal medulla are also dependent on glucose for meeting their fuel needs. Factors maintaining the blood glucose A. Factors which increase blood glucose are: 1. Absorption from intestines 2. Glycogenolysis (breakdown of glycogen) 3. Gluconeogenesis 4. Hyperglycemic hormones (glucagon, steroids) B. Factors which decrease blood glucose are: 1. Utilization by tissues for energy 2. Glycogen synthesis 3. Conversion of glucose into fat (lipogenesis) 4. Hypoglycemic hormone (insulin) I. Feeding State Regulation  Following a meal, glucose is absorbed from the intestine and enters the blood.  The rise in the blood glucose level stimulates the secretion of insulin from beta cells of islets of Langerhans of pancreas.  The uptake of glucose by muscles and adipose tissues is dependent on insulin.  Moreover, insulin helps in the storage of glucose as glycogen or its conversion to fat Red Arrows = Stimulated Pathways Blue Arrows = Inhibited Pathways By Dr Esam Radwan 28  II. Fasting State Regulation  Normally, 2 to 2½ hours after a meal, the blood glucose level falls to near fasting levels. It may go down further; but processes that increase blood glucose prevent this.  Hepatic glycogenolysis will take care of the blood glucose level.  Thereafter, gluconeogenesis will take charge of the situation  Liver is the major organ that supplies glucose for maintaining blood glucose level  Hormones like glucagon, epinephrine, glucocorticoids, growth hormone, ACTH and thyroxine will keep the blood glucose level Effects of Hormones on Glucose Level in Blood A. Insulin (hypoglycemic hormone) 1. Favors glycogen synthesis 2. Promotes glycolysis 3. Inhibits gluconeogenesis B. Glucagon (hyperglycemic hormone) 1. Promotes glycogenolysis 2. Enhances gluconeogenesis 3. Depresses glycogen synthesis 4. Inhibits glycolysis C. Cortisol (hyperglycemic hormone) 1. 2. Increases gluconeogenesis 2. Releases amino acids from the muscle D. Epinephrine or Adrenaline (hyperglycemic) 1. Promotes glycogenolysis 2. Increases gluconeogenesis By Dr Esam Radwan 29  3. Favors uptake of amino acids E. Growth Hormone (hyperglycemic) 1. Decreases glycolysis 2. Mobilizes fatty acids from adipose tissue Insulin Structure of insulin  Insulin is a protein hormone with two polypeptide chains joined together by two disulphide bonds.  The A-chain has 21 amino acids and B-chain has 30 amino acids. Biosynthesis of insulin 1. Insulin is a protein synthesized and secreted by the beta cells of the islets of Langerhans of the pancreas. 2. The insulin is synthesized as a larger precursor polypeptide chain, the pre-pro-insulin. It is rapidly converted to pro-insulin in the endoplasmic reticulum 3. The proinsulin is transported to Golgi apparatus where it is cleaved by a protease removing a connecting peptide between chain A & chain B called C-peptide. 4. Insulin with 51 amino acids is thus formed Secretion of insulin  The insulin is packed into granules. The molecules take shape of a hexamer with 2 zinc ions and one calcium ion.  Approximately 50 units of insulin are secreted per day. I. Factors increasing insulin secretion By Dr Esam Radwan 31  1. Glucose  Glucose is the major stimulant of insulin secretion. As blood glucose level increases, the insulin secretion also correspondingly increases. 2. Gastrointestinal hormones:  Insulin secretion is enhanced by secretin, cholecystokinin and gastrin. After taking food, these hormones are increased. 3. Proteins and amino acids: Leucine and arginine are insulin-secretion stimulants. 4. Glucagon and growth hormone. II. Factors decreasing the insulin secretion 1. Epinephrine:  During stressful conditions and during exercise, adrenal medulla releases adrenaline. This suppresses insulin release, and at the same time, mobilizes glucose from liver for energy purpose. 2. Degradation of insulin rapidly by liver  Plasma half-life is less than 5 minutes. An insulin specific protease (insulinase) is involved in the degradation of insulin. Actions of Insulin 1. Glucose Uptake a. Insulin increases Glucose Transporter 4 (GluT4) in muscles and adipose tissues. b. In diabetes mellitus, the GIuT4 is reduced. However, glucose uptake in liver (by GluT2) is not affected because it is independent of insulin. 2. Increase Utilization of Glucose a. Insulin stimulates glycolysis b. Insulin activates glycogen synthase enzyme and so, glycogenesis. c. Insulin favors synthesis of fatty acids from glucose and so, lipogenesis d. Insulin inhibits gluconeogenesis 3. Anti-ketogenic Effect a. Insulin depresses inhibit ketogenesis 4. Other General Effects of insulin: By Dr Esam Radwan 31  a. Insulin is an anabolic hormone increase protein synthesis. b. Insulin is an essential growth factor for all mammalian cells. Diabetes Mellitus (DM)  Diabetes mellitus is a metabolic disease due to absolute or relative insulin deficiency.  It is a common clinical condition. About 10% of the total population, and about 20% of persons above the age of 50, suffer from this disease.  It is a major cause for morbidity and mortality.  Insulin deficiency leads to increased blood glucose level. In spite of this high blood glucose, the entry of glucose into the cell is inefficient. Hence, all cells are starved of glucose. I. Type-1 DM (Insulin-dependent DM):  About 10% of total diabetic patients are of type 1.  Here circulating insulin level is deficient. II. Type-2 DM (Non-insulin dependent DM):  About 90% of total diabetic patients are of type-2.  Here circulating insulin level is normal or mildly elevated or slightly decreased, depending on the stage of the disease. DM may be secondary to other known causes: a. Cushing's disease, thyrotoxicosis, acromegaly b. Drug induced (steroids) c. Pancreatic diseases (chronic pancreatitis). Type-1 DM  It constitutes approximately 10% of all diabetics  Onset is usually below 20 years of age, most commonly during adolescence.  It is characterized by an absolute deficiency of insulin either idiopathic or caused by an autoimmune attack destruction of islets cells of Langerhans.  This destruction requires both a stimulus from the environment (such as a viral infection) and a genetic determinant By Dr Esam Radwan 32  The pancreas fails to respond adequately to ingestion of glucose and insulin therapy is required to restore metabolic control and prevent life-threatening ketoacidosis which is common. Metabolic changes in Type-1 DM  The metabolic abnormalities result from deficiency of insulin and excess of glucagon: 1. Hyperglycemia is caused by increased hepatic production of glucose through gluconeogenesis, combined with diminished peripheral use due to an inability of muscle and adipose cells to take up glucose 2. Ketosis results from increased mobilization of fatty acids from adipose tissue, combined with accelerated hepatic synthesis of ketone bodies 3. Hypertriacylglycerolemia & hypercholesterolemia:  The activity of hormone-sensitive Lipoprotein lipase enzyme is decreased due to insulin deficiency, and this leads to decrease metabolism of Chylomicrons & VLDL.  There is excessive mobilization of fatty acids from adipose tissue caused by anti-insulin hormones e.g. glucagon  Fatty acids are converted by liver to triacylglycerol leading to increased secretion of VLDL  Elevated VLDL and chylomicron levels result in both hypertriacylglycerolemia & hypercholesterolemia Diagnosis of Type-1 DM 1. The onset of type 1 diabetes is typically during childhood or puberty 2. Symptoms develop rapidly by Abrupt appearance of: a. polyuria (frequent urination), b. polydipsia (excessive thirst), and c. polyphagia (excessive hunger) 3. These symptoms are usually accompanied by fatigue, weight loss and weakness 4. Diagnosis is confirmed by assaying fasting and postprandial blood glucose levels 5. Ketosis is common Treatment of Type-1 DM  By exogenous insulin injected subcutaneously DAILY FOREVER By Dr Esam Radwan 33  Type-2 DM  90% of the all-diabetic patients belong to this type.  The disease is due to insulin resistance and dysfunctional β cells.  There is a relative insulin deficiency, but patients do not require insulin to sustain life.  Type-2 disease is commonly seen in individuals above 40 years.  About 60% of patients are obese and these patients have high plasma insulin levels.  Ketosis is less common. Insulin resistance  It is the decreased ability of target tissues, such as liver, adipose tissue, and muscles, to respond properly to insulin leading to uncontrolled hepatic glucose production through gluconeogenesis, and decreased glucose uptake by muscles and adipose tissue  Obesity is the most common cause of insulin resistance Metabolic changes in Type-2 DM  The metabolic abnormalities are the result of insulin resistance expressed primarily in liver, muscle, and adipose tissue 1. Hyperglycemia which is caused by increased hepatic production of glucose, combined with diminished peripheral use 2. Ketosis is usually minimal or absent 3. Hypertriacylglycerolemia & hypercholesterolemia: Plasma chylomicrons and VLDL levels are elevated, resulting in an increase of triacylglycerol and cholesterol levels Diagnosis of Type-2 DM A. Glucose tolerance test B. Glycated Hemoglobin  The best index of long-term control of blood glucose level is measurement of glycated hemoglobin or glyco-hemoglobin.  When there is hyperglycemia, proteins react irreversibly, with glucose by a nonenzymatic process  When once attached, glucose is not removed from hemoglobin. Therefore, it remains inside the erythrocyte, throughout the life span of RBCs (120 days)  The glycated hemoglobins are together called HbA1c fraction. By Dr Esam Radwan 34   Normally the level of Hb A1c is less than 6%. The value 6% denotes very good control of diabetes by treatment measures; 7% means adequate control; 8% inadequate control and 9% means very poor control. Glucose tolerance test:  Glucose tolerance test is commonly employed as a diagnostic test for diabetes mellitus  The patient is given 75 g of glucose dissolved in 200 ml of water, orally following an 10 - 12 hours fast  Blood glucose concentrations are determined at thirty minute intervals for the next 2 hours  In diabetics, fasting blood glucose is initially high (greater than 126 mg/dl) and it rises to concentrations greater than 200 mg/dl following the oral administration of glucose  When the rate of glomerular filtration of glucose exceeds that of tubular reabsorption in the kidney (renal threshold = 180 mg/dl), glucose will appear in the urine (glucosuria). Indications for OGTT  Patient has symptoms suggestive of diabetes mellitus; but fasting blood sugar value is inconclusive (between 100 and 126 mg/dl).  During pregnancy, excessive weight gaining is noticed, with a past history of big baby (more than 4 kg) or a past history of miscarriage.  To rule out benign renal glucosuria. Contraindications for OGTT  There is no indication for doing OGTT in a person with confirmed diabetes mellitus.  OGTT has no role in follow-up of diabetes. It is indicated only for the initial diagnosis. IGT = Impaired Glucose Tolerance By Dr Esam Radwan 35 Causes for Abnormal GTT Curve 1. Impaired Glucose Tolerance (IGT)  Here plasma glucose values are above the normal level, but below the diabetic levels  Such persons need careful follow-up because IGT progresses to frank diabetes at the rate of 2% patients per year 2. Impaired Fasting Glycemia (IFG)  In this condition, fasting plasma glucose is above normal (between 110 and 126 mg/dl); but the 2 hours post-glucose value is within normal limits (less than 140 mg/dl).  These persons need no immediate treatment; but are to be kept under constant checkup. 3. Gestational Diabetes Mellitus (GDM)  This term used when carbohydrate intolerance is noticed, for the first time, during a pregnancy.  A known diabetic patient, who becomes pregnant, is not included in this category.  Women with GDM are at increased risk for subsequent development of frank diabetes.  GDM is associated with an increased incidence of neonatal mortality.  Maternal hyperglycemia causes the fetus to secrete more insulin, causing stimulation of fetal growth and increased birth weight.  After the childbirth, the women should be re-assessed. 4. Alimentary Glucosuria  Here the fasting and 2 hr values are normal; but an exaggerated rise in blood glucose following the ingestion of glucose is seen.  This is due to an increased rate of absorption of glucose from the intestine.  This is seen in patients after a gastrectomy or in hyperthyroidism. 5. Renal Glucosuria  Normal renal threshold for glucose is 180 mg/dl and if blood glucose rises above this, glucose starts to appear in urine. By Dr Esam Radwan 36   When renal threshold is lowered, glucose is excreted in urine while the blood glucose levels are within normal limits.  Renal threshold is lowered physiologically in pregnancy; it is a harmless condition; it will not progress.  Renal glucosuria is associated also with some renal diseases Metabolic Complications of Diabetes Mellitus I. Acute Metabolic Complications A. Diabetic Ketoacidosis  Ketosis is more common in type-1 diabetes mellitus.  Normally the blood level of ketone bodies is less than 1 mg/dl and only traces are excreted in urine  When the rate of synthesis exceeds the ability of extrahepatic tissues to utilize them, there will be accumulation of ketone bodies in blood. This leads to ketonemia and ketonuria (excretion in urine) and smell of acetone in breath.  All these three together constitute the condition known as ketosis. Diagnosis of Ketosis  The presence of ketosis can be established by the detection of ketone bodies in urine  Estimation of serum electrolytes, acid–base parameters and glucose estimation. Causes for Ketosis 1. Diabetes Mellitus:  The combination of hyperglycemia, glucosuria, ketonemia and ketonuria is called diabetic ketoacidosis (DKA).  Untreated diabetes mellitus is the most common cause for ketosis due to deficiency of insulin which causes accelerated lipolysis and more fatty acids are released into circulation.  Oxidation of these fatty acids increases the acetyl CoA which increases ketone bodies formation. 2. Starvation:  In starvation, the dietary supply of glucose is decreased and there is increased rate of lipolysis which provides excess acetyl CoA which is used for ketone bodies formation. By Dr Esam Radwan 37  3. Glucagon favors ketogenesis. 4. Hyperemesis (vomiting) in early pregnancy may also lead to starvation-like condition and may lead to ketosis. Consequences of Ketosis 1. Metabolic acidosis: Acetoacetate and beta-hydroxy butyrate are acids. When they accumulate, metabolic acidosis results 2. Reduced buffers: The plasma bicarbonate is used up for buffering of these acids. 3. Kussmaul's respiration: Patients will have compensatory hyperventilation. 4. Smell of acetone in patient's breath. 5. Osmotic diuresis induced by ketonuria and glucosuria may lead to dehydration. 6. Sodium loss: The ketone bodies are excreted in urine as their sodium salt 7. High potassium: Due to lowered uptake of potassium by cells in the absence of insulin. 8. Dehydration: The sodium loss further aggravates the dehydration. 9. Coma: Hypokalemia, dehydration and acidosis contribute to the lethal effect of ketosis. Management of Ketosis: 1. Parenteral administration of insulin and glucose by intravenous route to control diabetes. 2. Intravenous bicarbonate to correct the acidosis. 3. Correction of water imbalance by normal saline. 4. Correction of electrolyte imbalance. 5. Treatment of underlying precipitating causes, such as infection. II. Chronic Complications of Diabetes Mellitus 1. Vascular Diseases:  Atherosclerosis in medium sized vessels and consequent intravascular thrombosis may take place.  If it occurs in cerebral vessels, the result is paralysis and if it is in coronary artery, myocardial infarction results.  In the case of small vessels (micro-angiopathy), where endothelial cells are damaged which may lead to diabetic retinopathy and nephropathy. By Dr Esam Radwan 38 2. Complications in Eyes:  Early development of cataract of lens is due hyperglycemia.  Retinal microvascular abnormalities lead to retinopathy and blindness. 3. Neuropathy:  Peripheral neuropathy with paresthesia is very common.  Neuropathy may lead to risk of foot ulcers and gangrene. 4. Pregnancy:  Diabetic mothers tend to have big babies, because insulin is an anabolic hormone.  Chances of abortion, premature birth and intrauterine death of the fetus are also more, if the diabetes is not properly controlled. 5. Advanced Glycation End Products (AGEs) a) Glycation of body proteins in diabetic patients form Advanced Glycation End Products (AGEs) b) AGEs once occurred, it is completely irreversible. c) Glycation of collagen alters its properties leading to loss of its elasticity d) AGEs lead to accumulation of LDL, and consequent atherosclerosis. e) In diabetic vascular tissues, the concentration of AGEP is four times that of normal. f) Uptake of AGEs by macrophages will lead to production of inflammatory cytokines. g) AGEs formation might have a role in cataract formation. h) Metformin is an inhibitor of the formation of AGEs; this may reduce the complications of diabetes mellitus. By Dr Esam Radwan 39