Carbohydrate Metabolism Disorders & Diabetes Mellitus PDF

CARBOHYDRATE METABOLISM DISORDERS & DIABETES Dr. Halil RESMİ 3-4.12.2024 1 2 3 Diabetes Mellitus The health implications of diabetes include its; – Direct effects, – (and) long term complications (including coronary heart disease and cerebrovascular diseas...

CARBOHYDRATE METABOLISM DISORDERS & DIABETES Dr. Halil RESMİ 3-4.12.2024 1 2 3 Diabetes Mellitus The health implications of diabetes include its; – Direct effects, – (and) long term complications (including coronary heart disease and cerebrovascular disease/stroke). A person with diabetes has a twofold greater risk for myocardial infarction than a nondiabetic person of the same age and sex. 4 Metabolic Syndrome Insulin resistance or glucose intolerance is a component of a cluster metabolic factors found in individuals who are prone to cardiovascular disease, diabetes and stroke. This cluster also includes; – Obesity (especially weight gain in the abdominal region), – Atherogenic dyslipidemia, – Hypertension, – Thromboembolic state (elevated fibrinogen), – Inflammatory state (as indicated by elevated CRP). 5 Common symptomes of DM The symptomes of DM; – High blood and urine glucose levels, (hyperglycemia and glucosuria), – Polyuria, – Polydipsia (excessive thrist), – Polyphagia (constant hunger), – Sudden weight loss, – During acute episodes excessive blood and urinary ketones (ketonemia and ketonuria). 8  All these syndromes result of an inability to regulate glucose metabolism and are the consequence of high glucose levels. 9  GLUCOSE: PROPERTIES & FUNCTIONS The principal biochemical function of glucose is to provide energy for the life, Glucose is oxidized in glycolytic and tricarboxylic acid pathways, These pathways are primary source of energy for the biosynthesis of ATP. 10 Principle Glucose Metabolic Pathways 1. Glycolysis 2. Tricarboxylic Acid Cycle (TCA) 3. Glycogenesis & Glycogenolysis 4. Gluconeogenesis 11 12 16 17 21 Insulin Signalling Pathways Insulin signaling is initiated through binding and activation of its cell-surface receptor and initiates a cascade of; – phosphorylation and dephosphorylation events, – second-messenger generation, and – protein-protein interactions that result in diverse metabolic events in almost every tissue. 22 23 Insulin Signalling Pathways Genetic variation and functional change of the protein molecules involved in the insulin signaling pathway cause abnormal signal transduction, which triggers insulin resistance. 25 Insulin Signalling Defects The INSR gene mutations that cause Rabson- Mendenhall syndrome reduce the number of insulin receptors that reach the cell membrane or diminish the function of these receptors. Although insulin is present in the bloodstream, without enough functional receptors it is less able to exert its effects. This severe resistance to the effects of insulin impairs blood sugar regulation and affects many aspects of development in people with Rabson- Mendenhall syndrome. 26 Hormone Regulation of Glucose Metabolism The hormonal regulation of glucose metabolism has two achievements; – To store glucose in glycogen form, – To mobilize stored glucose to maintain the blood glucose levels. The regulation of glucose is essential for brain (and other tissues/organs) because their primary energy source is glucose. 27  The condition in which there is excess glucose, insulin store glucose as glycogen (and fat). In response to low blood glucose (as in fasting period) hyperglycemic agent act to stored macromolecules to form glucose. Proteins are metabolized to form glucose (gluconeogenesis) in liver and release into blood to maintain glucose levels. 28 Anabolic & Catabolic Hormones The most important hyperglycemic agents are glucagon, epinephrine, cortisol, tyroxine, growth hormone, and certain intestinal hormones. While insulin promotes anabolic metabolism (synthesis of macromolecules) these hormones in part induce catabolic metabolism to break down large molecules. 29 INSULIN 31 GLUCAGON & CORTIZOL Glucagon is synthesized in the α-cells of the pancreas, In DM, because of insulin deficiency, glucagon levels are elevated and are not supressed by carbohydrate loading, Cortisol and other adrenal corticosteroids increase the rate of gluconeogenesis from proteins and amino acids especially in the liver. 32  Insulin and glucagon have opposite effects, Insulin inhibits proteolysis, lipolysis, gluconeogenesis and glycogenolysis, Stimulates lipid synthesis and glycogenesis in the liver; increases protein synthesis in muscle; and accelerates triacylglycerol synthesis in fat cells. Insulin acts as the body’s only hypoglycemic agent. 33  In contrast, glucagon stimulates lipolysis, ketogenesis, gluconeogenesis and glycogenolysis. A meal rich in carbohydrate induces insulin secretion and supresses glucagon release, Hypoglycemia stimulate the release of glucagon, The net (and collective) result of the hypoglycemic agent (insulin) and the hyperglycemic agents is glucose hemostasis. 34  Glucose Metabolism in Diabetes Metabolic Process in the Normal Individual In the postabsorptive (fasting) state of normal individuals, the blood insulin-to-glucagon ratio is low, With this low ratio; muscle and hepatic glycogens are degraded as a source of glucose. Additional fasting results in breakdown of protein to amino acids in skeletal muscle, and lipolysis of triglyceride to fatty acids in adipose tissue. 38  The amino acid alanin and glycerol are used to synthesize glucose by means of gluconeogenesis. In addition, free fatty acids can be used as fuel by the heart, skeletal muscle and the liver. Just minute after ingestion of a meal, blood insulin levels rapidly increases. 39  Glucose and amino acids are potent stimulant of β-cells, To the peripheral cells, glucose uptake increases, Thus after a meal, blood glucose levels increase by only 20% to 40% in nondiabetic individuals. 40 Metabolic Process in the Person with Diabetes In diabetic individuals, both the production and metabolism of glucose are abnormal. In the fasting state, hepatic glucose release is greatly elevated that allows diagnosis: fasting glycemia of diabetes Both the insulin release (type 1 diabetes) or cellulary response to insulin (insulin resistance in type 2 diabetes) are decreased in diabetics. 41  Decreased insulin control causes the diabetic individuals to be a state of semistarvation, with increase dependence on triglyceride (as a source of fuel) and on protein (as a source of glucose precursor). Thus; in the fasting state, the diabetic person may have increased blood free fatty acid and ketones, After a meal, a prolonged rise in blood glucose is detected. 42  Classification of Diabetes Type 1 Diabetes Account for 5% to 10% of the diagnosed cases of diabetes, Caused by insufficient insulin secretion (insulinopenia), Insulin injection is necessary, These individuals are prone to ketoacidosis (an excess formation of ketoacids) and low blood pH (acidosis). 44 Type 2 Diabetes T2D occures primarily in persons 40 years and older, Recent reports have shown that T2D is rapidly spreading in the younger population. The occurance of T2D has no correlation with blood insulin levels, Generally, T2 diabetic individuals are not dependent on insulin injection, They are not prone to ketoacidosis. 45 Secondary Diabetes Secondary diabetes can be caused by; – Pancreatic disease – Acromegaly (growth hormone excess) – Cushing’s syndrome (elevated cortisol) – Glucagonoma – Somatostatinoma – Severe liver disease – Administration of certain drugs (theophylline, oral contraceptives containing high doses of eostrogen). 46 Impaired Glucose Tolerance Impaired glucose tolerance (IGT) is a condition in which an individual have a abnormal glucose tolerance but no frank fasting hyperglycemia. It was demonstrated that IGT is the intermediate step of in the development of T2D, IGT now is referred to as pre-diabetes. 47 Gestational Diabetes GD refers to diabetes that occurs temporarily during pregnancy, It was found that in most women with GD, the diabetic condition progressed to T2D, Screening of pregnant women for GD is important to prevent perinatal complications associated with maternal hyperglycemia. 49  The reasons of gestational diabetes; – Increased nutritional needs for pregnancy, – The greater number of adipose cells during pregnancy, – Increased secretion of hyperglycemic hormones (human placental lactogene, cortisol, prolactin and progesteron). This results in a nearly four-fold increase in the need for insulin secretion. 50  COMPLICATION of DIABETES The principle complication of DM; – Retinopathy – Neuropathy – Angiopathy – Nephropathy – Suspectibility to infections – Hyperlipidemia – Ketoacidosis – Hyperglycemic hyperosmolar nonketotic coma (HHNC). These complications occur more frequently in T1D than T2D (except HHNC). 51 Hyperlipidemia & Atherosclerosis Abnormal triglyceride, cholesterol and very- low dansity lipoprotein (VLDL) levels often are associated with T2D, HDL levels is often lower in diabetics than nondiabetics. 54 Diabetic Ketoacidosis In nondiabetic individuals, ketoacid formation is a minor pathway, In diabetic individuals, insulinopenia causes triglyceride mobilization from adipose tissue, Fatty acid oxidation increases and as a consequence keto acid production increases, Increased production of ketoacids consume bicarbonate and thereby lowering blood pH (acidosis). Mortality rate; About 1% to 8%. 56 Hyperglycemic Hyperosmolar Nonketotic Coma It is characterized by; – Blood glucose level above 600 mg/dL, – Serum osmolality above 350 mOsm/kg, – Extreme thirst – Frequent urination – Normal keto acid levels, – Normal or slightly low blood pH, – Lethergy or coma. – HHS is an emergency that requires immediate medical care. (Mortality rate; About 10% to 20%). 57 Hypoglycemia Hypoglycemia causes numerous neurogenic problems, ranging from mild to severe coma, seizures and death, The glucose levels at which symptoms begins to appear is around 50 mg/dL, The most often reason is aggresive use of insulin to maintain normoglycemia. 58 FUNCTION TESTS 60  Postprandial Plasma Glucose This test is carried out after a carbohydrate load to find out glucose clearance from the blood, A meal rich in carbohydrates often is used as a carbohydrate load, but a 75 g glucose is usually preferred over a meal, This is called the postprandial test. Two consecutive postprandial tests are recommended for diagnosis. 61  Two postprandial tests with glucose levels of 200 mg/dL or higher at 2 hours are suggestive of diabetes. Many factor including age, weight, previous diet, activity, illness, medications etc. can vary the accuracy of the test. 62  Oral Glucose Tolerance Test The OGTT evaluates glucose clearance from the circulation after glucose loading under defined and controlled conditons. American Diabetes Association (ADA) has standardized the test. 63 Oral Glucose Tolerance Test Standard conditions call for; – A minimum carbohydrate intake of 150 g/day for 3 days before test, – A min. 8-hour fast before test, – The patient must be ambulatory (because inactivity decreases glucose tolerance), – Excercise and emotional stress should be avoided. 64 Oral Glucose Tolerance Test In accordance with WHO recommendation, a blood glucose measurement should be made 2 hours after a 75 g glucose ingestion. A value of greater than (or equal to) 200 mg/dL is suggestive for DM. 65 Oral Glucose Tolerance Test The shape of glucose tolerance curve is useful for evaluating the OGTT, Healthy subjects peak at ½ hour and return to fasting levels at 2 hours, Daibetic individuals peak late (approx. 1 hour) or show a plateau at 2 to 3 hours and return to baseline value after 3 hours. 66 67 69 Plasma Insulin after Glucose Load Plasma insulin levels after a glucose load differentiate T1D from T2D, In a nondiabetic person, insulin levels peak 1 hour after a glucose load and return to fasting levels at 2 to 3 hours. Person with T1D respond to a glucose load with little or no insulin release above fasting levels. Individuals with T2D respond to the glucose with a abnormally late and often excessive increase insulin levels. 70  Fasting Blood Glucose The OGTT has been critized because of the poor reproducibility, ADA recommends fasting plasma glucose level rather than OGTT for detection of DM. 73  But there are conditions in which an OGTT is still valuable; – Individuals who have a borderline fasting glucose levels, – To screen pregnant women, – To distinguish (with the help of insulin levels) type 1 from type 2 diabetes. 74  Random Plasma Glucose Test This test can be done at any time of the day when an individual has severe diabetes symptoms. Diabetes is diagnosed at blood glucose of greater than or equal to 200 mg/dL. 75  Glycated Hemoglobin/HbA1c A minor Hb derivative called HbA1c is produced by glycation, the covalent binding of glucose to hemoglobin. 77 Glycated Hemoglobin/HbA1c Because this reaction is nonenzymatic and because the RBC is completely permeable to glucose, the quantity of HbA1c is directly proportional the average plasma glucose level, during 120-day life span of erythrocyte. Diabetes is diagnosed at an HbA1c of greater than or equal to 6.5%. 78 79 80 Urinary Glucose Urinary glucose is a poor marker of DM. 81  Urinary Protein One of the earliest signs of impending glomerular nephropathy is increased excretion of albumin in the urine, also called microalbuminuria. Monitoring of patients for microalbuminuria is now standard practice. Determination of the urine albumin/creatinine ratio on random urine sample is an effective screening test. (20-30 mg/g is defined as microalbuminuria). 83  Insulin Resistance (IR) Diabetes mellitus (DM) is one of the largest global public healthcare concerns due to its unstoppable incidence in addition to its associated micro- and macrovascular complications. Diabetic symptoms usually occurs later period of the disease. Therefore, it is needed a marker of insulin (IR) resistance, which is the main pathophysiological mechanism of diabetes. Estimate of IR appears to be a good tool as it emerges years before the development of DM (and its complications). 84  HOMA-IR The Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) has been widely used for the estimation of insulin resistance in clinical practice. It is calculated multiplying fasting plasma insulin (FPI) by fasting plasma glucose (FPG), then dividing by the constant 22.5. HOMA-IR = (FPI×FPG)/22.5. 85  Normal Range Different studies agree that the higher HOMA- IR indicates the more insulin resistance. HOMA-IR; – less than 1; optimal insulin sensitivity, – above 1.9; signal for early insulin resistance, – above 2.9 signal significant insulin resistance. 86