Glucose Metabolism PDF

Glucose Metabolism Glucose is a primary source of energy for humans. The nervous system, including the brain, totally depends on glucose from the surrounding extracellular fluid (ECF) for energy. Nervous tissue cannot concentrate or store carbohydrates; therefore, it is critical to...

Glucose Metabolism Glucose is a primary source of energy for humans. The nervous system, including the brain, totally depends on glucose from the surrounding extracellular fluid (ECF) for energy. Nervous tissue cannot concentrate or store carbohydrates; therefore, it is critical to maintain a steady supply of glucose to the tissue. For this reason, the concentration of glucose in the ECF must be maintained in a narrow range. When the concentration falls below a certain level, the nervous tissue loses the primary energy source and are incapable of maintaining normal function.  Fate of Glucose Most of our ingested carbohydrates are polymers, such as starch and glycogen. Salivary amylase and pancreatic amylase are responsible for the digestion of these nonabsorbable polymers to dextrins and disaccharides, which are further hydrolyzed to monosaccharides by maltase, an enzyme released by the intestinal mucosa. Sucrase and lactase are two other important gut-derived enzymes that hydrolyze sucrose to glucose and fructose and lactose to glucose and When disaccharides are converted to monosaccharides, they are absorbed by galactose. the gut and transported to the liver by the hepatic portal venous blood supply Glucose is the only carbohydrate to be directly used for energy or stored as glycogen. Galactose and fructose must be converted to glucose before they can be used  After glucose enters the cell, it is quickly shunted into one of three possible metabolic pathways, depending on the availability of substrates or the nutritional status of the cell The ultimate goal of the cell is to convert glucose to carbon dioxide and water. The first step for all three pathways requires glucose to be converted to glucose-6-phosphate using the high energy molecule, ATP. This reaction is catalyzed by the enzyme hexokinase. Glucose-6-phosphate can enter the Embden-Myerhof pathway or the hexose monophosphate pathway or can be converted to glycogen The first two pathways are important for the generation of energy from glucose; the conversion to glycogen pathway is important for the storage of glucose  Regulation of Carbohydrate Metabolism During a brief fast, glucose is supplied to the ECF from the liver through glycogenolysis. When the fasting period is longer than 1 day, glucose is synthesized from other sources through gluconeogenesis. Control of blood glucose is under two major hormones: insulin and glucagon, both produced by the pancreas. Their actions oppose each other. Other hormones and neuroendocrine substances also exert some control over blood glucose concentrations, permitting the body to respond to increased demands for glucose or to survive prolonged fasts. It also permits the conservation of energy as lipids when excess substrates are ingested. Insulin is the primary hormone responsible for the entry of glucose into the cell. It is synthesized by the cells of islets of Langerhans in the pancreas. When these cells detect an increase in body glucose, they release insulin. The release of insulin causes an increased movement of glucose into the cells and increased glucose metabolism Insulin is normally released when glucose levels are high It decreases plasma glucose levels by increasing the transport entry of glucose in muscle and adipose tissue by way of nonspecific receptors. It also regulates glucose by increasing glycogenesis, lipogenesis, and glycolysis and inhibiting glycogenolysis. Insulin is the only hormone that decreases glucose levels and can be referred to as a hypoglycemic agent Glucagon is the primary hormone responsible for increasing glucose levels. It is synthesized by the cells of islets of Langerhans in the pancreas and released during stress and fasting states. When these cells detect a decrease in body glucose, they release glucagon. Glucagon acts by increasing plasma glucose levels by glycogenolysis in the liver and an increase in gluconeogenesis. It can be referred to as a hyperglycemic agent Epinephrine, produced by the adrenal medulla, increases plasma glucose by inhibiting insulin secretion, increasing glycogenolysis, and promoting lipolysis. Epinephrine is released during times of stress. Glucocorticoids, primarily cortisol, are released from the adrenal cortex on stimulation by adrenocorticotropic hormone (ACTH). Cortisol increases plasma glucose by decreasing entry into the cell and increasing Growth gluconeogenesis, hormone increasesliver glycogen, plasma and glucose by lipolysis. decreasing the entry of glucose into the cells and increasing glycolysis. Its release from the pituitary is stimulated by decreased glucose levels and inhibited by increased glucose Thyroxine that increases plasma glucose levels by increasing glycogenolysis, gluconeogenesis, and intestinal absorption of glucose. Somatostatin, produced by the islets of Langerhans of the pancreas, increases plasma glucose levels by the inhibition of insulin, glucagon, growth hormone, and other endocrine hormones.  HYPERGLYCEMIA Hyperglycemia is an increase in plasma glucose levels. In healthy patients, during a hyperglycemia state Insulin enhances membrane permeability to cells in the liver, muscle, and adipose tissue. It also alters the glucose metabolic pathways. Hyperglycemia, or increased plasma glucose levels, is caused by an imbalance of hormones.  Diabetes Mellitus ADA/World Health Organization (WHO) guidelines recommend the following categories of diabetes: Type 1 diabetes Type 2 diabetes Other specific types of diabetes Gestational diabetes mellitus (GDM) Type 1 diabetes is characterized by inappropriate hyperglycemia primarily a result of pancreatic islet –cell destruction and a tendency to ketoacidosis. Type 2 diabetes, in contrast, includes hyperglycemia cases that result from insulin resistance with an insulin secretory defect. An intermediate stage, in which the fasting glucose in increased above- normal limits but not to the level of diabetes, has been named impaired fasting glucose. Gestational diabetes mellitus is for women who develop glucose intolerance during pregnancy. Latent autoimmune diabetes of adults (LADA), often also late-onset autoimmune diabetes of adulthood or aging, slow onset type 1 diabetes or diabetes type 1.5 is a form of diabetes mellitus type 1 that occurs in adults, often with a slower course of onset. Adults with LADA may initially be diagnosed as having type 2 diabetes based on their age, particularly if they have risk factors for type 2 diabetes such as a strong family history or obesity. The diagnosis is based on the finding of high blood sugar together with the clinical impression that islet failure rather than insulin resistance is the main cause; detection of a low C-peptide and raised antibodies against the islets of Langerhans support the diagnosis. It can only be treated with the usual oral treatments for type 2 diabetes for a certain period of time,after which insulin treatment is usually necessary, as Maturity-onset well diabetes as long-term of youth monitoring (MODY) is a rare for complications. form The of diabetes concept that of LADA wasis first inherited inin introduced an1993. autosomal dominant fashion Type 1 diabetes mellitus is a result of cellular-mediated autoimmune destruction of the islets cells, causing an absolute deficiency of insulin secretion. Type 1 constitutes only 10% to 20% of all cases of diabetes and commonly occurs in childhood and adolescence. This disease is usually initiated by an environmental factor or infection (usually a virus) in individuals with a genetic predisposition and causes the immune destruction of the cells Idiopathic of the type pancreas 1 diabetes is and, therefore, a form of type 1a diabetes decreased production that of has no known insulin etiology, is strongly inherited, and does not have -cell autoimmunity. Pathogenesis of Type I DM Genetic Environment ? HLA-DR3/DR4 Viral infe..?? Autoimmune Insulitis ß cell Destruction Severe Insulin deficiency Type I DM Characteristics of type 1 diabetes include abrupt onset, insulin dependence, and ketosis tendency. One or more of the following markers are found in 85%to 90% of individuals with fasting hyperglycemia: Islet cell autoantibodies Insulin autoantibodies, Glutamic acid decarboxylase autoantibodies Tyrosine phosphatase IA-2 and IA-2B autoantibodies. Signs and symptoms include polydipsia (excessive thirst), polyphagia (increased food intake), polyuria rapid weight loss, hyperventilation, mental confusion, and possible loss of consciousness Complications include microvascular problems such as nephropathy, neuropathy, and retinopathy. Increased heart disease is also found in patients with diabetes Complications: Short term Complications: (metabolic) Hypoglycemia Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Lactic acidosis Long term Complications:(microangiopathy) Angiopathy, Retinopathy, Nephropathy, Neurophathy Long term Complications: Angiopathy Atherosclerosis Hyaline arteriolosclerosis Diabetic microangiopathy Nephropathy Nodular glomerulosclerosis Retinopathy Non Proliferative & Proliferative Neuropathy Peripheral axonal neuropathy Pathogenesis of Microangiopathy: Long standing diabetes Glycosylation of BV proteins. Protein deposits in the BM. Thick and Leaky blood vessels Exudation & Ischemia End Organ damage... Type 2 diabetes mellitus is characterized by hyperglycemia as a result of an individual’s resistance to insulin with an insulin secretory defect. This resistance results in a relative, not an absolute, insulin deficiency. Type 2 constitutes the majority of the diabetes cases. Most patients in this type are obese or have an increased percentage of body fat distribution in the abdominal region. This type of diabetes often goes undiagnosed for many years and is associated with a strong genetic predisposition, with patients at increased risk with an increase in age, obesity, and lack of physical exercise. Characteristics usually include adult onset of the disease and milder symptoms than in type 1, with ketoacidosis seldom occurring. However, these patients are more likely to go into a hyperosmolar coma and are at an increased risk of developing macrovascular and microvascular complications. Pathogenesis of Type II DM ß cell defect Environment Genetic Obesity ??? Abnormal Secretion Insulin resistance Relative Insulin Def. ß cell exhaustion Type II DM IDDM GDM is any degree of glucose intolerance with onset or first recognition during pregnancy Causes of GDM Include metabolic and hormonal changes. Patients withGDM frequently return to normal postpartum. However, this disease is associated with increased perinatal complications and an increased risk for development of diabetes in later years. Infants born to mothers with diabetes are at increased risk for respiratory distress syndrome, hypocalcemia, and hyperbilirubinemia. Fetal insulin secretion is stimulated in the neonate of a mother with diabetes. However, when the infant is born and the umbilical cord is severed, the infant’s oversupply of glucose is abruptly terminated, causing severe hypoglycemia  Pathophysiology of Diabetes Mellitus In both type 1 and type 2 diabetes, the individual will be hyperglycemic, which can be severe Glucosuria occur after the renal tubular transporter system for glucose becomes saturated. This happens when the glucose concentration of plasma As exceeds hepatic roughly glucose 180 mg/dLcontinues, the plasma glucose overproduction concentration reaches a plateau around 300 to 500 mg/dL (17–28 mmol/L). Provided renal output is maintained, glucose excretion will match the overproduction, causing the plateau. Note: mmol/L X 18 = mg/dL Infections in Diabetes: Blood vessel damage – ischemia Decreased intracellular glucose - defence Glycosylation of inflammatory mediators Glycosylation of immunoglobulins Lastly increased glucose in blood. *** Not just due to increased glucose….! In type 1, there is an absence of insulin with an excess of glucagon. This permits gluconeogenesis and lipolysis to occur. In type 2, insulin is present, as is (at times) hyperinsulinemia; therefore, glucagon is attenuated. Fatty acid oxidation is inhibited in type 2. This causes fatty acids to be incorporated into triglycerides for release as very low density lipoproteins (VLDL). DKA The laboratory findings of a patient with diabetes with ketoacidosis tend to reflect dehydration, electrolyte disturbances, and acidosis. Acetoacetate, beta hydroxybutyrate, and acetone are produced from the oxidation of fatty acids. The two former ketone bodies contribute to the acidosis. Lactate, fatty acids, and other organic acids can also contribute to a lesser degree. Bicarbonate and total carbon dioxide are usually decreased due to Kussmaul-Kien respiration (deep respirations). This is a compensatory mechanism to blow off carbon dioxide and remove hydrogen ions in the process. More typical of the untreated patient with type 2 diabetes is the nonketotic hyperosmolar state. The individualpresenting with this syndrome has an overproduction of glucose; however, there appears to be an imbalance between production and elimination in urine. Often, this state is precipitated by heart disease, stroke, or pancreatitis or infections The severe dehydration contributes to the inability to excrete glucose in the urine. Glucose concentrations exceed 300 to 500 mg/dL The laboratory findings of nonketotic hyperosmolar coma include Plasma glucose values exceeding1,000 mg/dL (55 mmol/L) Normal or elevated plasma sodium and potassium Slightly decreased bicarbonate, Elevated blood urea nitrogen (BUN) and creatinine An elevated osmolality (greater than 320 mOsm/dL).  Criteria for Testing for Prediabetes and Diabetes According to ADA recommendations, all adults older than 45 years should have a measurement of fasting blood glucose every 3 years unless the individual is otherwise diagnosed with diabetes. Testing should be carried out at an earlier age or more frequently in individuals who display overweight tendencies (i.e., body mass index [BMI] 25 kg/m2 Additional risk factors Habitually physically inactive Family history of diabetes in a first-degree relative In a high-risk minority population (e.g., African American,Latino, Native American, Asian American, and Pacific Islander) History of GDM or delivering a baby weighing more than 9 lb (4.1 kg) Hypertension (blood pressure 140/90 mm Hg) Low high-density lipoprotein (HDL) cholesterol concentrations (35 mg/dL [0.90 History of mmol/L]) impaired fasting glucose/impaired glucose tolerance Elevated Women with triglyceride concentrations polycystic 250 mg/dL ovarian syndrome (PCOS)(2.82 mmol/L) History of cardiovascular disease  Criteria for the testing for type 2 diabetes in asymptomatic children Initiation of testing at the age 10 years or at onset of puberty, if puberty occurs at a younger age, with follow-up testing every 2 years Overweight plus any two of the following Family history of type 2 diabetes in first or second degree relative Race/ethnicity (e.g., Native American, African American,Latino, Asian American…) Signs of insulin resistance or conditions associatedwith insulin resistance (e.g., acanthosis nigricans, hypertension, dyslipidemia, or PCOS) Maternal history of diabetes or GDM  Criteria for the Diagnosis of Diabetes Mellitus Three methods of diagnosis are suggested: 1) Symptoms of diabetes plus a random plasma glucose level of 200mg/dL 2) A fasting plasma glucose of 126 mg/dL, 3) An oral glucose tolerance test (OGTT) with a 2-hour postload (75-g glucose load) level 200 mg/dL, Each of which must be confirmed on a subsequent day by any one of the three methods The preferred test for diagnosing diabetes is measurement of the fasting plasma glucose level. Patients with fasting glucose levels more than 100 mg/dL but less than 126 mg/dL are called the impaired fasting glucose group. Another set of patients who had 2-hour OGTT levels of more than 140 mg/dL but less than 200 mg/dL was defined as having impaired glucose tolerance. Patients with impaired fasting glucose and/or impaired glucose tolerance are referred to as having “prediabetes,” indicating the relatively high risk for the development of diabetes in these patients.