Carbohydrate Metabolism PDF

12 Carbohydrate metabolism Chemistry 176 Hyperglycaemia and diabetes mellitus 183 Physiology 176 Hypoglycaemia...

12 Carbohydrate metabolism Chemistry 176 Hyperglycaemia and diabetes mellitus 183 Physiology 176 Hypoglycaemia 194 This chapter discusses carbohydrate metabolism and its synthesize glucose, abnormalities, with emphasis on diabetes mellitus and store glucose in significant amounts, hypoglycaemia. In the next decade it is predicted that metabolize substrates other than glucose and ketones there will be about 250 million people worldwide with – plasma ketone concentrations are usually very low type 2 diabetes mellitus. and ketones are of little importance as an energy source under physiological conditions, CHEMISTRY extract enough glucose from the extracellular fluid The main monosaccharide hexoses are reducing sugars. (ECF) at low concentrations for its metabolic needs, Naturally occurring polysaccharides are long-chain because entry into brain cells is not facilitated by carbohydrates composed of glucose subunits (Table insulin. 12.1): Normally the plasma glucose concentration remains Starch, found in plants, is a mixture of amylose between about 4 mmol/L and 10 mmol/L, despite the (straight chains) and amylopectin (branched intermittent load entering the body from the diet. The chains). maintenance of plasma glucose concentrations below Glycogen, found in animal tissue, is a highly branched about 10 mmol/L minimizes loss from the body as well polysaccharide. as providing the optimal supply to the tissues. Renal tubular cells reabsorb almost all the glucose filtered PHYSIOLOGY by the glomeruli, and urinary glucose concentration Functions of extracellular glucose is normally too low to be detected by the usual tests, The main function of glucose is as a major tissue energy Glucose source. The simplified pathways of glycolysis and the Krebs cycle [tricarboxylic acid (TCA) cycle] are shown in Figures 12.1 and 12.2. The brain is highly dependent Hexose phosphates upon the extracellular glucose concentration for its energy supply; indeed, hypoglycaemia is likely to impair Triose phosphates cerebral function or even lead to irreversible neuronal damage. This is because the brain cannot: 2-Phosphoglycerate Table 12.1 Common reducing and non-reducing sugars Phosphoenolpyruvate Reducing sugars Non-reducing sugars Monosaccharides Glucose Pyruvate Fructose Galactose Lactate Disaccharides Lactose Sucrose Figure 12.1 Simplification of glycolysis pathways. (galactose + glucose) (fructose + glucose) Reproduced with kind permission from Candlish Maltose JK and Crook M. Notes on Clinical Biochemistry. (glucose + glucose) Singapore: World Scientific Publishing, 1993.  Physiology 177 Glucose Glucose- Ribose- Insulin 6-phosphate 5-phosphate Insulin is the most important hormone controlling TPP Transketolase plasma glucose concentrations. A plasma glucose concentration of greater than about 5 mmol/L acting via Fructose- Sedoheptulose- the glucose transporter 2 stimulates insulin release from 7-phosphate 6-phosphate the pancreas b-cell. These cells produce proinsulin, which consists of the 51-amino-acid polypeptide insulin and a linking peptide (C-peptide, Fig. 12.3). Splitting of the peptide bonds by prohormone convertases releases via Fructose-1, 6-diphosphate intermediates (mostly 32–33 split proinsulin) equimolar amounts of insulin and C-peptide into the ECF. Insulin binds to specific cell surface receptors on muscle and adipose tissue, thus enhancing the rate Pyruvate Lactate of glucose entry into these cells. Insulin-induced Pyruvate activation of enzymes stimulates glucose incorporation TPP dehydrogenase into glycogen (glycogenesis) in liver and muscle (Fig Acetyl CoA 12.4). Insulin also inhibits the production of glucose (gluconeogenesis) from fats and amino acids, partly by inhibiting fat and protein breakdown (lipolysis and Oxaloacetate Citrate proteolysis). The transport of glucose into liver cells is insulin independent but, by reducing the intracellular glucose a-Ketoglutarate concentration, insulin does indirectly promote the Succinate passive diffusion of glucose into them. Insulin also a-Ketoglutarate dehydrogenase directly increases the transport of amino acids, TPP potassium and phosphate into cells, especially muscle; Figure 12.2 Simplification of the tricarboxylic acid (Krebs) these processes are independent of glucose transport. cycle. CoA, coenzyme A; TPP, thiamine pyrophosphate. In the longer term, insulin regulates growth and Reproduced with kind permission from Candlish JK and development and the expression of certain genes. Crook M. Notes on Clinical Biochemistry. Singapore: World Scientific Publishing, 1993. Glucagon Glucagon is a single-chain polypeptide synthesized even after a carbohydrate meal. Significant glycosuria by the a-cells of the pancreatic islets. Its secretion is usually occurs only if the plasma glucose concentration stimulated by hypoglycaemia. Glucagon enhances exceeds about 10 mmol/L – the renal threshold. hepatic glycogenolysis (glycogen breakdown) and gluconeogenesis. How the body maintains extracellular glucose concentrations Control of plasma glucose concentration C-PEPTIDE During normal metabolism, little glucose is lost unchanged from the body. Maintenance of plasma glucose concentrations within the relatively narrow COO– NH3+ range of 4–10 mmol/L, despite the widely varying input S S from the diet, depends on the balance between the S S glucose entering cells from the ECF and that leaving S them into this compartment. INSULIN S Hormones concerned with glucose homeostasis Figure 12.3 Structure of proinsulin, indicating the Some of the more important effects of hormones on cleavage sites at which insulin and C-peptide are glucose homeostasis are summarized in Table 12.2. produced. 178 Carbohydrate metabolism Table 12.2 Action of hormones that affect intermediary metabolism Insulin Glucagon Growth hormone Glucocorticoids Adrenaline Carbohydrate metabolism In liver Glycolysis + Glycogenesis + Glycogenolysis + + Gluconeogenesis – + + In muscle Glucose uptake + – – Glycogenesis + Glycogenolysis + Protein metabolism Synthesis + + Breakdown – + Lipid metabolism Synthesis + Lipolysis – + + + Secretion Stimulated by Hyperglycaemia Hypoglycaemia Hypoglycaemia Hypoglycaemia Hypoglycaemia Amino acids Amino acids Stress Stress Stress Glucagon Fasting Sleep Gut hormones Inhibited by Adrenaline Insulin Somatostatin Glucocorticoids b-blockers Fasting IGF-1 Somatostatin Plasma NEFA concentrations Fall Rise Rise Rise Rise Plasma glucose concentrations Fall Rise Rise Rise Rise +, stimulates; –, inhibits; IGF-1, insulin-like growth factor 1; NEFA, non-esterified fatty acid. Somatostatin in phaeochromocytoma (adrenaline and noradrenaline This peptide hormone is released from the D cells of see Chapter 24) and thus oppose the normal action of the pancreas and inhibits insulin and growth hormone insulin. release. Other hormones The liver When plasma insulin concentrations are low, for The liver is the most important organ maintaining a example during fasting, the hyperglycaemic actions constant glucose supply for other tissues, including the of hormones, such as growth hormone (GH), brain. It is also of importance in controlling the post- glucocorticoids, adrenaline (epinephrine) and prandial plasma glucose concentration. glucagon, become apparent, even if there is no increase Portal venous blood leaving the absorptive area of the in secretion rates. Secretion of these so-called counter- intestinal wall reaches the liver first, and consequently regulatory hormones may increase during stress and the hepatic cells are in a key position to buffer the in patients with acromegaly (GH, see Chapter 6), hyperglycaemic effect of a high-carbohydrate meal Cushing’s syndrome (glucocorticoids, see Chapter 8) or (Fig. 12.5).  Physiology 179 lactate or the carbon chains resulting from deamination of certain amino acids (mainly alanine) (Table 12.3). The liver contains the enzyme glucose-6-phosphatase, which, by hydrolysing G6P derived from either glycogenolysis Outer 1 1 1 1 branches or gluconeogenesis, releases glucose and helps to 1 1 maintain extracellular fasting concentrations. Hepatic 1 2 2 1 glycogenolysis is stimulated by the hormone glucagon, 2 2 secreted by the a-cells of the pancreas in response to a fall in the plasma glucose concentration, and by 3 3 Inner catecholamines such as adrenaline or noradrenaline. branches During fasting, the liver converts fatty acids, 4 released from adipose tissue as a consequence of low insulin activity, to ketones. The carbon chains of some amino acids may also be converted to ketones (Table R 12.3). Ketones can be used by other tissues, including the brain, as an energy source when plasma glucose concentrations are low. Figure 12.4 Structure of glycogen. Open circles depict glucose moieties in a-1,4 linkage and the black Other organs circles those in a-1,6 linkages at branch points. R indicates the reducing end group. The outer branches The renal cortex is the only other tissue capable of terminate in non-reducing end groups. Reproduced gluconeogenesis, and of converting G6P to glucose. The with permission from Nyhan WL and Barshop BA. Atlas gluconeogenic capacity of the kidney is particularly of Inherited Metabolic Diseases, 3rd edition. London: important in hydrogen ion homeostasis and during Hodder Arnold, 2012. prolonged fasting. Other tissues, such as muscle, can store glycogen but, because they do not contain glucose-6-phosphatase, The entry of glucose into liver and cerebral cells is they cannot release glucose from cells and so can only not directly affected by insulin, but depends on the use it locally; this glycogen plays no part in maintaining extracellular glucose concentration. The conversion of the plasma glucose concentration. glucose to glucose-6-phosphate (G6P), the first step in glucose metabolism in all cells, is catalysed in the liver Systemic effects of glucose intake by the enzyme glucokinase, which has a low affinity for The liver modifies the potential hyperglycaemic effect glucose compared with that of hexokinase, which is found of a high-carbohydrate meal by extracting relatively in most other tissues. Glucokinase activity is induced by more glucose than in the fasting state from the portal insulin. Therefore, hepatic cells extract proportionally plasma. However, some glucose does pass through less glucose during fasting, when concentrations in the liver and the rise in the systemic concentration portal venous plasma are low, than after carbohydrate ingestion. This helps to maintain a fasting supply of Table 12.3 Metabolism of the carbon skeleton of some glucose to vulnerable tissues such as the brain. amino acids to either carbohydrate (glycogenic) or fat The liver cells can store some of the excess glucose as (ketogenic) glycogen. The rate of glycogen synthesis (glycogenesis) from G6P may be increased by insulin secreted by Glycogenic Glycogenic and ketogenic Ketogenic the b-cells of the pancreas in response to systemic Alanine Isoleucine Leucine hyperglycaemia. The liver can convert some of the excess Arginine Lysine glucose to fatty acids, which are ultimately transported Glycine Phenylalanine as triglyceride in very low-density lipoprotein (VLDL) Histidine Tyrosine and stored in adipose tissue. Methionine Under normal aerobic conditions, the liver can Serine synthesize glucose by gluconeogenesis using the metabolic products from other tissues, such as glycerol, Valine 180 Carbohydrate metabolism BRAIN MUSCLE G6P Insulin GLYCOGEN INTESTINE CO2 + H2O G6P GLUCOSE Glucose Insulin Insulin G6P G6P GLYCOGEN Triose-P Triose-P Acetyl CoA Fatty acid + Glycerol-3-P Fatty acid + Glycerol-3-P Glycerol Triglyceride TRIGLYCERIDE  VLDL  LIVER ADIPOSE TISSUE Figure 12.5 Post-prandial metabolism of glucose. CoA, coenzyme A; G6P, glucose-6-phosphate; Glycerol-3-P, glycerol-3-phosphate; Triose-P, triose phosphate or glyceraldehyde 3-phosphate; VLDL, very low-density lipoprotein. stimulates the b-cells of the pancreas to secrete insulin. these actions are impaired. Both muscle and adipose Insulin may further enhance hepatic and muscle tissue store the excess post-prandial glucose, but the glycogenesis. More importantly, entry of glucose into mode of storage and the function of the two types of adipose tissue and muscle cells, unlike that into liver and cell are very different, as will be shown later. brain, is stimulated by insulin and, under physiological conditions, the plasma glucose concentration falls to Ketosis near fasting levels. Conversion of intracellular glucose Adipose tissue and the liver to G6P in adipose and muscle cells is catalysed by the Adipose tissue triglyceride is the most important long- enzyme hexokinase, which, because its affinity for term energy store in the body. Greatly increased use glucose is greater than that of hepatic glucokinase, of fat stores, for example during prolonged fasting, ensures that glucose enters the metabolic pathways in is associated with ketosis. Adipose tissue cells, acting these tissues at lower extracellular concentrations than in conjunction with the liver, convert excess glucose those in the liver. The relatively high insulin activity to triglyceride and store it in this form rather than after a meal also inhibits the breakdown of triglyceride as glycogen. The components are both derived from (lipolysis) and protein (proteolysis). If there is relative glucose, fatty acids from the glucose entering hepatic or absolute insulin deficiency, as in diabetes mellitus, cells and glycerol from that entering adipose tissue cells.  Physiology 181 In the liver, triglycerides are formed from glycerol- Most tissues, other than the brain, can oxidize fatty 3-phosphate (from triose phosphate or glyceraldehyde- acids to acetyl CoA, which can then be used in the TCA 3-phosphate) and fatty acids [from acetyl coenzyme A cycle as an energy source. When the rate of synthesis (CoA)]. The triglycerides are transported to adipose exceeds its use, the hepatic cells produce acetoacetic acid tissue cells incorporated in VLDL, where they are by enzymatic condensation of two molecules of acetyl hydrolysed by lipoprotein lipase. The released fatty CoA; acetoacetic acid can be reduced to b-hydroxybutyric acids (of hepatic origin) are re-esterified within these acid and decarboxylated to acetone. These ketones can cells with glycerol-3-phosphate, derived from glucose, be used as an energy source by brain and other tissues at which has entered this tissue under the influence of a time when glucose is in relatively short supply. insulin. The resultant triglyceride is stored and is far Ketosis occurs when fat stores are the main energy more energy dense than glycogen (see Chapter 13). source and may result from fasting or from reduced During fasting, when exogenous glucose is nutrient absorption, for example due to vomiting. Mild unavailable and the plasma insulin concentration ketosis may occur after as little as 12 h of fasting. After is therefore low, endogenous triglycerides are short fasts, metabolic acidosis is not usually detectable, reconverted to free non-esterified fatty acids (NEFAs) but, after longer periods, more hydrogen ions may and glycerol by lipolysis (Fig. 12.6). Both are be produced than can be dealt with by homeostatic transported to the liver in plasma, the NEFA being buffering mechanisms, depleting the plasma bicarbonate protein bound, predominantly to albumin. Glycerol concentration, which therefore falls (see Chapter 4). enters the hepatic gluconeogenic pathway at the The plasma glucose concentration is maintained triose phosphate stage; the glucose synthesized can be principally by hepatic gluconeogenesis, but during released from these cells, thus minimizing the fall in prolonged starvation, such as that in anorexia nervosa or glucose concentrations. during childhood, ketotic hypoglycaemia may occur. The BRAIN G6P Acetyl CoA CO2 + H2O Glucose KETONES + H+ Triglyceride G6P GLYCOGEN Triose-P Glycerol KETONES + H+ + Pyruvate Acetyl CoA NEFA FA LIVER ADIPOSE TISSUE Figure 12.6 Intermediary metabolism during fasting: ketosis. CoA, coenzyme A; FA, fatty acid; G6P, glucose-6-phosphate; NEFA, non-esterified fatty acid. 00_CBMM_4147_BOOK_3rd.indb 181 06/12/2011 08:13 180 Carbohydrate metabolism BRAIN MUSCLE G6P Insulin GLYCOGEN INTESTINE CO2 + H2O G6P GLUCOSE Glucose Insulin Insulin G6P G6P GLYCOGEN Triose-P Triose-P Acetyl CoA Fatty acid + Glycerol-3-P Fatty acid + Glycerol-3-P Glycerol Triglyceride TRIGLYCERIDE  VLDL  LIVER ADIPOSE TISSUE Figure 12.5 Post-prandial metabolism of glucose. CoA, coenzyme A; G6P, glucose-6-phosphate; Glycerol-3-P, glycerol-3-phosphate; Triose-P, triose phosphate or glyceraldehyde 3-phosphate; VLDL, very low-density lipoprotein. stimulates the b-cells of the pancreas to secrete insulin. these actions are impaired. Both muscle and adipose Insulin may further enhance hepatic and muscle tissue store the excess post-prandial glucose, but the glycogenesis. More importantly, entry of glucose into mode of storage and the function of the two types of adipose tissue and muscle cells, unlike that into liver and cell are very different, as will be shown later. brain, is stimulated by insulin and, under physiological conditions, the plasma glucose concentration falls to Ketosis near fasting levels. Conversion of intracellular glucose Adipose tissue and the liver to G6P in adipose and muscle cells is catalysed by the Adipose tissue triglyceride is the most important long- enzyme hexokinase, which, because its affinity for term energy store in the body. Greatly increased use glucose is greater than that of hepatic glucokinase, of fat stores, for example during prolonged fasting, ensures that glucose enters the metabolic pathways in is associated with ketosis. Adipose tissue cells, acting these tissues at lower extracellular concentrations than in conjunction with the liver, convert excess glucose those in the liver. The relatively high insulin activity to triglyceride and store it in this form rather than after a meal also inhibits the breakdown of triglyceride as glycogen. The components are both derived from (lipolysis) and protein (proteolysis). If there is relative glucose, fatty acids from the glucose entering hepatic or absolute insulin deficiency, as in diabetes mellitus, cells and glycerol from that entering adipose tissue cells.  Hyperglycaemia and diabetes mellitus 183 During gluconeogenesis, hydrogen ions are reused. hepatic and renal gluconeogenesis from lactate Under aerobic conditions, the liver consumes much cannot occur anaerobically, more lactate than it produces. anaerobic glycolysis is stimulated because the The physiological accumulation of lactic acid during falling adenosine triphosphate (ATP) levels cannot muscular contraction is a temporary phenomenon and be regenerated by the TCA cycle under anaerobic rapidly disappears at rest, when slowing of glycolysis conditions. allows aerobic processes to ‘catch up’. The combination of impaired gluconeogenesis and Pathological lactic acidosis increased anaerobic glycolysis converts the liver from an organ that consumes lactate and H+ to one that Lactic acid, produced by anaerobic glycolysis, may either generates large amounts of lactic acid. Severe hypoxia, be oxidized to CO2 and water in the TCA cycle or be for example following a cardiac arrest, causes marked reconverted to glucose by gluconeogenesis in the liver. lactic acidosis. If diabetic ketoacidosis is associated with Both the TCA cycle and gluconeogenesis need oxygen; significant volume depletion, this hypoxic syndrome anaerobic glycolysis is a non-oxygen-requiring pathway. may aggravate the acidosis. (See Chapter 4 for a further Pathological accumulation of lactate may occur because: discussion of lactic acidosis.) production is increased by an increased rate of The glycolytic pathway as well as the TCA cycle are anaerobic glycolysis, summarized in Figures 12.1 and 12.2. use is decreased by impairment of the TCA cycle or impairment of gluconeogenesis. HYPERGLYCAEMIA AND DIABETES Tissue hypoxia (Fig. 12.8) due to the poor tissue MELLITUS perfusion of the ‘shock’ syndrome is usually the most Hyperglycaemia may be due to: common cause of lactic acidosis. Hypoxia increases intravenous infusion of glucose-containing fluids, plasma lactate concentrations because: severe stress (usually a transient effect) such as the TCA cycle cannot function anaerobically and trauma, myocardial infarction or cerebrovascular oxidation of pyruvate and lactate to CO2 and water accidents, is impaired, diabetes mellitus or impaired glucose regulation. GLYCOGEN G6P G6P GLYCOGEN Pyruvate LACTATE + H+ LACTATE + H+ LACTATE+ H+ Pyruvate LIVER MUSCLE Figure 12.8 Metabolic pathways during tissue hypoxia. G6P, glucose-6-phosphate. 184 Carbohydrate metabolism Diabetes mellitus There is a spectrum of disorders ranging from mainly Diabetes mellitus is caused by an absolute or relative insulin resistance with relative insulin deficiency to a insulin deficiency. It has been defined by the World predominantly secretory defect with insulin resistance. Health Organization (WHO), on the basis of Other specific types of diabetes mellitus laboratory findings, as a fasting venous plasma glucose concentration of 7.0 mmol/L or more (on more than one A variety of inherited disorders may be responsible for occasion or once in the presence of diabetes symptoms) the syndrome, either by reducing insulin secretion or by or a random venous plasma glucose concentration causing relative insulin deficiency because of resistance of 11.1 mmol/L or more. Sometimes an oral glucose to its action or of insulin receptor defects, despite high tolerance test (OGTT) may be required to establish the plasma insulin concentrations. diagnosis in equivocal cases. The interpretation of this Genetic defects of b-cell function test is shown below, but, briefly, diabetes mellitus can be Maturity-onset diabetes of the young (MODY): diagnosed if the venous plasma glucose concentration – MODY 1: mutation of the hepatocyte nuclear is 7.0 mmol/L or more (fasting) and/or 11.1 mmol/L factor (HNF4A) gene, or more 2 h after the oral ingestion of the equivalent – MODY 2: mutation of the glucokinase gene, of 75 g of anhydrous glucose. Diabetes mellitus can be – MODY 3: mutation of the HNF1A gene. classified into the following categories. Some cases are thought to be point mutations in Type 1 diabetes mellitus mitochondrial deoxyribonucleic acid (DNA) associated Previously called insulin-dependent diabetes mellitus, with diabetes mellitus and deafness and are usually this is the term used to describe the condition in patients autosomal dominant. for whom insulin therapy is essential because they are Genetic defects of insulin action prone to develop ketoacidosis. It usually presents during childhood or adolescence. Most of these cases are due to Type A insulin resistance (insulin receptor defect), immune-mediated processes and may be associated with for example leprechaunism, lipoatrophy and other autoimmune disorders such as Addison’s disease, Rabson–Mendenhall syndrome. vitiligo and Hashimoto’s thyroiditis. It has been suggested Insulin deficiency due to pancreatic disease that many cases follow a viral infection that has damaged Chronic pancreatitis. the b-cells of the pancreatic islets. Individuals most Pancreatectomy. at risk are those with human leucocyte antigen (HLA) Haemochromatosis. types DR3 and DR4 of the major histocompatibility Cystic fibrosis. complex. Autoantibodies to islet cells, insulin, tyrosine phosphatases IA-2 and IA-2b and glutamic decarboxylase Endocrinopathies (GAD) are found in about 90 per cent of cases. There Relative insulin deficiency, due to excessive GH is a form of type 1 diabetes called idiopathic diabetes (acromegaly), phaeochromocytoma, glucocorticoid mellitus that is not autoimmune mediated but is strongly secretion (Cushing’s syndrome). inherited and more common in black and Asian people. Drugs The insulin requirement of affected people can fluctuate widely and the cause is unknown. There is also LADA Thiazide diuretics. (latent autoimmune diabetes of adults), sometimes Interferon-a. called slow-onset type 1 diabetes. Glucocorticoids. Infections Type 2 diabetes mellitus Septicaemia. Previously called non-insulin-dependent diabetes Congenital rubella. mellitus, this is the most common variety worldwide Cytomegalovirus. (about 90 per cent of all diabetes mellitus cases). Patients are much less likely to develop ketoacidosis than those Rare forms of autoimmune-mediated diabetes with type 1 diabetes, although insulin may sometimes Anti-insulin receptor antibodies. be needed. Onset is most usual during adult life; there Stiff man syndrome, with high levels of GAD is a familial tendency and an association with obesity. autoantibodies.  Hyperglycaemia and diabetes mellitus 185 Genetic syndromes associated with diabetes homeostasis and diabetes mellitus. The definition is Down’s syndrome. that the fasting venous plasma glucose is 6.1 mmol/L Turner’s syndrome. or more but less than 7.0 mmol/L, and less than Klinefelter’s syndrome. 7.8 mmol/L 2 h after an OGTT. Myotonic dystrophy. Subjects at risk of developing diabetes mellitus Gestational diabetes mellitus A strong family history of diabetes mellitus may suggest In the UK, about 4–5 per cent of pregnancies are that an individual is at risk of developing diabetes complicated by gestational diabetes mellitus (GDM). mellitus (particularly type 2), as may a family history It is associated with increased fetal abnormalities, of GDM, IGT or IFG. Those with predisposing HLA for example high birthweight, cardiac defects and types and autoimmune disease may be susceptible polyhydramnios. In addition, birth complications, to developing type 1 diabetes. Type 2 diabetes is maternal hypertension and the need for caesarean more common in certain racial groups, such as Afro- section may occur. If maternal diet/lifestyle factors fail Caribbeans, South Asians and Pacific Islanders. One of to restore glucose levels, insulin is usually required to the reasons why type 2 diabetes is on the increase is the try to reduce the risk of these complications. increasing tendency to obesity and central adiposity in Women at high risk for GDM include those who urbanized and more sedentary populations consuming have had GDM before, have previously given birth to a high-calorie diets. high-birthweight baby, are obese, have a family history of The thrifty phenotype (Barker–Hales) hypothesis diabetes mellitus and/or are from high-risk ethnic groups, proposes that nutritional deficiency in fetal and early for example black or South Asian. These women should infancy associated with low birthweight increases be screened at the earliest opportunity and, if normal, the risk of developing type 2 diabetes and insulin retested at about 24–28 weeks, as glucose tolerance resistance. progressively deteriorates throughout pregnancy. In some units 50 g oral glucose is used and the blood glucose is Insulin resistance syndrome or metabolic syndrome sampled at 1 h – plasma glucose of more than or equal to It has been recognized that certain coronary heart disease 7.8 mmol/L being diagnostic (O’Sullivan’s screening test risk factors occur together. There is an aggregation of for gestational diabetes). If fasting venous plasma glucose lipid and non-lipid risk factors of metabolic origin. is 7.0 mmol/L or more and/or the random measurement A particular cluster is known as the metabolic syndrome, gives a concentration of 11.1 mmol/L or more (some syndrome X or Reaven’s syndrome and is closely linked doctors prefer to use a lower cut-off of about 9.0 mmol/L to insulin resistance. One definition is the presence of in pregnancy), the woman has GDM. In equivocal cases, three or more of the following features: an OGTT is indicated. Six weeks post partum, the woman should be reclassified with a repeat OGTT. Abdominal obesity (waist circumference): – male more than 102 cm (40 in), Impaired glucose tolerance – female more than 88 cm (35 in). The WHO definition of impaired glucose tolerance Fasting plasma triglycerides more than 1.7 mmol/L. (IGT) is a fasting venous plasma glucose concentration Fasting plasma high-density lipoprotein (HDL) of less than 7.0 mmol/L and a plasma glucose cholesterol: concentration between 7.8 mmol/L and 11.1 mmol/L – male less than 1.0 mmol/L, 2 h after an OGTT. Some patients with IGT develop – female less than 1.3 mmol/L, diabetes mellitus later and may require an annual OGTT Blood pressure more than or equal to 130/85 mmHg. to monitor for this. However, because of the increased Fasting blood glucose more than 5.5 mmol/L. risk of vascular complications, secondary causes of IGT should be sought, dietary advice given, if necessary, and Plasma levels of insulin would be expected to be the patient followed up. In pregnancy IGT is treated as raised, that is, hyperinsulinaemia. Other associated GDM because of the risks to the fetus. features may include polycystic ovary syndrome, fatty liver, raised fibrinogen and plasminogen activator Impaired fasting glucose inhibitor 1 concentrations, renal sodium retention, Impaired fasting glucose (IFG), like IGT, refers to a hyperuricaemia and dense low-density lipoprotein metabolic stage intermediate between normal glucose (LDL) particles (see Chapter 13). 186 Carbohydrate metabolism Metabolic features of diabetes mellitus Long-term effects of diabetes mellitus Patients with type 1 diabetes tend to be diagnosed before Vascular disease is a common complication of diabetes the age of 40 years, are usually lean and have experienced mellitus. Macrovascular disease due to abnormalities of weight loss at the time of presentation. They may large vessels may present as coronary artery, cerebrovascular present with diabetic ketoacidosis. Conversely, patients or peripheral vascular insufficiency. The condition is with type 2 diabetes often present later, usually after the probably related to alterations in lipid metabolism and age of 40 years, and are often overweight or obese. The associated hypertension. The most common cause of death presentation can be insidious and they may have had is cardiovascular disease, including myocardial infarction. diabetes years before diagnosis. Microvascular disease due to abnormalities of small Hyperglycaemia blood vessels particularly affects the retina (diabetic retinopathy) and the kidney (nephropathy); both may If plasma glucose concentration exceeds about be related to inadequate glucose control. Diabetes is 10 mmol/L, glycosuria would be expected. High urinary one of the most common causes of patients requiring glucose concentrations produce an osmotic diuresis and renal dialysis. Microvascular disease of the kidney is therefore polyuria. Cerebral cellular dehydration due to associated with proteinuria. hyperosmolality, secondary to hyperglycaemia, causes Kidney disease is associated with several thirst (polydipsia). A prolonged osmotic diuresis may abnormalities, including proteinuria and progressive cause excessive urinary electrolyte loss. These ‘classic’ renal failure. Diffuse nodular glomerulosclerosis symptoms are suggestive of diabetes mellitus. (Kimmelstiel–Wilson lesions) may cause the nephrotic Diabetic patients on insulin may show the syndrome. The presence of small amounts of albumin following conditions. The ‘dawn’ phenomenon is the in the urine (microalbuminuria) is associated with an physiological response of the elevation of blood glucose increased risk of developing progressive renal disease, concentration in the early morning prior to breakfast which may sometimes be prevented by more stringent due to nocturnal spikes in GH concentration and a rise plasma glucose and blood pressure control. The renal in plasma cortisol concentration that increase hepatic complications may be partly due to the increased gluconeogenesis. Conversely, in some diabetic patients glycation of structural proteins in the arterial walls nocturnal hypoglycaemia may evoke a rebound supplying the glomerular basement membrane; similar counter-regulatory hyperglycaemia called the Somogyi vascular changes in the retina may account for the high phenomenon. Patient blood glucose checking at 02.00– incidence of diabetic retinopathy. Glycation of protein 04.00 h, or continuous glucose monitoring if available, in the lens may cause cataracts. may distinguish these conditions, as the Somogyi Infections are also more common in diabetic phenomenon reveals hypoglycaemia. It is sometimes patients, for example urinary tract or chest infections, possible to ameliorate these conditions by giving cellulitis and candida. Diabetic neuropathy can occur, intermediate-acting insulin before bedtime. which can be peripheral symmetric sensory, peripheral Abnormalities in lipid metabolism painful, acute mononeuropathies or autonomic. It These may be secondary to insulin deficiency. Lipolysis has been suggested that sorbitol is implicated in the is enhanced and plasma NEFA concentrations rise. aetiology of diabetic neuropathy through the action of In the liver, NEFAs are converted to acetyl CoA and aldolase reductase. Erectile dysfunction is also relatively ketones, or are re-esterified to form endogenous common and in some cases may be partly neurologically triglycerides and incorporated into VLDLs; the latter mediated. accumulate in plasma because lipoprotein lipase, which Diabetic ulcers, for example of the feet, can lead to is necessary for VLDL catabolism, requires insulin for gangrene and amputation. The ulcers can be ischaemic, optimal activity. High-density lipoprotein cholesterol neuropathic or infective. The joints can also be affected, concentration tends to be low in type 2 diabetes. If for example Charcot’s joints. Other features of diabetes insulin deficiency is very severe, there may also be mellitus are skin disorders, such as necrobiosis lipoidica, chylomicronaemia. The rate of cholesterol synthesis is and abscesses. also increased, with an associated increase in plasma LDL concentrations. Consequently, patients with Principles of management of diabetes mellitus diabetes may show high plasma triglyceride, raised The management of diabetes mellitus is considered cholesterol and low HDL cholesterol concentrations. briefly, although consulting a specialist text is  Hyperglycaemia and diabetes mellitus 187 recommended if further information is required. Insulin proximal tubular cells reabsorb most of the glucose requirements vary in patients with type 1 diabetes. For in the glomerular filtrate. Glycosuria, as defined example, the dose may need to be increased during above, occurs only when the plasma, and therefore any illness or during pregnancy and reduced if there is glomerular filtrate, concentrations exceed the tubular increased activity or meals are missed. reabsorptive capacity. This may be because the plasma In patients with type 2 diabetes, plasma glucose and glomerular filtrate concentrations are more than concentrations may be controlled by diet, associated about 10 mmol/L, and therefore the normal tubular with weight reduction, and increased physical activity, reabsorptive capacity is significantly exceeded. Very but insulin may be required during periods of stress rarely, if the glomerular filtration rate is much reduced, or pregnancy. In this group insulin secretion can be there may be no glycosuria despite plasma glucose stimulated by the sulphonylurea drugs, such as gliclazide, concentrations more than 10 mmol/L. A diagnosis of glipizide, glibenclamide or glimepiride. Biguanides, diabetes mellitus should never be made on the basis of usually metformin, can also be used and are particularly glycosuria. useful in obese patients. Metformin decreases intestinal Blood glucose glucose absorption and hepatic gluconeogenesis as well Blood glucose concentrations may be measured using as increasing tissue insulin sensitivity. Metformin can glucose testing reagent strips. The colour change of inhibit oxidative phosphorylation, which can, under the strip can be assessed visually or by using a portable certain circumstances, lead to lactic acid accumulation. glucose meter and the reaction often involves an enzyme Acarbose delays post-prandial absorption of glucose by determination of glucose, for example glucose oxidase. inhibiting a-glucosidase. Meters should ideally be overseen by laboratory staff Other oral agents are the thiazolidinediones or expert in point of care testing (see Chapter 30). Although ‘glitazones’, for example rosiglitazone and pioglitazone, the measurement of blood glucose concentrations which activate g-peroxisome proliferator-activated involves the discomfort of several skin punctures, receptors and which can reduce insulin resistance many motivated patients are able to adjust their insulin by a number of metabolic pathways, some of which dose more accurately based on these results than on involve increasing the transcription of nuclear proteins those obtained by testing their urine. This method of that control free fatty acid and tissue glucose uptake. testing is also useful in the detection of hypoglycaemia. Repaglinide is a meglitinide that increases insulin release For patients who do not like blood testing, urinary from pancreatic b-cells and enhances tissue insulin glucose testing can be used, but of course cannot detect sensitivity. The incretins are gastrointestinal hormones hypoglycaemia and is dependent on the renal glucose that increase insulin release from the pancreas after threshold. eating, for example glucagon-like peptide (GLP-1) and gastric inhibitory peptide (GIP). They are rapidly Glycated haemoglobin inactivated by the enzyme dipeptidyl peptidase-4 (DPP- Glycated haemoglobin (HbA1c) is formed by non- 4). Incretin mimetics such as exenatide or liraglutide enzymatic glycation of haemoglobin and is dependent or DPP-4 inhibitors such as sitagliptin, vildagliptin or on the mean plasma glucose concentrations and on the saxagliptin are being used in type 2 diabetes mellitus.. lifespan of the red cell; falsely low values may be found It is now recognized that diabetes mellitus is not in patients with haemolytic disease. Measurement of just a glucose disorder. It is important also to optimize blood HbA1c may not reveal potentially dangerous abnormal plasma lipids (see Chapter 13) and correct short-term swings and nor does HbA1c detect hypertension, particularly if there is microalbuminuria hypoglycaemic episodes and thus plasma glucose or proteinuria (see Chapter 19). estimations may also be useful. This was expressed as a percentage of total blood Monitoring of diabetes mellitus haemoglobin concentration and gives a retrospective Glycosuria assessment of the mean plasma glucose concentration Glycosuria can be defined as a concentration of during the preceding 6–8 weeks. The higher the urinary glucose detectable using relatively insensitive, glycated haemoglobin, the poorer the mean diabetic or but specific, screening tests. These tests often depend glycaemic control. on the action of an enzyme, such as glucose oxidase, Glycated haemoglobin used to be expressed in incorporated into a diagnostic strip. Usually, the percentage units but now is expressed as mmol/mol 188 Carbohydrate metabolism and conversion between the units is by the following and less than 3.5 g/mol in females. An abnormal result equation: IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c should be confirmed in two out of three urine samples (%) – 2.15] ¥ 10.929. HbA1c tests are certified by the in the absence of other causes of proteinuria (see National Glycohemoglobin Standardization Program Chapter 19). Apart from being predictive of diabetic (NGSP) to standardize them against the results of renal complications, urinary albumin excretion is also the 1993 Diabetes Control and Complications Trial associated with increased vascular permeability and (DCCT) but now are expressed as IFCC (International enhanced risk of cardiovascular disease. Federation of Clinical Chemistry) units. Intervention Optimization of glycaemic control can slow the trials for type 1 and type 2 diabetes have shown that progression of microalbuminuria, as can treating trying to optimize glycaemic control, as judged by HbA1c, hypertension. Some recommend a target blood to about 7 per cent (or above 53 mmol/mol) reduces pressure lower than 140/80 mmHg in type 2 diabetes, or the risk of microvascular diabetic complications. 135/75 mmHg or lower if microalbuminuria is present. The blood pressure targets are usually more aggressive Fructosamine in type 1 diabetes, partly as the lifetime risk of overt The measurement of plasma fructosamine concentrations nephropathy is greater. Angiotensin-converting may be used to assess glucose control over a shorter enzyme (ACE) inhibitor therapy, such as lisinopril time course than that of HbA1c (about 2–4 weeks), but in type 1 diabetic patients with microalbuminuria, the assay has methodological limitations. Fructosamine can result in a decline in the albumin excretion rate; reflects glucose bound to plasma proteins, predominantly similar findings have been shown with enalapril in albumin, which has a plasma half-life of about 20 days type 2 diabetes. This action of ACE inhibitors is only but is problematic in patients with hypoalbuminaemia, partially dependent on their blood pressure-lowering for example due to severe proteinuria. This assay may ability, and therefore they presumably also have other sometimes be useful in pregnancy and also if haemoglobin important renal protective actions. The angiotensin II variants, for example HbS or HbC, exist that may interfere receptor antagonists (ARAs), for example irbesartan with certain HbA1c assays. and losartan, have also been shown to have renal Blood ketones protective actions. Monitoring of blood ketones may have a place in the home management of type 1 diabetes. A Acute metabolic complications of diabetes mellitus b-hydroxybutyrate below 0.60 mmol/L is normal, Patients with diabetes mellitus may develop various whereas values between 0.60 mmol/L and 1.0 mmol/L metabolic complications that require emergency treat- may necessitate more insulin, and concentrations ment, including coma, and these include the following. greater than 1.0 mmol/L a warning to seek medical Hypoglycaemia advice. This is probably the most common cause of coma seen Urinary albumin determination and diabetic nephropathy in diabetic patients. Hypoglycaemia is most commonly One of the earliest signs of diabetic renal dysfunction caused by accidental overadministration of insulin or is the development of small amounts of albumin in the sulphonylureas or meglitinides. Precipitating causes urine, called microalbuminuria. Untreated, this can include too high a dose of insulin or hypoglycaemic progress to overt albuminuria or proteinuria (more drug; conversely, the patient may have missed a meal or than 300 mg/day), impaired renal function and finally taken excessive exercise after the usual dose of insulin end-stage renal failure. or oral hypoglycaemic drugs. Microalbuminuria is defined as a urinary albumin Hypoglycaemia is particularly dangerous, and excretion of 30–300 mg/day or 20–200 µg/min. An some patients lack awareness of this; that is to say, albumin concentration less than 30 mg/day or less than they lose warning signs such as sweating, dizziness 20 µg/min is defined as normoalbuminuria. A random and headaches. Driving is a major hazard under such urine sample or timed overnight collection can be circumstances. Patients should monitor their own useful to assess urinary albumin excretion, although blood glucose closely, carry glucose preparations the standard test is the urinary albumin to creatinine to abort severe hypoglycaemia and avoid high-risk ratio (ACR), which avoids a timed urine collection. activities during which hypoglycaemic attacks could This should normally be less than 2.5 g/mol in males be dangerous.  Hyperglycaemia and diabetes mellitus 189 CASE 1 CASE 2 A 34-year-old woman with known type 1 diabetes A 24-year-old woman presented to the casualty mellitus was admitted to hospital following a ‘black department in a coma. The relevant biochemical out’ while driving. She had recently increased her results were as follows: insulin dose because she felt unwell with ‘flu’ but Plasma unwisely had missed two meals during the day. The Sodium 130 mmol/L (135–145) results of some of her biochemistry tests were as Potassium 5.9 mmol/L (3.5–5.0) follows: Bicarbonate 10 mmol/L (24–32) Plasma Chloride 92 mmol/L (95–105) Sodium 135 mmol/L (135–145) Glucose 35 mmol/L (5.5–11.1) Potassium 4.0 mmol/L (3.5–5.0) pH 7.10 (7.35–7.45) Bicarbonate 23 mmol/L (24–32) PaCO2 3.1 kPa (4.6–6.0) Urea 5.4 mmol/L (2.5–7.0) PaO2 11.1 kPa (9.3–13.3) Creatinine 100 µmol/L (70–110) Urine was positive for ketones. Glucose 1.5 mmol/L (5.5–11.1) DISCUSSION pH 7.43 (7.35–7.45) The patient was shown to have type 1 diabetes PaCO2 5.3 kPa (4.6–6.0) mellitus and had presented in diabetic ketoacidosis, PaO2 12.1 kPa (9.3–13.3) with hyperglycaemia, hyponatraemia, hyperkalaemia DISCUSSION and a metabolic acidosis. The blood glucose shows hypoglycaemia, secondary to the patient having increased her insulin dose although euglycaemic diabetic ketoacidosis has been despite having missed meals. Hypoglycaemia can described when plasma glucose concentrations are only present with neurological impairment, including slightly elevated. impaired memory, loss of consciousness and coma. Hyperglycaemia causes glycosuria and hence an This can be treated in the emergency situation by osmotic diuresis. Water and electrolyte loss due to giving glucose intravenously to avoid irreversible vomiting, which is common in this syndrome, increases neurological damage. It is important for patients on fluid depletion. There may be haemoconcentration and insulin to monitor their own blood glucose closely, reduction of the glomerular filtration rate enough to particularly if they wish to drive. cause uraemia due to renal circulatory insufficiency. The extracellular hyperosmolality causes a shift of water out of the cellular compartment and severe cellular Diabetic ketoacidosis dehydration occurs. Loss of water from cerebral cells is Diabetic ketoacidosis may be precipitated by infection, probably the reason for the confusion and coma. Thus acute myocardial infarction or vomiting. The patient there is both cellular and extracellular volume depletion. who reasons ‘no food, therefore no insulin’ could The rate of lipolysis is increased because of decreased mistakenly withhold insulin. In the absence of insulin, insulin activity; more free fatty acids are produced than there is increased lipid and protein breakdown, can be metabolized by peripheral tissues. The free fatty enhanced hepatic gluconeogenesis and impaired acids are either converted to ketones by the liver or, glucose entry into cells. of less immediate clinical importance, incorporated The clinical consequences of diabetic ketoacidosis as endogenous triglycerides into VLDL, sometimes are due to: causing severe hypertriglyceridaemia (see Chapter 13). Hydrogen ions, produced with ketones other than hyperglycaemia causing plasma hyperosmolality, acetone, are buffered by plasma bicarbonate. However, metabolic acidosis, when their rate of production exceeds the rate of glycosuria. bicarbonate generation, the plasma bicarbonate falls. Plasma glucose concentrations are usually in the Hydrogen ion secretion causes a fall in urinary pH. range 20–40 mmol/L, but may be considerably higher, The deep, sighing respiration (Kussmaul’s respiration) 190 Carbohydrate metabolism and the odour of acetone on the breath are classic Table 12.4 Clinical and biochemical findings in a features of diabetic ketoacidosis. patient presenting with diabetic ketoacidosis Plasma potassium concentrations may be raised, Findings Underlying abnormality secondarily to the metabolic acidosis, before treatment Clinical is started. This is due to failure of glucose entry into cells in the absence of insulin and because of the low Confusion and later coma Hyperosmolality glomerular filtration rate. Despite hyperkalaemia, Hyperventilation (Kussmaul’s respiration) Metabolic acidosis there is a total body deficit due to increased urinary Signs of volume depletion Osmotic diuresis potassium loss in the presence of an osmotic diuresis. Biochemical During treatment, plasma potassium concentrations Plasma may fall as potassium re-enters cells, sometimes causing Hyperglycaemia Insulin deficiency severe hypokalaemia unless potassium is prescribed. Low plasma bicarbonate Metabolic acidosis Plasma sodium concentrations may be low (hyponatraemia) or low-normal at presentation, partly Initial hyperkalaemia Intracellular potassium moves out because of the osmotic effect of the high extracellular glucose concentration, which draws water from the cells and Mild uraemia Decreased glomerular filtration rate dilutes the sodium. In the presence of a very high plasma Urine glucose concentration, a normal or raised plasma sodium concentration is suggestive of significant water depletion. Glycosuria Insulin deficiency If there is severe hyperlipidaemia, the possibility of Ketonuria Insulin deficiency pseudohyponatraemia must be considered (see Chapter 2). When insulin is given, gluconeogenesis is inhibited, glucose enters cells and sodium-free water follows along of the symptoms, including those of confusion and the osmotic gradient. If plasma sodium concentrations coma, are related to it. However, the term ‘hyperosmolal’ rise rapidly, the patient may remain confused or even coma or ‘pre-coma’ is usually confined to a condition comatose as long as the plasma osmolality remains in which there is marked hyperglycaemia but no significantly raised, despite a satisfactory fall in plasma detectable ketoacidosis. The reason for these different glucose concentration. This may also occur if isosmolar presentations is not clear. It has been suggested that or stronger saline solutions are given inappropriately. insulin activity is sufficient to suppress lipolysis but Hyperphosphataemia followed by hypophosphataemia insufficient to suppress hepatic gluconeogenesis or to as plasma phosphate concentrations parallel those of facilitate glucose transport into cells. potassium may persist for several days after recovery from Hyperosmolal non-ketotic (HONK) coma now diabetic coma. Similarly, hypermagnesaemia can result, may be referred to as hyperosmolar hyperglycaemic partly because of the acidosis. state (HHS) and may be of sudden onset. It is Plasma and urinary amylase activities may be more common in older patients. Plasma glucose markedly elevated and, even in the presence of abdominal concentrations may exceed 50 mmol/L. The effects of pain mimicking an ‘acute abdomen’, do not necessarily glycosuria are as described above, but hypernatraemia indicate acute pancreatitis. In some patients the amylase due to predominant water loss is more commonly is of salivary rather than pancreatic origin. Some plasma found than in ketoacidosis and aggravates the plasma creatinine assays cross-react with ketones, resulting in a hyperosmolality. Cerebral cellular dehydration, which spurious plasma creatinine elevation. Sometimes severe contributes to the coma, may also cause hyperventilation, hypertriglyceridaemia and chylomicronaemia result, and a respiratory alkalosis, although sometimes plasma due to reduced lipoprotein lipase activity in the face lactic acid may rise, evoking a metabolic acidosis and of insulin deficiency. A summary of the usual clinical thus a mixed acid–base disturbance may occur. There and biochemical findings in a patient presenting with may also be an increased risk of thrombosis. diabetic ketoacidosis is shown in Table 12.4. Lactic acidosis Hyperosmolal non-ketotic coma Lactic acidosis can cause a high anion gap metabolic In diabetic ketoacidosis there is always plasma acidosis and coma. It may be due to the use of hyperosmolality due to the hyperglycaemia, and many metformin in certain situations, such as high doses in  Hyperglycaemia and diabetes mellitus 191 the very elderly, those with renal, liver or cardiac failure next hour and then 2 h and repeated at 4 h. Monitoring or those dehydrated or undergoing imaging tests with central venous pressure may be useful to assess fluid contrast media (see Chapter 4). replacement. Dextrose–saline may be used when the plasma glucose concentration is less than 15 mmol/L. Other causes of coma in patients with diabetes mellitus If the plasma glucose concentration is more than In addition to the comas described above, a patient 20 mmol/L, 10 U soluble insulin should be given. A with diabetes mellitus may present with other comas: sliding insulin scale should be instigated. Insulin is Cerebrovascular accidents are relatively common in given either by continuous intravenous infusion or diabetic patients because of the increased incidence by intermittent intramuscular injections, as soon as of vascular disease. the plasma glucose and potassium concentrations Diabetic patients can, of course, have any other are known. Once the patient is eating, subcutaneous coma, for example drug overdose. insulin can be given instead. Diabetic patients are also more at risk of diabetic If the metabolic acidosis is very severe (pH less than nephropathy and renal failure and thus uraemic coma. 7.0), bicarbonate may be infused, but only until the blood pH rises to between about 7.15 and 7.20. It is The assessment of a diabetic patient presenting in unnecessary and often dangerous to correct the plasma coma or pre-coma is outlined in Table 12.5. bicarbonate concentration completely; it rapidly returns Principles of treatment of diabetic coma to normal following adequate fluid and insulin therapy. Remember that 8.4 per cent sodium bicarbonate is Only the outline of treatment will be discussed. For very hyperosmolar and may cause hypernatraemia and details of management, the reader should consult a aggravate hyperosmolality. A rapid rise in the blood textbook of medical emergencies. pH may aggravate the hypokalaemia associated with Hypoglycaemia treatment. Hypoglycaemic coma needs prompt glucose replacement The plasma potassium concentration should be to avoid irreversible brain damage, for example 50 mL measured before insulin is given. It is almost always of 20 per cent glucose intravenously. If intravenous raised at presentation due to the metabolic acidosis and access is not an option, glucagon 1 mg can be given reduced glomerular filtration rate, although total body intramuscularly. Once the patient is awake, glucose- potassium may be decreased. The plasma potassium containing drinks can be given. concentration may fall rapidly once treatment is started, and therefore it should be monitored frequently Diabetic ketoacidosis and potassium given as soon as it starts to fall. Usually Repletion of fluid and electrolytes should be vigorous. 20 mmol/L potassium is given to each litre bag apart A 0.9 per cent normal saline solution should be from the first litre and provided there is no oliguria or administered, usually 1 L initially and then 1 L over the hyperkalaemia. Diabetic ketoacidosis is severe if blood Table 12.5 Clinical and biochemical features of a diabetic patient presenting in coma Laboratory findings Plasma Urine Diagnosis Clinical features Glucose Bicarbonate Lactate Creatinine Ketones Hypoglycaemia Sweaty, drowsy Low N N N Neg Ketoacidosis Volume depletion High Low N N or up Pos Hyperventilating Hyperosmolar coma Volume depletion Very high N or slightly low N or up N or up Neg May be hyperventilating Lactic acidosis Hyperventilating Variable Low Up N Neg Uraemia Hyperventilating Variable Low N or up Up Neg Cerebrovascular accident Neurological May be raised May be low N N Neg N, normal; Neg, negative; Pos, positive. 192 Carbohydrate metabolism ketones are greater than 6 mmol/L and the treatment Hyperosmolal non-ketotic coma aim is for these to be less than 0.30 mmol/L. The treatment of HONK coma is similar to that of Urinary volume should be monitored; if it fails to ketoacidosis. A sudden reduction of extracellular rise despite adequate rehydration, further fluid and osmolality may be harmful, and it is important to potassium should be given only if clinically indicated, give small doses of insulin to reduce plasma glucose and then with care. The risk of deep vein thrombosis is concentrations slowly, for example 1 U/h. These patients increased, in part due to dehydration, and thus heparin are often very sensitive to the action of insulin. Hypo- 5000 U every 8 h subcutaneously can be given. osmolal solutions are often used to correct volume Clinical conditions such as infection that may have depletion, but these too should be given slowly. Heparin precipitated the coma should be sought and treated. is usually given, as there is an increased risk of venous Frequent monitoring of plasma glucose, potassium and thrombosis. sodium concentrations is essential to assess progress and to detect developing hypoglycaemia, hypokalaemia or hypernatraemia. Acid–base balance should also be assessed. Initial investigation of a diabetic patient presenting in coma A diabetic patient may be in coma due to hyperglycaemia, CASE 3 hypoglycaemia or any of the causes shown in Tables 12.4 and 12.5. After a thorough clinical assessment, A 77-year-old man with known type 2 diabetes proceed as follows: mellitus presented to the casualty department feeling drowsy. His home blood glucose monitoring had Notify the laboratory that specimens are being taken recently averaged about 25 mmol/L and a recent and ensure that they are delivered promptly. This glycated haemoglobin (HbA1c) result obtained by his minimizes delays. general practitioner was 12 per cent (108 mmol/mol). Take blood immediately for estimation of: The following blood results were returned in hospital: – glucose, Plasma – sodium and potassium, Sodium 160 mmol/L (135–145) – urea and creatinine, Potassium 5.0 mmol/L (3.5–5.0) – bicarbonate, Bicarbonate 21 mmol/L (24–32) – arterial blood gases. Urea 15 mmol/L (2.5–7.0) Do a drug screen for aspirin and paracetamol if Creatinine 130 µmol/L (70–110) concomitant drug overdose suspected. Glucose 65 mmol/L (5.5–11.1) Determination of plasma lactate will help diagnose a Osmolality 380 mmol/kg (285–295) lactic acidosis (see Chapter 4). pH 7.38 (7.35–7.45) Test a urine sample or blood for ketones. PaCO2 5.2 kPa (4.6–6.0) A rapid assessment of blood glucose concentration PaO2 11.8 kPa (9.3–13.3) may be obtained using a point-of-care (POCT) Urine was negative for ketones. device, but results may be dangerously wrong so these should always be checked against the results DISCUSSION obtained from the laboratory (see Chapter 30). The patient was found to be in a hyperosmolal non- If severe hypoglycaemia is suspected on clinical ketotic (HONK) diabetic coma. Note the severe grounds or because of the results obtained using hyperglycaemia, hypernatraemia and high plasma reagent strips, glucose should be given immediately osmolality and presentation in an elderly patient. while waiting for the laboratory results. It is HONK coma is associated with type 2 diabetes less dangerous to give glucose to a patient with mellitus. Ketoacidosis is usually absent, as there has hyperglycaemia than to give insulin to a patient with been no conversion to ketone metabolism. This is hypoglycaemia. more common in the elderly, and severe dehydration The results of point-of-care testing (see Chapter 30) is present and there is an increased risk of thrombotic must be interpreted with caution. events and focal neurological signs. Treatment is with Also look for precipitating causes such as acute careful intravenous rehydration, insulin and heparin. myocardial infarction or infection.  Hyperglycaemia and diabetes mellitus 193 Investigation of suspected diabetes mellitus Oral glucose tolerance test In most cases a diagnosis can be established from either Before starting this test, contact your laboratory: local fasting or random blood glucose determinations. In details may vary. equivocal cases an OGTT may be required. Procedure The patient should be resting and should not smoke Initial investigations during the test. Blood for plasma glucose estimation should be taken if The patient fasts overnight (for at least 10 h but a patient presents with symptoms of diabetes mellitus not more than 16 h). Water, but no other beverage, is or glycosuria or if it is desirable to exclude the diagnosis, allowed. for example because of a strong family history. A venous sample is withdrawn for plasma glucose Blood samples may be taken: estimation. If the glucose concentration is measured in whole blood, the results will be approximately at least 10 h after a fast, 1.0 mmol/L lower. at random, A solution containing 75 g of anhydrous glucose as part of an oral glucose load test. in 300 mL of water is hyperosmolar, and not only may cause nausea and occasionally vomiting and Diabetes mellitus is confirmed if one of the following diarrhoea, but also, because of delayed absorption, is present: may affect the results of the test. It is therefore more a fasting venous plasma concentration of 7.0 mmol/L usual to give a solution of a mixture of glucose and or more on two occasions or once with symptoms, its oligosaccharides, because fewer molecules per unit a random venous plasma concentration of volume have less osmotic effect than the equivalent 11.1 mmol/L or more on two occasions or once with amount of monosaccharide; the oligosaccharides are symptoms. all hydrolysed at the brush border, and the glucose immediately enters the cells. Diabetes mellitus is unlikely if the fasting venous A solution that contains the equivalent of 75 g of plasma glucose concentration is less than 5.5 mmol/L anhydrous glucose is: 113 mL of Polycal made up to on two occasions. Samples taken at random times after approximately 300 mL with water. meals are less reliable for excluding than for confirming This solution should be drunk slowly over a few the diagnosis. minutes. Further blood is taken 2 h after the ingestion The indications for performing an OGTT to diagnose of glucose. diabetes mellitus may include: Note that in the investigation of acromegaly, sampling is half-hourly over the 2-h period (see Chapter 7). fasting venous plasma glucose concentration Interpretation of the OGTT is shown in Table between 5.5 mmol/L and less than 7.0 mmol/L 12.6. There is controversy as to how best to interpret – this is debatable as the WHO recommends an the OGTT in pregnancy because of the differences in OGTT only if fasting plasma glucose is greater than maternal glucose metabolism, as stated earlier. 6.0 mmol/L, The following factors may affect the result of the test: random venous plasma concentration between 7.0 mmol/L and less than 11.1 mmol/L, Previous diet No special restrictions are necessary if a high index of clinical suspicion of diabetes mellitus, the patient has been on a normal diet for 3–4 days. such as a patient at high risk of gestational diabetes However, if the test is performed after a period of with equivocal blood glucose results. carbohydrate restriction, for example as part of a weight-reducing diet, this may cause abnormal glucose The OGTT is sometimes also useful in the diagnosis tolerance, probably because metabolism is adjusted to of acromegaly (see Chapter 7). the ‘fasted state’ and so favours gluconeogenesis. It has been suggested that an HbA1c of greater than Time of day Most OGTTs are performed in the 6.5 per cent is diagnostic of diabetes mellitus, but morning and the reference values quoted are for this this is not universally agreed as other factors such as time of day. There is evidence that tests performed haemoglobin variants and abnormal erythrocyte in the afternoon yield higher plasma glucose lifespan may affect HbA1c levels. concentrations and that the accepted ‘reference 194 Carbohydrate metabolism Table 12.6 Interpretation of the oral glucose tolerance test (glucose mmol/L); venous plasma preferred Venous plasma Capillary whole blood Venous whole blood Fasting 2h Fasting 2h Fasting 2h Diabetes mellitus unlikely < 6.1 < 7.8 < 5.6 < 7.8 < 5.6 < 6.7 Impaired glucose tolerance < 7.0 7.8–11.1 < 6.1 7.8–11.1 < 6.1 6.7–10.0 Impaired fasting glucose 6.1–6.9 < 7.8 5.6–6.0 < 7.8 5.6–6.0 < 6.7 Diabetes mellitus ≥ 7.0 ≥ 11.1 ≥ 6.1 ≥ 11.1 ≥ 6.1 ≥ 10.0 values’ may not be applicable. This may be due to a Symptoms of hypoglycaemia may develop at higher circadian variation in islet cell responsiveness. concentrations if there has been a rapid fall from a Drug Steroids, oral contraceptives and thiazide previously raised value, when adrenaline secretion is diuretics may impair glucose tolerance. stimulated and may cause sweating, tachycardia and agitation. As discussed earlier, cerebral metabolism HYPOGLYCAEMIA (FIG. 12.9) depends on an adequate supply of glucose from ECF, By definition, hypoglycaemia is present if the plasma and the symptoms of hypoglycaemia may resemble glucose concentration is less than 2.5 mmol/L in a those of cerebral hypoxia (neuroglycopenia). Faintness, specimen collected into a tube containing an inhibitor dizziness or lethargy may progress rapidly to coma and, of glycolysis, for example fluoride oxalate. Blood if untreated, permanent cerebral damage or death may cells continue to metabolize glucose in vitro, and low occur. Existing cerebral or cerebrovascular disease may concentrations found in a specimen collected without aggravate the clinical picture. Whipple’s triad is defined su