16 Diabetes mellitus and hyperlipidaemia
Diabetes Mellitus
• Carbohydrate metabolism. Basal levels of insulin, present when fasting and between meals, inhibit hepatic enzymes that control the critical limiting steps in both gluconeogenesis (glucose synthesis from amino acids and lactate) and glycogenolysis. Thus hepatic glucose production, a major contributor to fasting glycaemic levels, is reduced by insulin. Post-prandial peaks of insulin stimulate glucose uptake into skeletal muscle (where it is used for energy) and adipose tissue (where it is used for the synthesis of triglycerides.)
• Fat metabolism. Insulin promotes triglyceride synthesis and inhibits its breakdown into free fatty acids and ketone bodies.
• Protein metabolism. Insulin inhibits protein breakdown into amino acids, which are precursors for hepatic gluconeogenesis.
Who classification of diabetes
Type 2 diabetes mellitus
Type 2 DM (> 90% of total) results from a progressive fall in insulin secretion with, in addition, resistance to the action of insulin. It is frequently associated with obesity and the ‘metabolic syndrome’ (p. 429). Early in the disease, there may be high levels of circulating insulin, in contrast to type 1 diabetes. Hyperglycaemia results from a progressive failure of the pancreatic β-cells to maintain high levels of insulin secretion to overcome peripheral resistance. The diagnosis is therefore often delayed since endogenous insulin levels are initially sufficient to prevent ketogenesis and a catabolic state. Intercurrent illness, with increased insulin resistance secondary to release of stress response hormones, is associated with worsening glycaemic control and consequent dehydration. The presentation is often with a concurrent illness in an adult with a history of polyuria, polydipsia and malaise over some weeks.
Higher-risk population groups that may benefit from screening for type 2 diabetes include:
Other types of diabetes
• Pancreatic disease. Chronic pancreatitis with progressive destruction of the β-cells results in diabetes that requires insulin in about one-third of patients. Simultaneous loss of α-cells with failure of glucagon secretion can result in profound hypoglycaemia, particularly in poorly nourished individuals; this is typically seen in patients with chronic alcohol abuse. Acute pancreatitis may be associated with transient hyperglycaemia.
• Genetic diseases. Genetic diseases such as cystic fibrosis and haemochromatosis have pancreatic damage which may lead to insulin-deficient diabetes, similar in clinical nature to type 1 diabetes.
• Genetic defects of β-cell function. A number of different genetic abnormalities produce type 2 diabetes at a young age (formerly called maturity onset diabetes of the young (MODY)). Presentation is before the age of 25, without features of type 1 diabetes. There is a strong family history of early-onset diabetes. The diabetes is often managed with oral antidiabetic agents alone, although insulin may be needed in some cases.
• Gestational diabetes. Glucose intolerance may develop during pregnancy due, in part, to increases in maternal insulin resistance resulting from circulating placental hormones. Tight control of maternal blood glucose levels in these patients reduces stillbirth rates, macrosomia, hydramnios and pre-eclampsia. Abnormal glucose tolerance returns to normal following delivery. It can be difficult to exclude pre-existing type 2 diabetes presenting for the first time in pregnancy. Gestational diabetes itself is a predictor of diabetes in later life and regular follow-up is required.
Diagnosis
Diagnostic criteria
• Impaired glucose tolerance (IGT)
Management of diabetes
The aims of management are to:
Insulin therapy
Insulin is the only therapy suitable for the treatment of type 1 diabetes and in cases where endogenous insulin production has been significantly reduced, such as haemochromatosis. Interruptions in insulin therapy render these individuals at risk of ketosis. Insulin is also used to cover periods of intercurrent illness in type 2 diabetes when insulin resistance is increased, or there are concerns that hepatic or renal clearance of an oral drug may be impaired. Progressive β-cell failure is seen in type 2 diabetes and thus oral antidiabetic agents may with time fail to control glycaemia adequately. While there is often resistance to injectable therapy, either through patient preference or a fear of weight gain, initiation of insulin in this group of patients should not be delayed.
Insulin formulations (Table 16.1)
• Short-acting ‘soluble’/rapid human insulins are administered intravenously, subcutaneously or intramuscularly. These insulin preparations are typically clear fluids with an onset of action within 15–30 mins when injected subcutaneously. They are therefore used to control mealtime glycaemic swings. They are the only insulins used for IV infusions and SC insulin pumps. The rapid-acting analogue insulins, which have an altered amino acid structure, are more rapidly absorbed than soluble (regular) insulin.
• Longer-acting insulins have a speed of absorption that is prolonged by complexing insulin to compounds such as protamine and zinc. The resulting cloudy crystalline solution is absorbed over a period of hours. These are administered by SC injection only and are used to provide steady levels of background insulin through the day and overnight. Pre-mixed (biphasic) formulations, containing fixed amounts of short- and longer-acting insulins, are available.
• Analogue insulin preparations offer improved profiles, with the rapid-acting insulin being absorbed more quickly, and the longer-acting insulin showing a smoother profile of action. These are intended for SC use. All are clear solutions, which can cause confusion with biosynthetic human short-acting insulin preparations.
Principles of insulin treatment
• Basal bolus regimen. This incorporates a background of longer-acting insulin and prandial short-/rapid-acting insulin. It typically requires four injections per day. This regimen is flexible in that the individual can alter injection times and doses to take into consideration activity levels, portion size, food type and time of eating.
• Pre-mixed insulin. Two injections per day of pre-mixed short-/rapid-acting and longer-acting insulin reduce flexibility and quality of blood sugar control compared to basal bolus, but are more convenient and therefore compliance may be improved. The fraction of short-acting insulin is usually indicated in the name of the mixture preparation (e.g. biphasic insulin aspart 30 contains 30% rapid-acting insulin aspart and 70% aspart protamine.)
• Once-daily insulin. A single injection of long-acting insulin helps in the management of those unable to inject themselves, or as a short-term measure to encourage conversion to insulin from oral therapy. It is also added to oral therapy as an additional agent to help control fasting hyperglycaemia.
• Continuous SC insulin infusion. To achieve this, a small portable insulin device is worn at all times, providing a continuous infusion of insulin at a basal rate designed to control background glycaemic levels. Additional mealtime boluses can be provided through the device by pressing a button, avoiding the need for additional injections. This technique should only be used by patients prepared to monitor their blood glucose levels regularly, as these patients have no protective reservoir of depot insulin.
• Continuous IV insulin infusions (in hospital management of hyperglycaemia). IV insulin infusions are used following admission with hyperglycaemic crises (see below) or when a patient with diabetes is unable to eat or drink. Choice lies between a variable rate of insulin (‘sliding scale’) and a steady rate of insulin infusion (glucose/potassium/insulin ‘GKI’ infusion). When the patient is otherwise stable, e.g. pre-operatively, good glycaemic control may be achieved by fixed rate infusion of soluble insulin and potassium. The variable rate, or sliding scale, of insulin infusion tends to be unsatisfactory on general wards, although it offers flexibility with close monitoring, such as in intensive care. The problem is that the rate of insulin is adjusted frequently in response to glycaemic excursions, rather than to avoid them, and can result in wild fluctuations in blood sugar without achieving good baseline control.
Oral antidiabetic drugs (Table 16.2)
Insulin secretagogues
• Sulphonylureas stimulate insulin release from the pancreatic β-cells, with a peak of insulin levels within 1–2 hours and a duration of action that varies between drugs. They reduce both fasting and post-prandial glucose by 2–4 mmol/L (36–72 mg/dL). They rely on a functional β-cell population, so efficacy may wane with time. Most are taken twice daily. The longer-acting agents are useful as once-daily preparations to aid compliance but hypoglycaemia, especially in the elderly or those with chronic kidney disease (CKD), is frequent. Therapy is associated with weight gain, largely due to the anabolic effects of higher insulin levels increasing appetite and the reduction in urinary glucose loss. Therefore these drugs are used as first-line agents in non-obese patients or those intolerant of metformin.
• Meglitinides act via a similar cellular mechanism as the sulphonylureas to induce pancreatic insulin release but action is augmented by glycaemia. This, together with a rapid onset of action (30–60 mins), makes them a good medication to take at mealtimes to counteract post-prandial blood glucose excursions. They are primarily metabolized in the liver. so have a better safety profile for use in CKD.
Insulin sensitizing agents
• Metformin, a biguanide, is not associated with weight gain and is the drug of choice in the overweight diabetic person. It improves insulin sensitivity and significantly reduces hepatic gluconeogenesis. It is not an insulin secretagogue and will not, therefore, cause hypoglycaemia when used in isolation. It has a similar impact on glycaemia and HbA1C to the sulphonylurea agents. Treatment is associated with gastrointestinal side-effects, e.g. diarrhoea, which can be minimized by a slow dose titration on initiation (e.g. starting dose of 500 mg daily with main meal, increasing by 500 mg increments each month). Anorexic side-effects may be viewed as beneficial in those trying to reduce food intake.
• Caution/contraindications: there is a small risk of lactic acidosis due, at least in part, to inhibition of hepatic gluconeogenesis, which consumes lactate. Situations where lactate production is increased (cardiac and respiratory failure), where lactate clearance is reduced (hepatic failure) or where metformin excretion is reduced (renal failure) predispose to lactic acidosis. Metformin should be stopped where creatinine clearance is < 60 mL/min. Metformin should be stopped for 48 hours after administration of iodinated contrast media to avoid consequent renal dysfunction.
• Thiazolidinediones (glitazones) influence glycaemic control at the level of gene transcription via nuclear receptors, so their maximal effect is not seen for up to 8 weeks after initiation of therapy. They enhance glucose utilization by skeletal muscle and adipocytes, and act via the peroxisome proliferator-activated receptor (PPAR) family, which is also implicated in the control of many genes, including those involved in lipid metabolism.
• Cautions/contraindications: avoid in pregnancy and breast feeding. This group of drugs should not be used in hepatic impairment, and liver biochemistry should be assessed prior to therapy and every 2 months for the first 12 months. Fluid retention and exacerbation of cardiac failure are also seen. Rosiglitazone is no longer recommended for general use.
Intestinal enzyme inhibitors
• Alpha-glucosidase inhibitor, e.g. acarbose 50 mg daily, increasing to a maximum of 200 mg daily, reduces post-prandial hyperglycaemia by inhibiting intestinal breakdown of complex starches and thus delaying carbohydrate absorption. It should be chewed with the first mouthful of food or swallowed whole with a little liquid before the meal. It is not as efficacious as other oral antidiabetic agents. Side-effects include abdominal bloating and diarrhoea.
Other therapies
• Incretins
• Glucagon-like peptide (GLP)-1. This is produced from the L-cells of the small intestine and is secreted after a meal. Oral glucose stimulates insulin secretion more than an IV glucose load (the incretin effect), partly due to GLP-1 release. Exenatide and liraglutide are GLP-1 analogues and bind to the GLP receptor. These drugs increase insulin secretion, inhibit glucagon secretion and slow gastric emptying. They are given by SC injection to patients with type 2 diabetes on metformin, sulphonylurea or both, if glycaemic control is poor. They produce weight loss, which is beneficial. Side-effects include persistent nausea and pancreatitis. Long-term studies are awaited.
• Dipeptidyl peptidase (DPP)-4 inhibitors. DPP-4 deactivates both glucose-dependent insulinotropic peptide (GIP) and GLP-1. Saxagliptin, sitagliptin and vildagliptin inhibit this enzyme to increase insulin secretion and lower glucagon. They can be given orally with metformin in type 2 diabetes. There is no associated hypoglycaemia.
• Amylin analogue. Amylin is stored in the pancreatic β-cells and is secreted along with insulin. It is deficient in type 1 diabetes and also, to a lesser extent, in type 2 patients requiring insulin. It decreases gastric emptying, suppresses glucagon secretion and decreases appetite. Pramlintide is an amylin analogue and is given at mealtimes as an SC injection. It is used in poorly controlled type 1 diabetic patients taking insulin and in type 2 patients when they are overweight and not well controlled on insulin. Side-effects include severe hypoglycaemia and nausea.
• Orlistat. Orlistat is a lipase inhibitor that reduces the absorption of fat from the diet. It promotes weight loss in patients on a low-fat diet, thus indirectly benefiting the diabetes. The low-fat diet is necessary to avoid unpleasant steatorrhoea.
• Bariatric surgery, e.g. gastric banding, gastric bypass surgery, roux-en-Y, is used in patients with type 2 diabetes and gross obesity unresponsive to 6 months of intensive attempts at dieting and graded exercise. One-third of patients become non-diabetic after surgery, those with recent onset of diabetes benefiting the most.
Practical management of type 1 DM
Monitoring
• Fasting blood glucose measurements indicate a background glycaemic control and should lie between 4 and 7 mmol/L (72–126 mg/dL). Measuring blood glucose 2 hours post-prandially gives an indication of glycaemic swings following food and levels should be < 10 mmol/L (180 mg/dL).
• HbA1c is a glycosylated haemoglobin reflecting glycaemia over the preceding 3 months. It should be measured every 2–6 months, depending on stability of the disease and changes in treatment. Good glycaemic control benefits both microvascular and macrovascular complications of diabetes. The aim is to achieve an HbA1c between 6.5 and 7.5% (48–59 mmol/mol), which requires good compliance with therapy with an increased risk of iatrogenic hypoglycaemia.
Pharmacotherapy
• Insulin therapy (p. 595). All type 1 patients require insulin therapy. All need careful training for a life with insulin. This is best achieved outside hospital, provided that adequate facilities exist for outpatient diabetes education.
• A multiple injection regimen, with short-acting insulin and a longer-acting insulin at night, is appropriate for most younger patients (Fig. 16.1b). The advantages of multiple injection regimens are that the insulin and the food go in at roughly the same time, so that mealtimes and sizes can vary without greatly disturbing metabolic control. The flexibility of multiple injection regimens is of great value to patients with busy jobs, shift workers and those who travel regularly.
• Some recovery of endogenous insulin secretion may occur over the first few months (the ‘honeymoon period’) in type 1 patients and the insulin dose may need to be reduced or even stopped for a period. Requirements rise thereafter.
• Some type 1 diabetes patients will opt for twice-daily mixed insulin injections (Fig. 16.1a) and put up with the lifestyle restrictions that this imposes (with twice-daily regimens, the size and timing of meals are fixed more rigidly). Target blood glucose values should normally be 4–7 mmol/L before meals, 4–10 mmol/L after meals.
• When to use insulin analogues. Hypoglycaemia between meals and particularly at night is the limiting factor for many patients on multiple injection regimens. The more expensive rapid-acting insulin analogues (Fig. 16.1c) are a useful substitute for soluble insulin in some patients. They reduce the frequency of nocturnal hypoglycaemia due to reduced carry-over effect from the daytime. They are often used on grounds of convenience, since patients can inject shortly before meals, but this is illogical since standard insulins injected at the same time give equivalent overall control. High or erratic morning blood glucose readings can prove a problem for about a quarter of all patients on conventional multiple injection regimens because the bedtime intermediate-acting insulin falls and the absorption is variable. The long-acting insulin analogues, insulin glargine and insulin detemir, help to overcome these problems and reduce the risk of nocturnal hypoglycaemia.
Fig. 16.1 Insulin regimens. Profiles of soluble insulins are shown as dashed lines; intermediate- or long-acting insulin as solid lines (purple); and rapid-acting insulin as dotted lines (blue). The arrows indicate when the injections are given. B, breakfast; L, lunch; S, supper; Sn, snack (bedtime).
Risk factor reduction (Table 16.3)
• BP control (see also p. 335): BP of below 130/80 mmHg should be achieved using lifestyle changes, e.g. dietary control for reduction in weight, stopping smoking, reduction in intake of alcohol and salt, and taking exercise. If necessary, an ACE inhibitor, e.g. lisinopril 20 mg daily maintenance, or an angiotensin receptor II antagonist, e.g. candesartan 8–32 mg daily, is prescribed.
• Lipid monitoring. A total cholesterol of < 4.0 mmol/L (< 150 mg/dL), low-density lipoprotein cholesterol (LDL-C) of < 2.00 mmol/L (< 76 mg/dL), a fasting triglyceride of < 1.7 mmol/L (< 150 mg/dL) and a high-density lipoprotein (HDL) cholesterol of > 1 mmol/L (> 38 mg/dL) should be aimed for as ideal goals. To achieve these levels most diabetics require statin therapy (p. 617–8).
• Aspirin. Low-dose aspirin 75–150 mg/daily should be given as a secondary prevention strategy in those with a history of cardiovascular events, e.g. myocardial infarction, stroke, peripheral vascular disease or angina. Its benefits in primary prevention are less clear but it should be used in patients with a high cardiovascular risk. Patients allergic to aspirin or with a bleeding tendency should use clopidogrel. Aspirin is not recommended for patients under the age of 21 years because of an increased risk of Reye’s syndrome.
• Exercise. Exercise improves insulin sensitivity and 30 mins of moderate physical activity, 5 days a week, is recommended. In the young type 1 diabetic, both diet and insulin doses will require adjustment. Prior to undertaking a new exercise programme, individuals should receive a cardiovascular assessment, including physical examination, BP and ECG. Peripheral nervous system and vascular supply to the feet should be looked at and advice given on adequate footwear. Diabetic complications, such as autonomic neuropathy, should be excluded, as they make exercise more hazardous.
| Parameter | Ideal | Reasonable |
|---|---|---|
| HbA1c | < 7% | < 8% |
| BP (mmHg) | < 130/80 | < 140/80 |
| Total cholesterol (mmol/L) | < 4.0 | < 5.0 |
| LDL | < 2.0 | < 3.0 |
| HDL* | > 1.1 | > 0.8 |
| Triglycerides | < 1.7 | < 2.0 |
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Practical management of type 2 DM
Diet
• Total fat: < 35% of energy intake (with saturated fat < 10%, n-6 polyunsaturated fat < 10%, n-3 no absolute quantity but more oily fish intake, cis-monosaturated fat 10–15%).
• Total carbohydrate: 40–60% of total energy intake. The glycaemic index (GI) describes the rise in blood glucose after carbohydrate ingestion. For example, the blood glucose peak level after eating pasta is much flatter (low GI) than that seen after eating the same amount of white potato (high GI). Low GI foods are encouraged.
Monitoring
• Fasting blood glucose measurements are as for type 1 diabetes (p. 602), with glycaemic control to lie between 4 and 7 mmol/L (72–126 mg/dL).
Indications for hospital admission
• Diabetic ketoacidosis (DKA, p. 608). This occurs mainly in type 1 DM, with a mortality in developed countries of 5–10%. Cardinal features are hyperglycaemia (> 11 mmol/L; 250 mg/dL), or known diabetes mellitus and metabolic acidosis (pH < 7.3; bicarbonate < 15 mmol/L or < 5 mEq/L). Any diabetic with heavy ketonuria should be monitored closely.
• Hyperosmolar hyperglycaemic state (HHS) (p. 610). There is severe hyperglycaemia (> 22 mmol/L; > 400 mg/dL) and an elevated serum osmolality (> 320 mosm/kg). There is no significant hyperketonaemia or acidosis (pH > 7.3). It is characteristic of type 2 uncontrolled diabetes.
• Hypoglycaemia (p. 612). If this is severe, it may cause confusion, fits or coma. It may be prolonged following sulphonylurea therapy.
Diabetics required to fast for surgery and other procedures
The procedure for insulin-treated patients is simple:
• Patients whose diabetic control is inadequate and for whom surgery is not an emergency should have their diabetic control reassessed and therapy adjusted with HbA1c < 8.5%, if possible pre-operatively.
• The patient’s usual insulin is given the night before the operation and, whenever possible, diabetic patients should be first on the morning procedure/operating list.
• An infusion of glucose, insulin and potassium is given during the procedure/surgery. The insulin can be mixed into the glucose solution or administered separately by syringe pump. A standard combination is 16 U of soluble insulin with 10 mmol of KCl in 1 L of 5–10% glucose, infused at 125 mL/hour. The insulin dose is adjusted:
• Post-operatively, the infusion is maintained until the patient is able to eat. Other fluids needed in the peri-operative period must be given through a separate IV line and must not interrupt the glucose/insulin/potassium infusion. Glucose levels are checked every 2–4 hours and potassium levels are monitored. The amount of insulin and potassium in each infusion bag is adjusted either upwards or downwards according to the results of regular monitoring of the blood glucose and serum potassium concentrations.
Diabetes and pregnancy
Glycaemic control should be optimized prior to conception to reduce the risk of congenital malformations. Women on oral hypoglycaemic agents should be switched to insulin, although metformin may be continued. Poorly controlled diabetes in pregnancy is associated with stillbirth, pre-eclampsia, fetal macrosomia and hydramnios. Women should be monitored intensively by both the diabetic and the obstetric teams.
Diabetic ketoacidosis
Diagnosis and management
Diagnosis and management are shown in Box 16.1. The patient should be closely monitored until stable.
• Water depletion. Insulin deficiency leads to hyperglycaemia with resultant osmotic diuresis and dehydration. Uncontrolled lipolysis and production of ketone bodies result in a metabolic acidosis that may be associated with nausea and vomiting, exacerbating the level of dehydration. The typical fluid deficit seen in DKA is between 5 and 7 L for an average adult patient. Assessment may be complicated by pre-existing autonomic neuropathy leading to BP instability.
• Electrolytes (Box 16.2). Total body potassium will be depleted by about 350 mmol (mEq) but the measured serum potassium may be within the normal range, or even high as a result of acidosis. Potassium should therefore be replaced even when the serum level is within the normal range, but not if the serum potassium is > 6.5 mmol/L, particularly if there is acute kidney injury. There is hyponatraemia with total body sodium being depleted by 500 mmol (mEq).
• Insulin therapy. An IV insulin infusion is commenced at a fixed rate of 0.1 U/kg/hour via an infusion pump. If the blood ketone measurements or venous bicarbonate levels are not normalizing, the fixed rate may be increased. Blood ketone levels should fall by at least 0.5 mmol/hour; venous bicarbonate levels should increase by 3 mmol/L/hour. Do not stop insulin IV until SC insulin is started. If the patient is using a long-acting analogue insulin as part of the normal regime, this should be continued alongside the insulin infusion. If facilities for IV infusion are not available, give 20 U insulin IM, followed by 6 U IM every hour. When blood glucose concentration falls to 10 mmol/L (180 mg/dL) give IM injections every 2 hours. N.B. Absorption may be variable, particularly with hypotension; watch for late hypoglycaemia.
• Frequency of monitoring. This depends on the severity. In severe DKA, glucose should be monitored hourly and electrolytes 2-hourly for 8 hours.
Box 16.1 Guidelines for the diagnosis and management of diabetic ketoacidosis
Phase 1 management
Box 16.2 Electrolyte changes in diabetic ketoacidosis and the hyperosmolar hyperglycaemic state
Examples of blood values
| Severe ketoacidosis | Hyperosmolar hyperglycaemic state | |
|---|---|---|
| Na+ (mmol/L) | 140 | 155 |
| K+ (mmol/L) | 5 | 5 |
| Cl– (mmol/L) | 100 | 110 |
| HCO3– (mmol/L) | 5 | 25 |
| Urea (mmol/L) | 8 | 15 |
| Glucose (mmol/L) | 30 | 50 |
| Arterial pH | 7.0 | 7.35 |
The normal range of osmolality is 285–300 mOsm/kg. It can be measured directly, or can be calculated approximately from the formula:
For instance, in the example of severe ketoacidosis given above:
and in the example of the hyperosmolar hyperglycaemic state:
The normal anion gap is less than 17. It is calculated as (Na+ + K+) − (Cl− + HCO3−). In the example of ketoacidosis the anion gap is 40, and in the example of the hyperosmolar hyperglycaemic state the anion gap is 25. Mild hyperchloraemic acidosis may develop in the course of therapy. This will be shown by a rising plasma chloride and persistence of a low bicarbonate even though the anion gap has returned to normal.
Hyperosmolar hyperglycaemic state
Hyperosmolar hyperglycaemic state (HHS) is the hyperglycaemic crisis associated with type 2 diabetes. It is due to a reduction in effective circulating insulin levels, exacerbated by elevated levels of counter-regulatory hormones such as cortisol, growth hormone and catecholamines. Thus hepatic glucose production is increased but there is sufficient insulin to prevent significant ketosis. Mortality rates for HHS are as high as 15%, increasing with age and co-morbidity.
Investigations (see Box 16.2)
• Blood glucose is often > 50 mmol/L (900 mg/dL); bedside capillary blood glucose testing kits are extremely inaccurate at this level of glycaemia.
• A 25% deficit in total body water is usual, which for a 70 kg man equates to about 10 L of fluid. The severity of dehydration correlates with the patient’s mental state.
• Measurement or calculation of serum osmolality is useful. Reduced consciousness would be unexpected with a serum osmolality < 340 mosmol/kg, and if present in such a situation, an alternative cause should be sought.
• Since the brain is relatively permeable to both glucose and urea, serum sodium alone may give a more accurate indication of the degree of cerebral dehydration. However, measured sodium is a poor indicator of sodium status since intravascular hyperglycaemia results in movement of free water from the intracellular space to the extracellular space with a consequent dilution effect. The measured sodium level may be corrected for the degree of hyperglycaemia by increasing the measured sodium level by 1.6 mmol/L for every 5.6 mmol/L increment of serum glucose above the normal level.
Management
• Rehydration is the mainstay of treatment; it must be undertaken slowly in patients with coexistent cardiac failure. Isotonic 0.9% saline is the fluid of choice.
• Gradual reduction in serum glucose is largely achievable with rehydration; about 3 mmol/L per hour is the aim. Slow insulin replacement (< 3 U/hour) avoids precipitous falls in serum glucose. Glucose levels initially should be repeated half-hourly. The osmotic pressure exerted by glucose within the intravascular space helps maintain circulating volume in severely dehydrated patients and rapid reductions in glucose without adequate fluid replacement can result in circulatory collapse.
• Hypokalaemia may be dilutional but it also results from potassium being driven into cells following insulin therapy and rehydration. Electrolytes should be measured every 1–2 hours initially and potassium added to the saline infusion as necessary.
• Mental status must be monitored. Rapid osmotic changes in the brain can lead to cerebral oedema and an abrupt deterioration in conscious level. The brain attempts to control its intracellular water content in prolonged hyperglycaemia by accumulating intracellular electrolytes and other osmotically active substances. This process takes several hours and allows the brain to achieve osmotic equilibrium with the external environment, with minimal loss of water. These substances only slowly diffuse out of the brain, so in the event of rapid corrections in serum osmolality, water will accumulate within the brain cells, causing oedema.
• IV infusion of insulin is stopped following resolution of HHS, and SC insulin injections started. Ultimately, it may be possible to place the patient on oral antidiabetic agents. Insulin requirements will fall gradually following an episode of HHS and this must be closely monitored over several weeks to avoid iatrogenic hypoglycaemia.
Hypoglycaemia
Repeated episodes of hypoglycaemia in a previously well-controlled diabetic should raise the possibility of malabsorption, such as that seen in coeliac disease, a loss of counter-regulatory hormones as in Addison’s disease, or chronic kidney disease with reduced clearance of hypoglycaemic agents, including insulin. Recurrent hypoglycaemia is sometimes treated with insulin pump therapy.
Complications of diabetes
Macrovascular disease
Management of hypertension
Hypertension predisposes to cardiovascular disease and also contributes to the deterioration in diabetic nephropathy and retinopathy. In type 1 diabetes hypertension may result from underlying nephropathy; in type 2 diabetes it occurs as part of the metabolic syndrome with associated dyslipidaemia and central obesity (p. 613).
Nephropathy
Management
• Good glycaemic control for type 1 and 2 DM is required. In type 2, change to insulin if poorly controlled; if renal function is impaired, stop metformin and the renally excreted sulphonylureas, e.g. glibenclamide.
• Hypertension is controlled to a level of 125/75 mmHg. An ACE inhibitor/blocker is the drug of choice as it delays the progression of nephropathy. More than one antihypertensive may be required, e.g. a low-dose thiazide diuretic or calcium channel blocker.
Retinopathy
• Non-proliferative background retinopathy consisting of microaneurysms, hard exudates, and ‘dot and blot’ haemorrhages is not a threat to vision but may progress to pre-proliferative retinopathy with cotton wool spots (representing local infarction of retinal nerve fibre layer), venous beading and loops, and intra-retinal microvascular abnormalities.
• Maculopathy, with oedema or proliferative retinopathy, is a common cause of blindness and requires elective/urgent laser photocoagulation therapy.
Neuropathy
• Diffuse symmetrical polyneuropathy, with sensory symptoms predominantly in a ‘glove and stocking’ distribution, is seen, although the feet and legs are typically more affected than the upper limbs. This is a diagnosis made after exclusion of other common causes of peripheral neuropathy that may be amenable to treatment, such as hypothyroidism, or vitamin B12 or thiamin deficiency. Patients may remain asymptomatic and thus annual foot assessment is imperative to detect an early sensory deficit that may predispose to trauma not perceived by the individual. Many patients, however, experience sharp, burning, or paraesthesic pains, which are typically worse at night.
• Acute painful neuropathy with sudden onset of severe sensory symptoms and allodynia requires treatment with e.g. pregabalin 50 mg 3 times daily, duloxetine 60 mg daily and amitriptyline 25 mg daily. Mononeuritis and mononeuritis multiplex can affect any nerve in the body and damage usually recovers spontaneously.
Other complications
Erectile dysfunction
This is common in diabetes and may be attributed to autonomic neuropathy, although contributory factors, including vascular insufficiency, drugs and other endocrine causes, as well as psychological factors and alcohol, play a role. Treatment is with a phosphodiesterase 5 inhibitor, e.g. sildenafil 50 mg. Do not use with nitrate therapy, as severe hypotension can be fatal.
The diabetic foot
Management
• Non-infected ulcers should be dressed and weight-bearing should be avoided, e.g. by elevation or specially designed shoes.
• Non-healing ulcers with signs of active infection should be treated with broad-spectrum antibiotics. There is little evidence for any specific antimicrobial regimen. Penicillins, such as flucloxacillin and amoxicillin with metronidazole if anaerobic infection is suspected, are examples. IV administration of antibiotics should be offered in cases of cellulitis or systemic illness. Dead tissue should be removed by debridement — either surgical, chemical or other (larvae). If bone is seen at the base of an ulcer, an MRI is useful to look for osteomyelitis. A plain X-ray of the foot is less helpful.
Hyperlipidaemia
• Hypertriglyceridaemia. The majority of these cases reflect a polygenic disorder with a moderate increase in triglyceride levels. Familial hypertriglyceridaemia is inherited in an autosomal dominant manner and there may be a history of pancreatitis or retinal vein thrombosis.
• Hypercholesterolaemia
• Familial hypercholesterolaemia results in under-expression of the LDL cholesterol receptor in the liver, leading to high LDL levels. It is relatively common, occurring in 1 in 500 individuals. Homozygotes have a total absence of LDL receptors and die in their teens from coronary artery disease if not aggressively treated. Heterozygotes may remain well, or develop coronary artery disease in their forties. Clinical features include tendon xanthomas and xanthelasmas.
Treatment
• Goals of treatment
• Estimation of coronary heart disease risk Prediction charts help identify individuals likely to benefit from lipid reduction therapy but will tend to underestimate risk in diabetes and those with a strong family history of premature cardiovascular disease or diabetes.
• Primary prevention. Anyone with a 10-year risk of developing cardiovascular disease > 20%, as defined by a risk calculator (systolic BP total cholesterol : HDL ratio), or with strong predisposing factors such as diabetes should be offered therapy.
• Aim of treatment. The aim is to reduce serum total cholesterol to below 5.0 mmol/L (190 mg/dL) (< 4.0 mmol/L, 150 mg/dL for patients with diabetes and hypertension) or by 20–25%, whichever will achieve the lower level. LDL should be reduced by 30% (or to below 3.0 mmol/L or 100 mg/dL) and triglyceride levels should fall below 2.3 mmol/L (200 mg/dL). HDL levels should be > 1.0 mmol/L (> 38 mg/dL).
• Therapy (Table 16.4)
• HMG CoA reductase inhibitors (statins). Statins inhibit the rate-limiting step in cholesterol biosynthesis, reducing LDL levels by between 10 and 15%. Most statins undergo rapid first-pass metabolism in the liver. Efficacy is improved if they are taken with the evening meal or at bedtime. Atorvastatin is unusual in that it has a longer period of action and thus may be given in the morning if needed. It is possible that statins may hold benefits over and above reducing LDL cholesterol, including modulation of inflammatory, immune and coagulation responses. Response to treatment can be assessed 4 weeks after therapeutic changes. The dose response to dose increments is not linear and it is often better to combine agents to maximize effect.
• Ezetimibe inhibits intestinal cholesterol absorption and interferes with the enterohepatic circulation of cholesterol synthesized in the liver. It is useful as an adjunct to statin therapy in reducing LDL cholesterol levels. The effect on clinical outcomes is unclear.
• Bile acid sequestrants. These agents pass unabsorbed through the gastrointestinal tract, binding bile acids and reducing enterohepatic recirculation, resulting in increased conversion of cholesterol into bile salts within the liver. This reduction in hepatocyte cholesterol leads to an increase in HMG CoA reductase activity, which is effectively blocked by combination therapy with a statin.
• Fibric acid derivatives (fibrates). The fibrates stimulate peroxisome proliferator activator receptor-α (PPAR-α). They enhance clearance of triglycerides and reduce very low-density lipoprotein (VLDL) synthesis. Fibrate therapy is associated with moderate reduction of cardiovascular risk and these drugs are therefore mainly used where high triglyceride levels confer a risk of pancreatitis, or in combination therapy with a statin (increased risk of rhabdomyolysis). Fibrates tend to be well tolerated.
• Nicotinic acid. This appears to reduce lipoprotein synthesis and inhibit peripheral production of free fatty acids. It benefits all aspects of the lipid profile but its use is limited by side-effects, which include flushing (reduced in some individuals by taking aspirin prior to administration), gastrointestinal effects, gout, hepatotoxicity and glucose intolerance. Nicotinic acid combined with laropiprant, which is a selective antagonist of prostaglandin D2 receptor Type 1, stops the flushing.
• Omega fatty acids. The omega fatty acids offer an alternative to fibrates and nicotinic acid for targeting hypertriglyceridaemia by reducing hepatic secretion of triglyceride-rich lipoproteins (VLDL). More clinical trials are needed to evaluate their place in the management of hyperlipidaemia further.
American Diabetic Association. Diagnosis and classification of diabetes mellitus — position statement. Diabetes Care. 2010;33(Suppl 1)):562-569.
Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. www.library.nhs.uk/diabetes/, 2010. Available from
2009 The International Expert Committee Report on the Role of the A1C Assay in Diagnosis of Diabetes. Diabetes Care. 2009;32:1327-1334.
