Introduction:
Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia due to absolute or relative deficiency of insulin. Long-standing metabolic derangement can lead to the development of complications of diabetes, which characteristically affect the eye, kidney and nervous system. Diabetes occurs worldwide and its prevalence is rising; 366 million people had diabetes in 2011, and this is expected to reach 552 million by 2030. Diabetes is a major burden upon health-care facilities in all countries.
Normal glucose and fat metabolism Blood glucose is maintained within a narrow range by homeostatic mechanisms. The brain relies on glucose for energy as the blood–brain barrier is impermeable to free fatty acids (FFAs). Glucose enters the circulation from the liver and gut and is taken up by peripheral tissues, particularly skeletal muscle.
After ingestion of a carbohydrate meal, insulin, the primary regulator of glucose metabolism, is secreted from pancreatic β cells into the portal circulation in response to a rise in blood glucose. This rise, together with a fall in portal glucagon, suppresses hepatic glucose production, results in net hepatic glucose uptake and stimulates glucose uptake in skeletal muscle and fat. Between meals, portal vein insulin and glucose concentrations fall while glucagon levels rise, causing increased hepatic glucose output via gluconeogenesis and glycogen breakdown.
Insulin is also the major regulator of fatty acid metabolism. High insulin levels after meals promote triglyceride accumulation, while in the fasting state, low insulin levels permit lipolysis and the release of FFAs and glycerol, which can be oxidised by many tissues.
Their partial oxidation in the liver produces ketone bodies, whichcan be utilised as metabolic fuel, but may accumulate during starvation.
Aetiology and pathogenesis of diabetes:
In both of the common types of diabetes, environmental factors interact with genetic susceptibility to determine which people develop the clinical syndrome, and the timing of its onset. However, the underlying genes, precipitating environmental factors and pathophysiology differ substantially between type 1 and type 2 diabetes.
Type 1 diabetes
Type 1 diabetes is invariably associated with profound insulin deficiency requiring replacement therapy. It is a T-cell-mediated autoimmune disease leading to progressive destruction of the insulin-secreting β cells. Classical symptoms of diabetes occur only when 80–90% of β cells have been destroyed. Pathology shows insulitis (infiltration of the islets with mononuclear cells), in which β cells are destroyed, but cells secreting glucagon and other hormones remain intact. Islet cell antibodies can be detected before clinical diabetes develops and disappear with increasing duration of diabetes; however, they are not suitable for screening or diagnostic purposes. Glutamic acid decarboxylase (GAD) antibodies may have a role in identifying late-onset type 1 autoimmune diabetes in adults (LADA). Type 1 diabetes is associated with other autoimmune disorders, including thyroid disease, coeliac disease, Addison’s disease, pernicious anaemia and vitiligo.
Genetic predisposition
Genetic factors account for about one-third of the susceptibility to type 1 diabetes, with 35% concordance between monozygotic twins. The human leucocyte antigen (HLA) haplotypes DR3 and/or DR4 on chromosome 6 are associated with increased susceptibility to type 1 diabetes.
Environmental factors
Wide geographic and seasonal variations in incidence suggest that environmental factors have an important role in type 1 diabetes. Viral infections implicated in the aetiology include mumps, Coxsackie B4, retroviruses, congenital rubella, cytomegalovirus and Epstein–Barr virus. Various dietary nitrosamines (found in smoked and cured meats) and coffee have been proposed as potentially diabetogenic toxins. Bovine serum albumin (BSA – a constituent of cow’s milk) has been implicated in triggering type 1 diabetes, since infants who are given cow’s milk are more likely to develop type 1 diabetes in later life than those who are breastfed. Reduced exposure to microorganisms in early childhood may limit maturation of the immune system and increase susceptibility to autoimmune disease (the ‘hygiene hypothesis’).
Metabolic disturbances in type 1 diabetesP atients with type 1 diabetes present when adequate insulin secretionc an no longer be sustained. High glucose levels may be toxic to the remaining β cells, so that profound insulin deficiency rapid lyensues.
Hyperglycaemia leads to glycosuria and dehydration, which in turn induces secondary hyperaldosteronism. Unrestrained lipolysis and proteolysis result in weight loss, increased gluconeogenesis and ketogenesis. When generation of ketone bodies exceeds their metabolism, ketoacidosis results. Secondary hyperaldosteronism encourages urinary loss of K+. Thus patients usually present with a short history of hyperglycaemic symptoms (thirst, polyuria, fatigue and infections) and weight loss, and may have developed ketoacidosis.
Type 2 diabetes
Type 2 diabetes is only diagnosed after excluding other causes of hyperglycaemia, including type 1 diabetes. Patients retain some capacity to secrete insulin but there is a combination of resistance to the actions of insulin followed by impaired pancreatic β-cell function, leading to ‘relative’ insulin deficiency.
Insulin resistance: Type 2 diabetes is often associated with other medical disorders; when these coexist, they are termed ‘metabolic syndrome’ (Box 11.1), with a predisposition to insulin resistancebeing the primary defect. It is strongly associated with macrovasculardisease (coronary, cerebral, peripheral) and an excess mortality.
The primary cause of this syndrome remains unclear, and multipledefects in insulin signalling are found. ‘Central’ adipose tissuemay amplify insulin resistance by releasing FFAs and hormones (adipokines). Sedentary people are more insulin-resistant thanactive people with the same degree of obesity. Inactivity downregulates insulin-sensitive kinases and may also increase the accumulation of FFAs within skeletal muscle. Exercise also allows non-insulin-dependent glucose uptake into muscle, reducing the ‘demand’ on the pancreatic β cells to produce insulin. Many patientsalso develop non-alcoholic fatty liver disease.
Pancreatic β-cell failure: In early type 2 diabetes, only around 50% of β-cell function is lost. Amyloid deposits are found around pancreatic islet cells. While β-cell numbers are typically reduced, β-cell mass is unchanged and glucagon secretion is increased, which may contribute to the hyperglycaemia.
Genetic predisposition
Genetic factors are important in type 2 diabetes; different ethnic groups have different susceptibility but monozygotic twins have concordance rates approaching 100%. However, many genes are involved, and individual risk of diabetes is also influenced by environmental factors.
Environmental and other risk factors
Epidemiological studies indicate that type 2 diabetes is associated with overeating, especially when combined with obesity and underactivity. The risk of developing type 2 diabetes increases tenfold in people with a body mass index (BMI) > 30 kg/m2. However, only a minority of obese people develop diabetes. Obesity probably acts as a diabetogenic factor in those who are genetically predisposed both to insulin resistance and to β-cell failure.
Age: Type 2 diabetes is principally a disease of the middle-aged
and elderly. In the UK, it affects 10% of the population > 65, and > 70% of all cases of diabetes occur after the age of 50 yrs.
Metabolic disturbances in type 2 diabetes
Relatively small amounts of insulin are required to suppress lipolysis, and some glucose uptake is maintained in muscle, so that weight loss and ketoacidosis are rare. Hyperglycaemia develops slowly, so that osmotic symptoms (polyuria and polydipsia) are usually mild.
Thus, patients are often asymptomatic but usually present with a long history (typically many months) of fatigue, with or without osmotic symptoms. In some patients, presentation is late and pancreatic β-cell function has declined to the point where there is profound insulin deficiency. These patients may present with weight loss, although ketoacidosis remains uncommon. In some ethnic groups, such as African Americans, however, half of those first presenting with diabetic ketoacidosis have type 2 diabetes.
Intercurrent illness, e.g. infection, increases the production of stress hormones that oppose insulin (cortisol, growth hormone, catecholamines). This can precipitate more severe hyperglycaemia and dehydration.
Other forms of diabetes
These include:
● Pancreatic disease (e.g. pancreatitis, haemochromatosis, cystic fibrosis).
● Excess endogenous production of insulin antagonists (acromegaly, Cushing’s disease, thyrotoxicosis).
● Genetic defects of β-cell function (e.g. maturity-onset diabetes of the young (MODY), a rare autosomal dominant disease, < 5% of diabetes cases).
● Genetic defects of insulin action.
● Drug-induced diabetes (corticosteroids, thiazides, phenytoin).
● Diabetes associated with genetic syndromes (e.g. Down’s, DIDMOAD – diabetes insipidus, diabetes mellitus, optic atrophy, deafness).
Investigations
Urine testing
Glucose
Urine dipsticks are used to screen for diabetes. Testing should ideally use urine passed 1–2 hrs after a meal, since this will maximise sensitivity. Glycosuria always warrants further assessment by blood testing; however, glycosuria can be due to a low renal threshold.
This is a benign condition unrelated to diabetes, common during pregnancy and in young people. Another disadvantage is that some drugs (such as β-lactam antibiotics, levodopa and salicylates) may interfere with urine glucose tests.
Ketones
Ketonuria may be found in normal people who have been fasting, exercising or vomiting repeatedly, or those on a high-fat, low carbohydrate diet. Ketonuria is therefore not pathognomonic of diabetes but, if it is associated with glycosuria, diabetes is highly likely.
In diabetic ketoacidosis , ketones can also be detected in plasma using test sticks (see below).
Protein
Standard dipstick testing will detect urinary albumin > 300 mg/L but smaller amounts (microalbuminuria) require specific sticks or laboratory urinalysis. Microalbuminuria or proteinuria, in the absence of urinary tract infection, is an important indicator of diabetic nephropathy and/or increased risk of macrovascular disease.
Blood testing
Glucose
Laboratory blood glucose testing is cheap and highly reliable.
Capillary blood glucose can also be measured with a portable electronic meter, used to monitor diabetes treatment. Glucose concentrations are lower in venous than in arterial or capillary (fingerprick) blood. Whole blood glucose concentrations are lower than plasma concentrations because red blood cells contain relatively little glucose. Venous plasma values are the most reliable for diagnostic purposes.
Ketones
Whole blood ketone monitoring detects β-hydroxybutyrate and is useful in guiding insulin adjustment during intercurrent illness or sustained hyperglycaemia to prevent or detect DKA. It is also useful in monitoring resolution of DKA in hospitalised patients.
Glycated haemoglobin
Glycated haemoglobin (Hb) provides an accurate and objective measure of glycaemic control over a period of weeks to months.
The non-enzymatic covalent attachment of glucose to Hb (glycation) increases the amount in the HbA1c fraction relative to nonglycated adult Hb (HbA0). The rate of formation of HbA1c is directly proportional to the blood glucose concentration; a rise of 1% in HbA1c corresponds to an increase of 2 mmol/L (36 mg/dL) in blood glucose. HbA1c concentration reflects blood glucose over the erythrocyte lifespan (120 days); it is most sensitive to glycaemic control in the past month. To enable international comparisons, most countries now report International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)-standardised HbA1c values [IFCC HbA1c (mmol/mol) = (HbA1c (%)−2.15) × 10.929].
HbA1c estimates may be erroneously diminished in anaemia and pregnancy, and may be difficult to interpret in uraemia and haemoglobinopathy.
PRESENTING PROBLEMS IN DIABETES
Newly discovered hyperglycaemia
The key goals are to establish whether the patient has diabetes, what type of diabetes it is and how it should be treated.
Establishing the diagnosis of diabetes
Glycaemia can be classified as either normal, impaired (pre-diabetes) or diabetes. The glucose cut-off that defines diabetes is the level above which there is a significant risk of microvascular complications (retinopathy, nephropathy, neuropathy). Those with pre-diabetes have a negligible risk of microvascular complications but are at increased risk of developing diabetes. Also, because there is a continuous risk of macrovascular disease (atheroma of large blood vessels) with increasing glycaemia in the population, people with pre-diabetes have increased risk of cardiovascular disease (myocardial infarction, stroke and peripheral vascular disease).
In symptomatic patients, diabetes can be confirmed with either a fasting glucose ≥ 7.0 mmol/L (126 mg/dL) or a random glucose ≥ 11.1 mmol/L (200 mg/dL) . Asymptomatic individuals should have a second confirmatory test. Diabetes should not be diagnosed by capillary blood glucose results. The WHO guidelines also include an IFCC HbA1c of > 48 mmol/mol as diagnostic of diabetes.
Pre-diabetes can be diagnosed either as ‘impaired fasting glucose’ (IFG; fasting plasma glucose 6.1–6.9 mmol/L) or ‘impaired glucose tolerance’ (IGT; glucose 7.8–11 mmol/L 2 hrs after 75-g oral glucose drink). Patients with pre-diabetes should be advised of their risk of progression to diabetes, should be given lifestyle advice to reduce this risk, and should receive aggressive management of cardiovascular risk factors such as hypertension and dyslipidaemia.
Stress hyperglycaemia occurs when conditions impose a burden on the pancreatic β cells, e.g. during pregnancy, infection or treatment with corticosteroids. It usually disappears after the acute illness has resolved, but blood glucose should be remeasured.
When diabetes is confirmed, other investigations should include:
● U&Es.
● Creatinine.
● LFTs
● TFTs.
● Lipids.
● Urine: ketones, protein, microalbuminuria.
Clinical assessment
The clinical features of the two main types of diabetes are compared. Symptoms at presentation include:
● Thirst.
● Polyuria/nocturia.
● Fatigue.
● Blurred vision.
● Pruritus vulvae/balanitis.
● Nausea.
● Hyperphagia.
● Irritability, poor concentration, headache.
Patients with type 2 diabetes may be asymptomatic or present with chronic fatigue or malaise. Uncontrolled diabetes is associated with increased susceptibility to infection and patients may present with skin infections. A history of pancreatic disease (particularly with alcohol excess) makes insulin deficiency more likely.
Overlap occurs, particularly in age at onset, duration of symptoms and family history. Typical type 2 diabetes occurs increasingly in obese young people. Older adults may have evidence of autoimmune activity against β cells, a slowly evolving variant of type 1 diabetes (LADA). More than 80% of patients with type 2 diabetes are overweight, 50% have hypertension and hyperlipidaemia is common.
Management
Aims are to improve symptoms and minimise complications:
● Type 1 diabetes: urgent therapy with insulin and prompt referral to a specialist.
● Type 2 diabetes: advice about dietary and lifestyle modification, followed by initiation of oral antidiabetic drugs if needed.
● Hypertension, dyslipidaemia and smoking cessation.
Patient education: This can be achieved by a multidisciplinary team (doctor, dietitian, specialist nurse and podiatrist) in the outpatient setting. Patients requiring insulin need intensive training in how to measure insulin doses, give their own injections, and adjust the dose depending on glucose monitoring, exercise, illness and hypoglycaemia. They must understand the principles of diabetes, recognise the symptoms of hypoglycaemia, and receive advice about the risks of driving with diabetes.
Self-assessment of glycaemic control: Patients with type 2 diabetes do not usually need regular self-assessment of blood glucose, unless they use insulin, or are at risk of hypoglycaemia on sulphonylureas.
Insulin-treated patients should be taught to monitor blood glucose using capillary blood glucose meters, and to use the results to guide insulin dosing and to manage exercise and illness. Pre-meal blood glucose values of 4–7 mmol/L (72–126 mg/dL) and 2-hr postmeal values of 4–8 mmol/L represent optimal control. Urine testing for glucose is not recommended because variability in renal threshold means that some patients with inadequate glycaemic control will not have glycosuria.
Long-term supervision of diabetes
Diabetes is a complex disorder, which progresses in severity with time. Patients with diabetes should therefore be seen at regular intervals for life. A checklist for follow-up visits needed. The frequency of visits varies from weekly during pregnancy to annually in well-controlled type 2 diabetes.
Therapeutic goals
The target HbA1c depends on the patient. Early on in diabetes (i.e. patients managed by diet or one or two oral agents), a target of 48 mmol/mol (6.5%) or less may be appropriate. However, a higher target of 58 mmol/mol (7.5%) may be more appropriate in older patients with pre-existing cardiovascular disease, or those treated with insulin and therefore at risk of hypoglycaemia. The benefits of lower target HbA1c (primarily a lower risk of microvascular disease) need to be weighed against any increased risks (primarily hypoglycaemia in insulin-treated patients). Type 2 diabetes is usually a progressive condition, so that there is normally a need to increase diabetes medication over time to achieve the individualised target HbA1c.
Treatment of hypertension and dyslipidaemia is important to reduce cardiovascular risk. Statins are indicated in those with type 2 diabetes aged > 40, regardless of cholesterol level. In all diabetic patients, total cholesterol should be < 4 mmol/L (150 mg/dL) and LDL cholesterol < 2 mmol/L (75 mg/dL).
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a medical emergency, principally occurring in people with type 1 diabetes. Mortality is low in the UK (~2%), but higher in developing countries and among nonhospitalised patients. It may be the presenting feature of diabetes, or may be precipitated by stress, particularly infection, in those with established diabetes. Sometimes, DKA develops because of errors in self-management. In young patients with recurrent episodes of DKA, up to 20% may have psychological problems complicated by eating disorders.
The cardinal biochemical features of DKA are:
● Hyperglycaemia.
● Hyperketonaemia.
● Metabolic acidosis.
Hyperglycaemia causes an osmotic diuresis, leading to dehydration and electrolyte loss. Ketosis is caused by insulin deficiency, exacerbated by stress hormones (e.g. catecholamines), resulting in unrestrained lipolysis and supplying FFAs for hepatic ketogenesis.
When this exceeds the capacity to metabolise acidic ketones, these accumulate in blood. The resulting acidosis forces hydrogen ions into cells, displacing potassium ions, which are lost in urine or through vomiting. The average loss of fluid and electrolytes in moderately severe DKA in an adult. Patients with DKA have a total body potassium deficit but this is not reflected by plasma potassium levels, which may initially be raised due to disproportionate water loss. Once insulin is started, however, plasma potassium can fall precipitously due to dilution by IV fluids, potassium movement into cells, and continuing renal loss of potassium.
Investigations
The following are important but should not delay IV fluid and insulin replacement:
● U&Es, blood glucose, plasma bicarbonate (< 12 mmol/L indicates severe acidosis).
● Urine and plasma for ketones.
● ECG.
● Infection screen: FBC, blood/urine culture, CRP, CXR. Leucocytosis invariably occurs, representing a stress response rather than infection.
Management
Patients should be treated in hospital, preferably in a highdependency area, and the diabetes specialty team should be involved. Regular clinical and biochemical monitoring is essential, particularly during the first 24 hrs. The principal components of treatment are insulin, fluid and potassium.
Insulin: The preferred route is IV infusion at 0.1 U/kg/hr, but (exceptionally) if this is not possible, 10–20 U can be given IM, followed by 5 U IM hourly thereafter. Blood glucose should ideally fall at 3–6 mmol/L/hr (~55–110 mg/dL/hr); a more rapid fall in blood glucose should be avoided, as it can cause cerebral oedema, particularly in children. Failure of blood glucose to fall within 1 hr of commencing insulin infusion should lead to a re-assessment of insulin dose. When the blood glucose has fallen, 10% dextrose is introduced and insulin infusion continued to encourage glucose uptake into cells and restoration of normal metabolism. SC insulin should be delayed until the patient is eating and drinking normally.
Fluid replacement:
Potassium: Plasma potassium is often high at presentation; treatment should be started cautiously and carefully monitored. Large amounts may be required (100–300 mmol in the first 24 hrs). Cardiac rhythm should be monitored in severe cases because of the risk of arrhythmia.
Bicarbonate: Adequate fluid and insulin replacement should resolve the acidosis, so IV bicarbonate is currently not recommended. Acidosis may reflect an adaptive response, improving oxygen delivery to the tissues, and excessive bicarbonate has been implicated in the pathogenesis of cerebral oedema in children and young adults.
Hyperglycaemic hyperosmolar state Hyperglycaemic hyperosmolar state (HHS; formerly known as hyperosmolar non-ketotic coma) is characterised by severe hyperglycaemia (> 30 mmol/L (600 mg/dL) ), hyperosmolality (serum > 320 mOsm/kg) and dehydration without significant ketoacidosis.
It typically affects elderly patients but is seen increasingly in younger adults. The onset is slow (days to weeks), and dehydration and hyperglycaemia are profound.
Plasma osmolality should be measured or osmolarity calculated using the following formula: Plasma osmolarity = 2[Na+ ] + [glucose] + [urea] (all mmol/L) The normal value is 280–290 mmol/kg and the conscious level is depressed when it is > 340 mmol/kg. The patient should be given 0.9% saline, switching to 0.45% if the osmolality is rising, and aiming for a positive fluid balance of 3–6 L in the first 12 hrs. IV insulin (0.5 U/kg/hr) should only be given if the glucose fails to fall with 0.9% saline or if ketonaemia develops. Give prophylactic heparin (thromboembolic complications). Mortality is higher than in DKA – up to 20% in the USA.
Hypoglycaemia
Hypoglycaemia (blood glucose < 3.5 mmol/L (63 mg/dL) ) occurs in a person with diabetes as a result of treatment with insulin and occasionally sulphonylureas. Hypoglycaemia in a non-diabetic person is called ‘spontaneous’ hypoglycaemia . The risk of hypoglycaemia limits the attainment of near-normal glycaemia; fear of hypoglycaemia is common among patients and their relatives.
Clinical assessment
● Symptoms of autonomic nervous system activation: sweating, trembling, palpitation, hunger and anxiety.
● Symptoms of glucose deprivation of the brain (neuroglycopenia), including confusion, drowsiness, poor coordination and speech difficulty.
Hypoglycaemia also affects mood, inducing a state of increased tension and low energy. Educating patients to recognise the onset of hypoglycaemia is important in insulin-treated patients. The severity of hypoglycaemia is defined by the ability to self-treat; ‘mild’ episodes are self-treated, while ‘severe’ episodes require assistance for recovery.
Circumstances of hypoglycaemia: Risk factors and causes of hypoglycaemia in patients taking insulin or sulphonylurea drugs. Severe hypoglycaemia can have serious morbidity (e.g. convulsions, coma, focal neurological lesions) and has a mortality of up to 4% in insulin-treated patients. Rarely, sudden death during sleep occurs in otherwise healthy young patients with type 1 diabetes. Severe hypoglycaemia is very disruptive and impinges on employment, driving, travel, sport and personal relationships.
Nocturnal hypoglycaemia in type 1 diabetes is common but often undetected, as hypoglycaemia does not usually waken a person.
Patients may describe poor sleep quality, morning headaches and vivid dreams or nightmares, or a partner may observe profuse sweating, restlessness, twitching or even seizures. The only reliable way to identify this problem is to measure blood glucose during the night.
Exercise-induced hypoglycaemia occurs in people with wellcontrolled, insulin-treated diabetes because of hyperinsulinaemia. In health, exercise suppresses endogenous insulin secretion to allow increased hepatic glucose production to meet the increased metabolic demand. In insulin-treated diabetes, insulin levels may increase with exercise because of improved blood flow at injection sites, leading to hypoglycaemia.
Awareness of hypoglycaemia: For most individuals, the glucose threshold at which they become aware of hypoglycaemia varies according to the circumstances (e.g. during the night or during exercise).
In addition, with longer duration of disease, and in response to frequent hypoglycaemia, the threshold for symptoms shifts to a lower glucose concentration. This cerebral adaptation has a similar effect on the counter-regulatory hormonal response to hypoglycaemia. Taken together, this means that individuals with type 1 diabetes may have reduced (impaired) awareness of hypoglycaemia.
Symptoms can be experienced less intensely, or even be absent, despite blood glucose concentrations < 2.5 mmol/L (45 mg/dL). Impaired awareness of hypoglycaemia affects ~20–25% of people with type 1 diabetes and < 10% with insulin-treated type 2 diabetes.
Management
Treatment of acute hypoglycaemia depends on severity and on whether the patient is conscious. If hypoglycaemia is recognised early, oral fast-acting carbohydrate, followed by a complex carbohydrate snack, is sufficient. In those unable to swallow, IV glucose (75 mL of 20–50% dextrose, 0.2 g/kg in children) or IM glucagon (1 mg, 0.5 mg in children) should be administered. Viscous glucose gel solution or jam can be applied into the buccal cavity but should not be used if the person is unconscious. Full recovery may not occur immediately and reversal of cognitive impairment may take 60 mins. The possibility of recurrence should be anticipated in those on longacting insulins or sulphonylureas; a 10% dextrose infusion, titrated to the patient’s blood glucose, may be necessary. Cerebral oedema may have developed in patients who fail to regain consciousness after blood glucose is restored to normal. This has a high mortality and morbidity, and requires urgent treatment with mannitol and high-dose oxygen.
Following recovery, it is important to try to identify a cause, make appropriate adjustments to therapy and educate the patient. The management of self-poisoning with oral antidiabetic agents.
Prevention of hypoglycaemia
Patient education must cover risk factors for, and treatment of hypoglycaemia. The importance of regular blood glucose monitoring and the need to have glucose (and glucagon) readily available should be stressed. A review of insulin and carbohydrate management during exercise is particularly useful.
Relatives and friends also need to be familiar with the symptoms and signs of hypoglycaemia and should be instructed in how to help (including how to inject glucagon).
Diabetes in pregnancy
Gestational diabetes
Glucose metabolism changes during pregnancy. Marked insulin resistance develops, particularly by the second half of pregnancy, due to maternal hormones such as human placental lactogen. Fasting glucose decreases slightly, while blood glucose may be increased post-prandially.
Gestational diabetes is defined as diabetes with first onset or recognition during pregnancy. While this includes a few who develop type 1 or type 2 diabetes during pregnancy, the majority can expect to return to normal glucose tolerance immediately after pregnancy. The definitions of diabetes in pregnancy are based on maternal glucose levels associated with increased fetal growth, and are lower than the definitions for non-gestational diabetes, either:
● Fasting venous plasma glucose > 5.1 mmol/L (92 mg/dL) or
● > 10 mmol/L (> 180 mg/dL) at 1 hr or > 8.0 mmol/L (144 mg/dL) at 2 hrs after a 75-g glucose load.
Patients at high risk include those with a BMI > 30, previous macrosomia or gestational diabetes, family history of type 2 diabetes or a high-risk ethnic group (South Asian, black Caribbean, Middle Eastern).
Management of gestational diabetes
The aim is to normalise maternal blood glucose to prevent excessive fetal growth. Dietary restriction of refined carbohydrate is important. Women with gestational diabetes should regularly check pre- and post-prandial blood glucose, aiming for pre-meal levels < 5.5 mmol/L (100 mg/dL) or post-meal levels < 7.0 mmol/L (125 mg/dL). If treatment is necessary, metformin or glibenclamide is generally safe in pregnancy, but other therapies should be avoided. Insulin may be required, especially late in pregnancy. If maternal blood glucose is poorly controlled peri-partum, the resulting fetal hyperinsulinaemia leads to neonatal hyperinsulinaemia, which in turn can cause neonatal hypoglycaemia. After delivery, maternal glucose usually returns rapidly to prepregnancy levels. Women should be tested at least 6 wks postpartum with an oral glucose tolerance test. Those who have returned to normal glucose tolerance remain at considerable risk for developing type 2 diabetes (5-yr risk 15–50%), depending on the population, and should be given diet and lifestyle advice to reduce this risk.
Pregnancy in women with established diabetes
Maternal hyperglycaemia early in pregnancy can lead to fetal abnormalities, including cardiac, renal and skeletal malformations, of which the caudal regression syndrome is the most characteristic. Diabetic women should receive pre-pregnancy counselling and be encouraged to achieve excellent glycaemic control before conceiving.
High-dose folic acid (5 mg, rather than the usual 400 μg, daily) should be initiated before conception to reduce the risk of neural tube defects. Good glycaemic control is often difficult to achieve. Pregnancy carries an increased risk of ketosis, which is dangerous for the mother and is associated with a high rate (10–35%) of fetal mortality.
Pregnancy is associated with worsening of diabetic retinopathy and nephropathy. Heavy proteinuria and/or renal dysfunction before pregnancy indicate an increased risk of pre-eclampsia and irreversible loss of renal function. These risks need to be carefully discussed before considering a pregnancy. Diabetes increases perinatal mortality by 3–4 times and congenital malformation 5–6-fold.
Surgery and diabetes
Surgery causes catabolic stress and secretion of counter-regulatory hormones, resulting in increased glycogenolysis, gluconeogenesis, lipolysis, proteolysis and insulin resistance. This normally leads to increased secretion of insulin, which exerts a restraining and controlling influence. In diabetic patients, insulin deficiency leads to increased catabolism and ultimately metabolic decompensation. In addition, hyperglycaemia increases infection risk and impairs wound healing. Hypoglycaemia risk, particularly dangerous in the semiconscious patient, should be minimised.
Pre-operative assessment
This includes assessment of:
● Glycaemic control (HbA1c and pre-prandial glucose).
● Cardiovascular and renal function.
● Foot risk (peri-operative pressure relief)
● A review of diabetic treatments.
If significant alterations need to be made, patients may need admission prior to surgery. For emergency patients with significant hyperglycaemia or ketoacidosis, this should be corrected first with an IV infusion of saline and/or dextrose plus insulin, 6 U/hr, and potassium as required.
Peri-operative management
The management of patients with diabetes undergoing surgery requiring general anaesthesia is summarised in Figure 11.2. Postoperatively, IV insulin and fluids should be continued (containing appropriate dextrose, sodium and potassium), until the patient’s intake of food is adequate, when the normal regimen can be resumed. If the infusion is prolonged, urea, electrolytes and urinary ketones should be checked daily.
Diabetes presenting through complications
Diabetic complications may be the presenting finding in a patient not known to have diabetes. Around 20% of people with type 2 diabetes have established complications at the time of diagnosis. Patients presenting with hypertension or a vascular event should have coexistent diabetes excluded.
MANAGEMENT OF DIABETES
Of new cases of diabetes, approximately 50% can be controlled adequately by diet alone, 20–30% will need oral antidiabetic medication, and 20–30% will require insulin. Regardless of aetiology, the choice of treatment is determined by the adequacy of residual β-cell function. However, this cannot be determined easily by measurement of plasma insulin concentration because a level that is adequate in one patient may be inadequate in another, depending on sensitivity to insulin. Ideal management allows the patient to lead a completely normal life, to remain symptom-free and to escape the long-term complications of diabetes. The correct treatment may change with time as β-cell function is lost.
Diet and lifestyle
Lifestyle changes, such as taking regular exercise, observing a healthy diet, reducing alcohol consumption and stopping smoking, are important but difficult for many to sustain.
Healthy eating
Dietary measures are required in the treatment of all people with diabetes. People with diabetes should have access to dietitians at diagnosis, at review and at times of treatment change. Nutritional advice should be tailored to individuals and take account of their age and lifestyle. The aims are to improve glycaemic control, manage weight, and avoid both acute and long-term complications.
Carbohydrate
Both the amount and type of carbohydrate determine post-prandial glucose. The effect of a particular ingested carbohydrate on blood glucose relative to the effect of a glucose drink is termed the glycaemic index (GI). Starchy foods, such as rice, porridge and noodles, are favoured, as they have a low GI and produce only a gradual rise in blood glucose. It is now possible to match the amount of carbohydrate in a meal with a dose of short-acting insulin using methods such as DAFNE (dose adjustment for normal eating). This enables motivated individuals with type 1 diabetes to achieve and maintain good glycaemic control, while avoiding post-prandial hyper- and hypoglycaemia. For people with type 2 diabetes, avoidance of refined carbohydrate and restriction of carbohydrate to 45–60% of total energy intake is recommended.
Fat
The intake of total fat should be restricted to < 35% of energy intake, with < 10% as saturated fat, 10–20% from monounsaturated fat and < 10% from polyunsaturated fat.
Salt
People with diabetes should follow the advice given to the general population: namely, to limit sodium intake to no more than 6 g daily.
Weight management
A high percentage of people with type 2 diabetes are overweight or obese, and many antidiabetic medications and insulin encourage weight gain. Abdominal obesity also predicts insulin resistance and cardiovascular risk. Weight loss is achieved through a reduction in energy intake and an increase in energy expenditure through physical activity. In extreme cases, bariatric surgery can induce marked weight loss and improvement in HbA1c in patients with type 2 diabetes, sometimes enabling treatment withdrawal.
Exercise
All patients with diabetes should be advised to achieve a significant level of physical activity (e.g. walking, gardening, swimming or cycling) and to maintain this long term. Supervised exercise programmes may be of particular benefit to people with type 2 diabetes.
US guidelines suggest that adults (18–64 yrs) should build up to a weekly minimum of 2.5 hrs of moderate-intensity exercise or 75 mins of vigorous-intensity exercise. The aerobic (moderateintensity) activity should be performed for at least 10 mins each time and spread throughout the week, with at least 30 mins on at least 5 days of the week. Recently, it has also been suggested that a combination of both aerobic and resistance exercise may lead to greater improvements in glycaemic control.
Alcohol
Alcohol can be consumed in moderation. As alcohol suppresses gluconeogenesis, it can precipitate or prolong hypoglycaemia, particularly in patients taking insulin or sulphonylureas. Drinks containing alcohol can be a substantial source of calories and may have to be reduced to assist weight reduction.
Drugs to reduce hyperglycaemia
Most drugs used to treat type 2 diabetes depend upon a supply of endogenous insulin and therefore have no effect in patients with type 1 diabetes. The sulphonylureas and biguanides have been the mainstay of treatment in the past, but a variety of newer agents are now available and the optimal place for these in treatment is yet to be determined.
Biguanides
In the UK Prospective Diabetes Study, metformin reduced myocardial
infarctions, and it is now used widely as first-line therapy in
type 2 diabetes. Approximately 25% of patients develop mild gastrointestinal
side-effects (diarrhoea, abdominal cramps, bloating and
nausea) with metformin, but only 5% are unable to tolerate it even
at low dose. It improves insulin sensitivity and peripheral glucose
uptake, and impairs both glucose absorption by the gut and hepatic
gluconeogenesis. Endogenous insulin is required for its glucoselowering
action, but it does not increase insulin secretion and seldom
causes hypoglycaemia. Metformin does not increase body weight
and it is therefore preferred for obese patients. It acts synergistically
with sulphonylureas, allowing the two to be combined. Metformin
is given with food, 2–3 times daily. The usual starting dose is 500 mg
twice daily (usual maintenance 1 g twice daily). Its use is contraindicated
in alcohol excess and in impaired renal or hepatic function
due to the increased risk of lactic acidosis. It should be discontinued
temporarily if another serious medical condition develops (especially
shock or hypoxaemia).
Sulphonylureas
Sulphonylureas stimulate the release of insulin from the pancreatic
β cell (insulin secretagogue). They are best used to treat non-obese
people with type 2 diabetes who fail to respond to dietary measures,
as treatment is often associated with weight gain. They are known
to reduce microvascular complications with long-term use.
Gliclazide and glipizide cause few side-effects, but glibenclamide
is long-acting and prone to induce hypoglycaemia so should be
avoided in the elderly.
Sulphonylureas are often used as an add-on if metformin fails to
produce adequate glycaemic control.
Alpha-glucosidase inhibitors
These delay carbohydrate absorption in the gut by selectively inhibiting
disaccharidases. Acarbose or miglitol is taken with each meal
and lowers post-prandial blood glucose. Side-effects are flatulence,
abdominal bloating and diarrhoea.
Thiazolidinediones
These drugs (TZDs; ‘glitazones’ or PPARγ agonists) bind and activate
peroxisome proliferator-activated receptor-γ found in adipose
tissue, and work by enhancing the actions of endogenous insulin.
Plasma insulin concentrations are not increased and hypoglycaemia
is not a problem.
TZDs have been prescribed widely since the late 1990s, but
recently a number of adverse effects have become apparent and
their use has declined. Rosiglitazone was reported to increase
the risk of myocardial infarction and was withdrawn in 2010.
The other TZD in common use, pioglitazone, does not appear to
increase the risk of myocardial infarction but it does exacerbate
cardiac failure by causing fluid retention, and recent data show
that it increases the risk of bone fracture and possibly bladder
cancer. These observations have reduced the use of pioglitazone
dramatically.
Pioglitazone can be effective in patients with insulin resistance
and also has a beneficial effect in reducing fatty liver and nonalcoholic
steatohepatitis (NASH; p. 502). Pioglitazone is usually
added to metformin with or without sulphonylurea therapy. It may
be given with insulin, when it can be very effective, but the combination
of insulin and TZDs markedly increases fluid retention and risk
of cardiac failure, so should be used with caution.
Incretin-based therapies: DPP-4 inhibitors
and GLP-1 analogues
The incretin effect is the augmentation of insulin secretion seen
when glucose is given orally rather than intravenously, due to the
release of gut peptides (glucagon-like peptide 1 (GLP-1) and gastric
inhibitory polypeptide (GIP) ). These are broken down by dipeptidyl
peptidase 4 (DPP-4).
DPP-4 inhibitors: Prevent breakdown and therefore increase
endogenous GLP-1 and GIP levels. Examples include sitagliptin,
vildagliptin, saxagliptin and linagliptin. They are well tolerated and
are weight-neutral.
GLP-1 receptor agonists: Mimic GLP-1 but are modified to resist
DPP-4. They have to be given by SC injection but have a key advantage
over DPP-4 inhibitors: they decrease appetite at the level of the
hypothalamus. Thus, GLP-1 analogues lower blood glucose and
result in weight loss – a major advantage in obese patients with type
2 diabetes. Examples include exenatide (twice daily), exenatide MR
(once weekly) and liraglutide (once daily).
Incretin-based therapies do not cause hypoglycaemia. Insulin
The duration of action of the main groups of insulin preparation is
given in Box 11.10.
Subcutaneous multiple dose insulin therapy
Insulin is injected subcutaneously into the anterior abdominal wall,
upper arms, outer thighs and buttocks. The rate of absorption of
insulin may be influenced by the insulin formulation, the site, depth
and volume of injection, skin temperature (warming), local massage
and exercise. Absorption is delayed from areas of lipohypertrophy
at injection sites.
Once absorbed into the blood, insulin has a half-life of just a few
minutes. Excretion is hepatic and renal, so insulin levels are elevated
in hepatic or renal failure.
Insulin delivered by re-usable syringe has largely been replaced
by that delivered by pen injectors containing sufficient insulin for
multiple dosing.
Insulin analogues have largely replaced soluble and isophane
insulins, especially for type 1 diabetes, because they allow more
flexibility and convenience. Unlike soluble insulin, which should be
injected 30 mins before eating, rapid-acting insulin analogues can be
administered immediately before, during or even after meals. Longacting
insulin analogues are better able than isophane insulin to
maintain ‘basal’ insulin levels for up to 24 hrs, so need only be
injected once daily.
The complications of insulin therapy include:
● Hypoglycaemia. ● Weight gain. ● Peripheral oedema (insulin treatment
causes salt and water retention in the short term). ● Insulin
antibodies (animal insulins). ● Local allergy (rare). ● Lipodystrophy
at injection sites.
A common problem is fasting hyperglycaemia (the ‘dawn phenomenon’)
caused by the release of counter-regulatory hormones
during the night, which increases insulin requirement before
wakening.
Insulin dosing regimens
The choice of regimen depends on the desired degree of glycaemic
control, the severity of insulin deficiency, the patient’s lifestyle, and
their ability to adjust the insulin dose. Most people with type 1
diabetes require two or more insulin injections daily. In type 2 diabetes,
insulin is usually initiated as a once-daily long-acting insulin,
with or without oral hypoglycaemic agents.
Twice-daily administration: A short-acting and intermediateacting
insulin (usually soluble and isophane), given before breakfast
and the evening meal, is the simplest regimen. Initially, two-thirds
of the daily insulin is given in the morning in a ratio of short- to
intermediate-acting of 1 : 2; the remainder is given in the evening.
Pre-mixed formulations containing fixed proportions of soluble and
isophane insulins are useful if patients have difficulty mixing insulins,
but the individual components cannot be adjusted independently.
Fixed-mixture insulins also have altered pharmacokinetics,
i.e. the peak insulin and time to peak effect are significantly reduced
compared with the same insulins injected separately.
Multiple injection regimens: These are popular, with short-acting
insulin before each meal, plus intermediate- or long-acting insulin
injected once or twice daily (basal-bolus regimen). This regimen
allows greater freedom of meal timing and more variable day-to-day
physical activity.
Portable pumps: Pumps infusing continuous SC or IV insulin can
achieve excellent glycaemic control but will not be widely adopted
until they become cheaper and incorporate a miniaturised glucose
sensor.
Transplantation
Whole pancreas transplantation presents problems relating to exocrine
pancreatic secretions and long-term immunosuppression is
necessary. At present, the procedure is usually undertaken only in
patients with end-stage renal failure who require a combined
pancreas/kidney transplantation and in whom diabetes control is
particularly difficult, e.g. because of recurrent hypoglycaemia.
Transplantation of isolated pancreatic islets (usually into the liver
via the portal vein) has been achieved safely in an increasing number
of centres around the world. Progress is being made towards
meeting the needs of supply, purification and storage of islets, but
the problems of transplant rejection, and of destruction by the
patient’s autoantibodies against β cells, remain.
COMPLICATIONS OF DIABETES
People with diabetes have a mortality rate over twice that of ageand
sex-matched controls. The range of complications of diabetes is
summarised in Box 11.9. Cardiovascular disease accounts for 70% of
all deaths. Atherosclerosis in diabetic patients occurs earlier and is
more extensive and severe. Diabetes amplifies the effects of the other major cardiovascular risk factors: smoking, hypertension and
dyslipidaemia.
Disease of small blood vessels (diabetic microangiopathy) is
a specific complication of diabetes. It damages the kidneys, the
retina and the peripheral and autonomic nerves, causing substantial
morbidity and disability: blindness, difficulty in walking, chronic
foot ulceration, and bowel and bladder dysfunction. The risk
of microangiopathy is related to the duration and degree of
hyperglycaemia.
Preventing diabetes complications
The evidence that improved glycaemic control decreases the risk of
microvascular complications of diabetes comes from the Diabetes
Control and Complications Trial (DCCT) in type 1 diabetes, and the
UK Prospective Diabetes Study (UKPDS) in type 2 diabetes. The
DCCT lasted 9 yrs and showed a 60% overall reduction in the risk
of diabetic complications in patients with type 1 diabetes on intensive
therapy with strict glycaemic control, compared to conventional
therapy. However, the intensively treated group had three times the
rate of severe hypoglycaemia. The UKPDS showed that, in type 2
diabetes, the frequency of diabetic complications is lower and progression
is slower with good glycaemic control and effective treatment
of hypertension, irrespective of the type of therapy used.
Extrapolation from the UKPDS suggests that, for every 11 mmol/
mol (1%) reduction in HbA1c, there is a 21% reduction in deaths
related to diabetes, a 14% reduction in myocardial infarction and
30–40% reduction in risk of microvascular complications.
These trials demonstrate that diabetic complications are preventable
and that the aim of treatment should be ‘near-normal’ glycaemia.
However, the recent Action to Control Cardiovascular Risk
in Diabetes study showed increased mortality in a high-risk subgroup
of patients who were treated aggressively to lower HbA1c to
< 48 mmol/mol (6.5%). Therefore, whilst a low target HbA1c is
appropriate in younger patients with earlier diabetes without underlying
cardiovascular disease, aggressive glucose-lowering is not
beneficial in older patients with long duration of diabetes and multiple
comorbidities.
RCTs have also shown that aggressive management of lipids and
BP limits complications. ACE inhibitors are valuable in improving
outcome in heart disease and in preventing diabetic nephropathy.
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