Disorders of Carbohydrates Metabolism PDF

PMC 403 Disorders of Carbohydrates Metabolism Diabetes Mellitus Lecture 8 Outline Glucose Diabetes Symptoms Causes Diagnosis Treatment Glucose Glucose is a major energy substrate. It typically provides...

PMC 403 Disorders of Carbohydrates Metabolism Diabetes Mellitus Lecture 8 Outline Glucose Diabetes Symptoms Causes Diagnosis Treatment Glucose Glucose is a major energy substrate. It typically provides more than half the total energy obtained from a ‘western’ diet. Glucose is the only utilizable source of energy for some tissues, e.g. erythrocytes and the central nervous system. Many tissues are capable of oxidizing glucose completely to carbon dioxide; others metabolize it only as far as lactate, which can be converted back into glucose, principally in the liver and also in the kidneys, by gluconeogenesis. Even in tissues capable of completely oxidizing glucose, lactate is produced if insufficient oxygen is available. Sources of glucose are dietary carbohydrate (exogenous) glycogenolysis (release of glucose stored as glycogen) and gluconeogenesis (glucose synthesis from, for example, lactate, glycerol and most amino acids). Glycogen is stored in the liver and skeletal muscle, but only the former contributes to plasma glucose. Glucose Metabolism Glucose metabolism involves multiple processes, including glycolysis, gluconeogenesis, and glycogenolysis, and glycogenesis. Glycolysis in the liver is a process that involves various enzymes that encourage glucose catabolism in cells. Major process of the Glucose metabolism to produce chemical energy (ATP): Glycolysis + TCA cycle + Oxidative Phosphorylation When oxygen is limited, pyruvate is disposed in the form of lactate and glycolysis becomes the main source for ATP production Glucose levels Plasma glucose concentration depends on the relative rates of influx of glucose into the circulation and of its utilization. Fasting condition: Usually 2.5 mmol/L at any time or rising above 8.0 mmol/L in healthy subjects after a meal or above 5.0 mmol/L after an overnight fast. After a meal: Glucose is stored as glycogen, which is mobilized during fasting. Plasma glucose concentration usually falls to premeal concentrations within 4 h of a meal, but then continues to fall somewhat as fasting continues and hepatic glycogen stores are used up until, after about 24 h, adaptive changes lead to the attainment of a new steady state. After ∼72 h, plasma glucose concentration stabilizes and can then remain constant for many days. The principal source of glucose becomes gluconeogenesis, from amino acids and glycerol, whereas ketones, derived from fat, become the major energy substrate. Gluocse homeostasis The control of plasma glucose concentration, is achieved through the concerted action of various hormones, mainly insulin (the actions of which tend to lower plasma glucose concentration) and the ‘counterregulatory’ hormones, namely glucagon, cortisol, catecholamines and growth hormone Insulin Insulin is a 51–amino acid polypeptide, secreted by the β-cells of the pancreatic islets of Langerhans in response to a rise in plasma glucose concentration. It is synthesized as a prohormone, proinsulin. This molecule undergoes cleavage before secretion to form insulin and C-peptide. Insulin secretion is also stimulated by gut hormones collectively known as incretins, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, formerly known as gastric inhibitory polypeptide). Incretin release is stimulated by food, so that insulin secretion begins to increase before plasma glucose concentration. Functions of Insulin (1) Insulin promotes the removal of glucose from the blood through stimulating the relocation of insulin-sensitive GLUT-4 glucose transporters from the cytoplasm to cell membranes, particularly in adipose tissue and skeletal muscle. Fucnctions of Insulin (2) Insulin also stimulates glucose uptake in the liver, but by a different mechanism: it induces the enzyme glucokinase, which phosphorylates glucose to form glucose 6- phosphate, a substrate for glycogen synthesis. This process maintains a low intracellular glucose concentration, and thus a concentration gradient that facilitates glucose uptake. Fucnctions of Insulin (3) Insulin stimulates glycogen synthesis (and inhibits glycogenolysis) through interaction with an exquisitely coordinated control mechanism that is central to the regulation of plasma glucose concentration. In summary, binding of insulin to its receptor leads to activation of phosphoprotein phosphatase. Active phosphoprotein phosphatase dephosphorylates glycogen synthase (thereby activating it and promoting glycogen synthesis) and dephosphorylates phosphorylase kinase (rendering it inactive, and thus preventing the activation of glycogen phosphorylase, the key enzyme of glycogenolysis). As a result of these actions, in the fasting state, when insulin secretion is inhibited, hepatic glycogenolysis is stimulated and glucose is liberated into the blood. Fucnctions of Insulin (4) Insulin stimulates glycolysis and inhibits gluconeogenesis, by stimulating the expression of phosphofructokinase, pyruvate kinase and the synthesis of its key allosteric activator, fructose 2,6-bisphosphate. Fucnctions of Insulin (5) Insulin is also important in the control of fat metabolism: it stimulates lipogenesis and inhibits lipolysis. It stimulates amino acid uptake and protein synthesis (anabolic). It also stimulates the cellular influx of the predominantly intracellular ions potassium, magnesium and phosphate. Both insulin and incretins have a paracrine effect in the pancreas, reducing the secretion of glucagon by α-cells. Glucagon Glucagon is a 29–amino acid polypeptide secreted by the α-cells of the pancreatic islets; Its secretion is decreased by a rise in the plasma glucose concentration. In general, its actions oppose those of insulin: it stimulates hepatic (although not muscle) glycogenolysis through activation of glycogen phosphorylase, gluconeogenesis, lipolysis and ketogenesis. Disordered glucose homoeostasis can lead to hyperglycaemia (often to a degree diagnostic of diabetes) or hypoglycaemia. Diabetes Mellitus Aetiology & Pathogenesis Diabetes mellitus (DM) is a systemic metabolic disorder characterized by a tendency towards chronic hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism that arise from a defect in insulin secretion or action, or both. It is defined clinically from plasma glucose concentrations above which patients are at increased risk of retinopathy, nephropathy and neuropathy. It is a common condition, with a prevalence rate of ∼8% in the developed world. Diabetes can occur secondarily to other diseases (e.g. chronic pancreatitis), after pancreatic surgery and in conditions where there is increased secretion of hormones antagonistic to insulin (e.g. Cushing syndrome and acromegaly). Secondary diabetes is, however, uncommon. There are two main types of primary diabetes. In type 1 DM, there is destruction of pancreatic cells, leading to a decrease in, and eventually cessation of, insulin secretion. Approximately 10% of all patients with diabetes have type 1. They have an absolute requirement for insulin. In type 2 DM, insulin secretion is defective and delayed, and there is resistance to its actions. Most patients with type 2 DM can initially be successfully treated by diet, with or without antidiabetic drugs, but many eventually require treatment with insulin to achieve adequate glycaemic control. Type 1 DM usually presents acutely in younger people, with symptoms developing over a period of days or only a few weeks. However, there is evidence that the appearance of symptoms is preceded by a ‘prediabetic’ period of several months, during which growth failure (in children), a decline in insulin response to glucose and various immunological abnormalities can be detected. Type 2 DM tends to present more insidiously in middle-aged and elderly adults (although it is increasingly being diagnosed in obese young people), with symptoms developing over months or even longer. The prevalence rate of type 2 DM is >10% in individuals older than 75 years Approximately 10% of young adult patients present initially with apparent type 2 DM (but often without obesity), but although initially treated successfully with diet or antidiabetic drugs, subsequently progress quite rapid. Diagnosis The diagnosis of diabetes depends on the demonstration of hyperglycaemia, using values defined by the World Health Organization (WHO). In a patient with classic symptoms and signs of thirst and polyuria, a random venous plasma glucose concentration ≥11.1 mmol/L is diagnostic of diabetes; so, too, is a fasting venous plasma glucose concentration ≥7.0 mmol/L. Most patients presenting with type 1 DM, and some with type 2 DM clearly exceed these diagnostic limits and require no further tests to establish a diagnosis. In the absence of symptoms, these limits must be exceeded on more than one occasion for the diagnosis to be made. Even in symptomatic patients, diabetes is unlikely if a random venous plasma glucose concentration is ≤5.5 mmol/L. Diagnosis Individuals who have fasting plasma glucose concentrations that are elevated but not in the diabetic range have impaired fasting glycaemia (IFG). The lower threshold for IFG defined by the WHO and used in the UK and much of the rest of the world is 6.1 mmol/L, although the American Diabetes Association (ADA) recommends a value of 5.6 mmol/L. The WHO recommends that patients found to have IFG should undergo an oral glucose tolerance test (OGTT) to determine whether they have impaired glucose tolerance (IGT) or diabetes. However, many clinicians treat IFG simply as a state of intermediate glucose intolerance, and the ADA does not endorse the use of the OGTT in this group. Diagnosis Chronic hyperglycaemia can also be diagnosed using measurements of glycated haemoglobin (HbA 1c ), which is a marker of average plasma glucose concentration over many weeks. Haemoglobin undergoes glycation in vivo at a rate proportional to the plasma glucose concentration; the reaction proceeds through a reversible stage but, once the major stable product (HbA1c) is formed, it persists in that state for the lifetime of the red cell. Diagnosis HbA1c therefore provides a ‘time-weighted’ average of plasma glucose concentrations over the previous 2–3 months. More recent glucose concentrations contribute to a greater extent to this average than more historical ones (50% of the HbA1c concentration is accounted for by the average plasma glucose concentration during the last 30 days). HbA1c concentration is expressed as a proportion of total haemoglobin. In the UK and many other countries worldwide, it is reported as mmol/mol haemoglobin, although in some countries it is reported as percentage (%).