Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 36) doc

35 Diabetes mellitus, insulin, oral antidiabetes agents, obesity Many doctors, after they have developed a disease, take up the speciality in it But that was not so with me I was studying for surgery when diabetes took me up The great book of Joslin said that by starving you might live four years with luck [He went to Italy and, whilst his health was declining there, he received a letter from a biochemist friend which said] there was something called 'insulin' appearing with a good name in Canada, what about going there and getting it I said 'No thank you; I've tried too many quackeries for diabetes; I'll wait and see' Then I got peripheral neuritis So when [the friend] cabled me and said, 'I've got insulin — it works — come back quick', I responded, arrived at King's College Hospital, London, and went to the laboratory as soon as it opened It was all experimental for [neither of us] knew a thing about it So we decided to have 20 units a nice round figure I had a nice breakfast I had bacon and eggs and toast made on the Bunsen I hadn't eaten bread for months and months by o'clock in the afternoon my urine was quite sugar free That hadn't happened for many months So we gave a cheer for Banting and Best.1 But at pm I had a terrible shaky feeling and a terrible sweat and hunger pain That was my first experience of hypoglycaemia We remembered that SYNOPSIS Diabetes mellitus affects 1-2% of many national populations Its successful management requires close collaboration between the patient and the doctor • Diabetes mellitus and insulin • Insulins in current use (including choice, formulations, adverse effects, hypoglycaemia, insulin resistance) Oral antidiabetes drugs Treatment of diabetes mellitus Diabetic ketoacidosis Surgery in diabetic patients Obesity and overweight Diabetes mellitus and insulin HISTORY Insulin (as pancreatic islet cell extract) was first administered to a 14-year-old insulin-deficient patient on 11 January 1922 in Toronto, Canada An adult sufferer from diabetes who developed the disease in 1920 and who, because of insulin, lived until 1968, has told how: F G Banting and C H Best of Toronto, Canada (see also Journal of Laboratory and Clinical Medicine 1922 7: 251) 679 35 DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY Banting and Best had described an overdose of insulin in dogs So I had some sugar and a biscuit and soon got quite well, thank you.2 Type I (formerly, insulin dependent diabetes mellitus, IDDM) which typically occurs in younger people who cannot secrete insulin Type (formerly, non-insulin dependent diabetes mellitus, NIDDM), which typically occurs in older, often obese people who retain capacity to secrete insulin but who are resistant to its action.These terms and abbreviations are used in this chapter as insulin emp (Enzyme Modified Porcine), prb (Proinsulin Recombinant in Bacteria) and pyr (Precursor insulin Yeast Recombinant) Although one of the incentives for introducing human insulin was avoidance of insulin antibody production, the allergies to older insulins were largely caused by impurities in the preparations, and are avoided equally well by using the highly purified, monocomponent porcine and bovine insulins Other preparations have been withdrawn There is no systematic difference in activity between human and animal insulin, but any change in preparation prescribed to a patient should be monitored with care (see below) Sources of insulin Insulin is synthesised and stored (bound to zinc) in granules in the (Hslet cells of the pancreas Daily secretion amounts to 30-40 units, which is about 25% of total pancreatic insulin content The principal factor that evokes insulin secretion is a high blood glucose concentration Insulin is a polypeptide with two peptide chains (A chain, 21 amino acids and B chain, 30) linked by two disulphide bridges The basic structure having metabolic activity is common to all mammalian species but there are minor species differences, which result in the development of antibodies in all patients treated with animal insulins, as well as to unavoidable impurities in the preparations, minimal though these now are • Bovine insulin differs from human insulin by three amino acids and is more antigenic to man than is • Porcine insulin differs from human by only one amino acid • Human insulin (1980) is made either by enzyme modification of porcine insulin, or by using recombinant DNA to synthesise the proinsulin, precursor molecule for insulin This is done by artificially introducing the DNA into either Escherichia coli or yeast The three forms of human insulin have the same amino acid sequence, but are separately designated Abbreviated from Lawrence R D 1961 King's College Hospital Gazette 40: 220 Transcript from a recorded after dinner talk to students' Historical Society 680 Insulin receptors Insulin binds to the a subunit of its receptor The (3 subunit is a tyrosine kinase which is activated by insulin binding and is autophosphorylated Tyrosine kinase also phosphorylates other substrates so that a signalling cascade is initiated and biological response ensues Insulin receptors are present on the surface of the target cells (mostly liver, muscle, fat) Receptors vary in number inversely with the insulin concentration to which they are exposed, i.e with high insulin concentration the number of receptors declines (down-regulation) and responsiveness to insulin also declines (insulin resistance); with low insulin concentration the number of receptors increases (up-regulation) and responsiveness to insulin increases Type diabetes patients have insulin resistance Hyperinsulinaemia predates the onset of diabetes and the resistance is thought to be secondary to down-regulation of insulin receptors as well as postreceptor, intracellular events Obesity is a major factor in the development of insulin resistance Patients may recover insulin responsiveness as a result of dieting so that the insulin secretion decreases, cellular receptors increase and insulin sensitivity is restored Actions of insulin The effects of stimulation of the insulin receptors include activation of glucokinase and glucose phosphatase Insulin also increases glucose transport DIABETES MELLITUSAND as well as its utilisation, especially by muscle and adipose tissue Its effects include: • Reduction in blood glucose due to increased glucose uptake in the peripheral tissues (which convert it into glycogen or fat), and reduction of hepatic output of glucose (diminished breakdown of glycogen and diminished gluconeogenesis) When the blood glucose concentration falls below the renal threshold (10 mmol/1 or 180 mg/100 ml) glycosuria ceases, as does the osmotic diuresis of water and electrolytes Polyuria with dehydration and excessive thirst are thus alleviated As the blood glucose falls, appetite is stimulated • Other metabolic effects In addition to enabling glucose to pass across cell membranes, the transit of amino acids and potassium into the cell is enhanced Insulin regulates carbohydrate utilisation and energy production It enhances protein synthesis It inhibits breakdown of fats (lipolysis) An insulin-deficient diabetic (Type 1) becomes dehydrated due to osmotic diuresis, and is ketotic because fats break down faster than the ketoacid metabolites can be metabolised Uses • Diabetes mellitus is the main indication • Insulin promotes the passage of potassium simultaneously with glucose into cells, and this effect is utilised to correct hyperkalaemia (see p 537) • Insulin-induced hypoglycaemia can also be used as a test of anterior pituitary function (growth hormone and corticotropin are released) Pharmacokinetics • Insulin, naturally secreted by the pancreas, enters the portal vein and passes straight to the liver, where half of it is taken up The rest enters and is distributed in the systemic circulation so that its concentration (in fasting subjects) is only about 15% of that entering the liver • When insulin is injected s.c it enters the systemic circulation and both liver and other peripheral organs receive the same concentration INSULIN 35 This difference may have clinical importance and this is why some continous infusion pumps (see below) deliver insulin intraperitoneally rather than subcutaneously In conventional use, insulin is injected (s.c., i.m or i.v.) as it is digested if swallowed It is absorbed into the blood3 and is inactivated in the liver and kidney; about 10% appears in the urine The t1/, is In addition to needles and syringes, alternative techniques for insulin administration have been developed, some availing themselves of the kinetics of insulin: insulin pens (supplied preloaded or with replaceable cartridges), external infusions and implantable pumps These latter are convenient for an accurately controlled continuously functioning biofeedback system, but pose difficulties for routine replacement in insulin deficiency Therefore sustained-release (depot) formulations are used to provide an approach reasonably near to natural function and compatible with the convenience of daily living An even closer approach is provided by the development of (at present inevitably expensive) miniaturised infusion pumps which can be used by reliable patients DIFFERENCES BETWEEN HUMAN AND ANIMAL INSULINS Human insulin is absorbed from subcutaneous tissue slightly more rapidly than animal insulins and it has a slightly shorter duration of action Human insulin is less immunogenic than bovine, but not porcine, insulin When changing from animal to human insulin, patients taking < 100 units of animal insulin are likely to require 10% less human insulin, and if taking > 100 units animal insulin, 25% less human insulin There has been concern that patients taking human insulin may experience more frequent and more severe hypoglycaemic attacks, especially when Peak plasma insulin (s.c.) concentration is attained in 60-90 Absorption is slower if there is peripheral vascular disease or smoking, and faster if the patient takes a hot bath or uses an ultraviolet light sunbed (which may induce a hypoglycaemic fit) or exercises The effects are due to changes in peripheral blood flow 681 _35_ DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY transferring from animal insulins Such occurrences are likely to be due to management problems rather than to pharmacological differences There is some evidence of a lessened awareness of hypoglycaemia with human insulin, i.e the counter-regulatory physiological responses to animal and human insulin may differ It is claimed that with human insulin patients experience less adrenergic symptoms (sweating, tremor, palpitations), which are such a useful warning, although the neurological (neuroglycopenic) symptoms (dizziness, headache, inability to concentrate) are unchanged It now seems likely that the reduced awareness is a paradoxical response to improved glycaemic control Thus patients with a normal level of glycosylated haemoglobin (HbAlc) show no reduction in glucose uptake in the brain during episodes of hypoglycaemia that trigger a symptomatic and neuroendocrine response in patients with elevated levels of HbAlc (see Boyle et al 1995, in Guide to Further Reading) PREPARATIONS OF INSULIN (Fig 35.1) There are three major factors: • Strength (concentration) • Source (human, porcine, bovine) • Formulation — short-acting solution of insulin for use s.c., i.m or i.v — intermediate and longer acting (sustained release) preparations in which the insulin has been physically modified by combination with protamine or zinc to give an amorphous or crystalline suspension; this is given s.c and slowly dissociates to release insulin in its soluble form (given i.m., which is not advised, the time course of release would be different) Dosage is measured in international units now standardised by chemical assay Diabetes mellitus may be managed from a choice of four types of insulin (animal or human) preparations, having: Short duration of action (and rapid onset): Soluble Insulin (neutral insulin) The most recent addition to this class of insulin, insulin lispro (Humalog), is a modified human insulin in which the reversing of two amino acids has 682 resulted in a very rapid onset of action (within 15 minutes of injection) Insulin aspart is similar Intermediate duration of action (and slower onset): Isophane Insulin, a suspension with protamine; Insulin Zinc Suspensions, amorphous or a mixture of amorphous and crystalline Longer duration of action: Insulin Zinc Suspension, crystalline, or Protamine Zinc Insulin (insulin in suspension with both zinc and protamine) A mixture of soluble and isophane insulins, officially called biphasic insulins The shortacting analogue insulins are now also available in mixtures Other mixtures are available, but infrequently used Insulin nomenclature This is potentially confusing The problems have arisen because insulin is a naturally occuring molecule (differing slightly among species), which has been formulated in many ways — partly catering for differing patient requirements, and partly reflecting a variety of manufacturing processes used by pharmaceutical companies Fortunately, there has been considerable rationalisation of the preparations but it may be helpful to explain some remaining ambiguities • Soluble and neutral insulin are the same; the British National Formulary favours the former term, but neutral is the INN (internationally approved) name, dating back to when there were acid and neutral pH formulations of soluble insulin Human, porcine and beef are available • Isophane insulin is the only approved name for suspensions of insulin with protamine Human, porcine and beef are available; the latter is rarely used • Biphasic insulins are, with one exception, proprietary mixtures of soluble (neutral) insulin and isophane insulin, which provide soluble (neutral) insulin at concentrations between 10% and 50% of the total insulin concentration Human, porcine and beef are available, but most preparations in this group are of human insulin These preparations remove the need for patients to mix soluble and isophane insulins, without DIABETES MELLITUSAND INSULIN Preparation Onset, peak activity and duration of action in hours (approx) Species Neutral insulin injection 35 10 12 14 16 18 20 22 24 26 28 30 32 34 Humalog (insulin lispro) Human actrapid (pyr) Human velosulin (emp) Humulin S (prb) Hypurin neutral Pork velosulin Biphasic insulin injection The numbers refer to Human mixtard 10, 20, 30, 40, or 50 (pyr) Humulin the proportion of soluble insulin in the mixture, between 10 and 50% Ml, 3, or {pyr) Pork mixtard 30 Rapitard MC Insulin zinc suspension (amorphous) Semitard MC Isophane insulin injection Human insulatard (pry) Humulin (prb) Hypurin isophane Pork insulatard Insulin zinc suspension (mixed) Human monotard (pyr) Humulin lente (prb) Hypurin lente Lentard MC Insulin zinc suspension (cystalline) Human ultratard (pry) Humulin zn (prb) Protamine zinc insulin injection Hypurin protamine zinc (prb) - produced from prc insulin synthesised by bacteria using recombinant DNA technology; (pyr) - produced from a precursor synthesised by yeast using recombinant DNA technology; (emp) - produced by enzymatic modification of porcine insulin Fig 35.1 Insulin chart Reproduced with permission of the Monthly Index of Medical Specialities.This chart is subject to change as companies develop their products 683 35 DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY losing the flexible administration of the right amount of soluble (neutral) insulin to cover the meal following the dose • Mixed insulin zinc suspension is, confusingly, the approved name for proprietary mixtures of crystalline and amorphous zinc suspension Mixed insulins are not, therefore, the same as biphasic insulins While the different proprietary formulations in this group have differing time courses of action (see Fig 35.1) depending on their (unstated) proportions of amorphous and crystalline suspension, it is not expected that doctors or patients would vary the formulation prescribed The important thing is for the doctor to get to know well a range that will serve most patients (For insulin regimens and injection techniques, see p 691.) NOTES FOR PRESCRIBING INSULIN There is no need to change a stabilised diabetic from animal to human insulin Unexplained requirement of above 100 units/d is usually due to noncompliance and less often to antibodies since the withdrawal of the older insulin preparations Allergy still occurs to additives (protamine), to the preservative, e.g phenol, cresol, or to insulin itself It may take the form of local reactions (inflammatory or fat atrophy) or of insulin resistance Antibodies to insulin, provided they are moderate in amount, may be actually advantageous They act as a carrier or store, binding insulin after injection and releasing it slowly as the free insulin in the plasma declines In this way they smooth and prolong insulin action But too high antibody concentrations cause insulin resistance An adverse effect of easy self-monitoring is that a minority of obsessional patients, told of the desirability of blood glucose concentrations being kept in the normal range to prevent diabetic complications, become obsessed with monitoring, and experience great anxiety when they find what are, in fact, normal fluctuations They then anxiously change their insulin doses daily and as a result induce frequent hypoglycaemia, e.g one patient had 33 episodes in 44 days, many with loss of consciousness (Beer S F et al 1989 British Medical Journal 298: 362) 684 Compatibility Soluble insulin may be mixed in the syringe with insulin zinc suspensions (amorphous, crystalline) and with isophane and mixed (biphasic) insulin, and used at once: but there are insulins in which protamine is used as a carrier, and spare protamine will bind some of the short-acting neutral insulin, thus blunting its effects Intravenous insulin Only Soluble (neutral, clear) Insulin Inj should be used The standard strength of insulin preparations is 100 units per ml in a large and growing number of countries Even very low doses can be accurately measured with modern special syringes Solutions of 40 units and 80 units remain available in many countries, and healthcare providers should be aware of this Insulins in current use CHOICE OF PREPARATION That insulin preparations should be both precise and of uniform strength all over the world is vital to the health and safety of millions of diabetics Advances in technology now allow biological standardisation in animal insulin to be replaced by physicochemical methods (high performance liquid chromatography: HPLC) Soluble insulin inj (neutral, regular insulin) is an aqueous solution of insulin It is simple to use, being given s.c 2-3 times a day, 30 before meals There is little risk of serious hypoglycaemic reaction if it is used sensibly If a meal must be delayed, then the insulin injection should be delayed The dose can easily be adjusted according to self-performed blood glucose measurements.4 For these reasons it is often used initially to balance diabetics needing insulin and always for the treatment of diabetic ketoacidosis The biggest disadvantages of soluble insulin for long-term use are the need for frequent injections, and the occurrence of high blood glucose before breakfast Soluble insulin is neutral, adjusted to pH 7.0 Acid formulations of soluble insulin are no longer available INSULINS IN Intravenous soluble (neutral) insulin is used in diabetic ketoacidosis It may be given intermittently (i.v or i.m.) but continous infusion is preferred If the insulin is infused by drip in physiological saline (40 units/1) as much as 60-80% can be lost due to binding to the fluid container and tubing It is necessary to take this into account in dosing Polygeline (Haemaccel) may be added to bind the insulin in competition with the apparatus and so carry it into the body Use of a slow-infusion pump with a concentrated solution (insulin 1.0 unit/ml) is recommended Insulin loss is minimised and control of dose is more accurate than when more dilute solutions are used (For i.v doses see diabetic ketoacidosis, below.) Insulin is suitable for adimistration by continuous i.v infusion because its short il/2 (5 min) means that the plasma concentration rapidly reaches steady state after initiating the infusion or altering its rate (5 x t1/,, see p 101) Long-acting (sustained-release) preparations must not be given i.v Insulin zinc suspensions and isophane insulin (see Fig 35.1) are sustained-release formulations in which rate of release is controlled by modifying particle size Neutral pH, soluble insulin can be mixed with them without altering the time course of effect of either and these formulations can be a great convenience Duration of action Patients live by a 24-hour cycle and plainly insulins having a duration of action exceeding 24 hours can cause problems, especially early morning hypoglycaemia DOSE AND USAGE The total daily output of endogenous insulin from pancreatic islet cells is 30-40 units (determined by the needs of completely pancreatectomised patients), and most insulin-deficient diabetics will need 30-50 unit/day (0.5-0.8 units/kg) of insulin (two-thirds in the morning and one-third in the evening) Initial treatment for a Type (IDDM) patient, who does not present with ketoacidosis, will usually be outside hospital with two injections of intermediateacting insulin, or a mixed insulin Other permutations, including soluble insulin before each meal, CURRENT USE _35_ and an intermediate-acting insulin at bedtime, can follow later The following is a guide to initial daily dose requirements: • 0.3 units/kg (16-20 units daily) • increasing to 0.5 units/kg The dose is adjusted according to the usual monitoring of blood5 glucose (or urine, if glucose meters are unavailable) Daily (total) dose increments should be units at 3-4-day intervals If it is decided to give the patient only one injection per day, then 10-14 units of an intermediate-acting isophane suspension may be given Dose increments (4 units) may be made on alternate days Soluble insulin (neutral) may be added, or mixed (biphasic) insulins may be used, according to the patient's response When stable, patients usually receive either a biphasic insulin or a mixture of soluble, short-acting human insulin, and a longer-acting suspension of insulin with protamine or zinc Excessive dose of insulin leads to overeating and obesity; it also leads to hypoglycaemia (especially nocturnal), that may be followed by rebound morning hyperglycaemia that is mistakenly treated by increased insulin, thus establishing a vicious cycle (Somogyi effect) Physical activity increases carbohydrate utilisation and insulin sensitivity, so that hypoglycaemia is likely if a well-stabilised patient changes suddenly from an inactive existence to a vigorous life If this is likely to happen the carbohydrate in the diet may be increased and/or the dose of insulin reduced by up to one-third and then readjusted according to need This is less marked in patients on oral agents See also Selection of therapy and Ketoacidosis (below) ADVERSE EFFECTS OF INSULIN Adverse effects of insulin are mainly those of overdose.6 Because the brain relies on glucose as its The normal (fasting) blood glucose range is 3.9-5.8 mmol/1 (70-105 mg/100 ml) Suicidal overdose (in diabetics) is well recorded Surgical excision of the skin and subcutaneous tissue at the injection site of an enormous dose of long-acting insulin has been used effectively 685 35^ DIABETES M ELLITU S, INSULIN, ORAL ANTI DIABETES AGENTS, O B E S I T Y source of energy, an adequate blood glucose concentration is just as essential as an adequate supply of oxygen, and hypoglycaemia may lead to coma, convulsions and even death (in 4% of diabetics under 50 years of age) It is usually easier to differentiate hypoglycaemia from severe diabetic ketosis than from other causes of coma, which are as likely in a diabetic as in anyone else It is unsound to advocate blind administration of i.v glucose to comatose diabetics on the basis that it will revive them if they are hypoglycaemic and no harm if they are hyperglycaemic A minority of comatose insulin-dependent diabetics have hyperkalaemia and added glucose can cause a brisk and potentially hazardous rise in serum potassium (mechanism uncertain), in contrast to nondiabetics in whom glucose causes a fall in serum potassium Hypoglycaemia may manifest itself as disturbed sleep (nightmares) and morning headache For details of treatment see below Other adverse reactions to insulin are lipodystrophy (atrophy or hypertrophy) at the injection sites (rare with purified pork and human insulin), after they have been used repeatedly These are unsightly, but otherwise harmless The site should not be used further, for absorption can be erratic, but the patient may be tempted to continue if local anaesthesia has developed, as it sometimes does Lipoatrophy is probably allergic and lipohypertrophy is due to a local metabolic action of insulin Local allergy also is manifested as itching or painful red lumps Generalised allergic reactions are very rare, but may occur to any insulin (including human) and to any constituent of the formulation Change of brand of insulin, especially to highly purified preparations (or to one with a different mode of manufacture) may rectify allergic problems But zinc occurs in all insulins (though very little in soluble insulin) and can be the allergen TREATMENT OF A HYPOGLYCAEMIC ATTACK Prevention depends very largely upon patient education, but it is an unavoidable aspect of intensive glycaemic control Patients should not miss meals, must know the early symptoms of an attack, and always carry glucose with them.7 Treatment is 686 to give sugar, either by mouth if the patient can still swallow or glucose (dextrose) i.v (20-50 ml of 50% solution, i.e 10-25 g; this concentration is irritant especially if extravasation occurs and the veins of diabetics are precious, so compress the vein immediately after completion of injection; administration of 50-125 ml of 20% glucose is less thrombotic, if available The response is usually dramatic The patient should be given a meal to avoid relapse But if the patient does not respond within 30 min, it may be because of cerebral oedema, which recovers slowly and may require treatment with i.v dexamethasone If the patient has been severely hypoglycaemic or if very large amounts of insulin or sulphonylurea have been taken, then 20% glucose should be given by i.v infusion Very severe attacks sometimes damage the central nervous system permanently (See also use of glucagon, below.) After recovery from a severe attack and elucidation of the cause, the patient's treatment regimen should be carefully reviewed with appropriate educational input Hypoglycaemia due to other causes, e.g alcohol, is treated similarly INSULIN RESISTANCE AND HORMONES THAT INCREASE BLOOD GLUCOSE Insulin resistance may be due to a decline in number and/or affinity of receptors (see above) or to defects in postreceptor mechanisms A diabetic patient requiring more than 200 units/day is rare and regarded as insulin resistant (occasional patients have needed as much as 5000 units/day) Insulin resistance has become much less frequent with the wide availability of purified, mono-component and human insulins If the requirement is acquired and genuine, it is due to antibodies binding insulin in a biologically inactive complex (though it can dissociate as with protein binding of drugs) De novo insulin resistance occurs in a small number of genetic syndromes, e.g in combination with the skin condition acanthosis nigricans In the early stages of insulin treatment, it can be very useful training to allow a patient to experience hypoglycaemia once by delaying a meal ORAL ANTI DIABETES Where animal insulins are still in use, change to a highly purified pork or human insulin may be successful in reducing resistance Responsiveness to insulin may sometimes be restored by immunosuppression, e.g an adrenocortical steroid (prednisolone 20-40 mg/d) over weeks (or a few months), to suppress antibody production Obviously, if this is successful, insulin dosage will have to be reduced in accordance with the unpredictable reduction in antibodies Patients need to be carefully monitored to avoid severe hypoglycaemia Ketoacidosis also reduces the effect of insulin Glucagon (il/2 4min) is a polypeptide hormone (29 amino acids) from the a-islet cells of the pancreas It is released in response to hypoglycaemia and is a physiological regulator of insulin effect, acting by causing the release of liver glycogen as glucose Glucagon has been used to treat insulininduced hypoglycaemia, but in about 45 from onset of coma the hepatic glycogen will anyway be exhausted and glucagon will be useless Its chief advantage is that, as it can be given s.c or i.m (1.0 mg), glucagon can be used in a severe hypoglycaemic attack by somebody, e.g a member of the patient's family, who is unable to give an i.v injection of glucose If a comatose patient does not recover sufficiently in 20 to allow oral therapy, i.v glucose is essential Glucagon is ineffective in substantial hepatic insufficiency Glucagon has a positive cardiac inotropic effect by stimulating adenylyl cyclase; it appears to have value in acute overdose of (3-adrenoceptor blockers (see Index) Adrenaline (epinephrine) raises the blood sugar by mobilising liver and muscle glycogen; it does not antagonise the peripheral actions of insulin Glycosuria and diabetic symptoms may occur in patients with phaeochromocytoma Adrenal steroids, either endogenous or exogenous, antagonise the actions of insulin, although this effect is only slight with the primarily mineralocorticoid group; the glucocorticoid hormones increase gluconeogenesis and reduce glucose uptake and utilisation by the tissues Patients with Cushing's syndrome thus develop diabetes very readily and DRUGS 35 may be resistant to insulin Patients with Addison's disease, hypothyroidism and hypopituitarism are abnormally sensitive to insulin action Oral contraceptives can impair carbohydrate tolerance Growth hormone antagonises the actions of insulin in the tissues Acromegalic patients may develop insulin-resistant diabetes Thyroid hormone increases the requirements for insulin Oral antidiabetes drugs Oral antidiabetes drugs are of two kinds: sulphonamide derivatives (sulphonylureas) and guanidine derivatives (biguanides) They are used by 30% of all diabetics Unlike insulin they are not essential for life Following the observation in 1918 that guanidine had hypoglycaemic effect, guanides were tried in diabetes in 1926, but were abandoned a few years later for fear of hepatic toxicity In 1930 it was noted that sulphonamides could cause hypoglycaemia, and in 1942 severe hypoglycaemia was found in patients with typhoid fever during a therapeutic trial of sulphonamide In the 1950s a similar observation was made during a chemotherapeutic trial in urinary infections This was followed up and effective drugs soon resulted The first sulphonylureas were introduced into clinical practice in 1954 MODE OF ACTION Sulphonylureas block the ATP-sensitive potassium channels on the p-islet cell plasma membrane This results in the release of stored insulin in response to glucose They not increase insulin formation Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the postreceptor complex enzyme reactions mediated by insulin The principal result is decreased hepatic 687 35 DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY glucose output and increased glucose uptake in muscle They are ineffective in totally insulindeficient patients and for successful therapy probably require about 30% of normal [3-cell function to be present Their main adverse effects are hypoglycaemia and weight gain Secondary failure (after months or years) occurs due to declining f}-cell function and to insulin resistance Biguanides These agents have been in use since 1957 Metformin is the only biguanide in current use, and is a major agent in the management of Type diabetes Its cellular mode of action is uncertain but the most important effect is reduction of hepatic glucose production Other effects include enhancement of peripheral insulin sensitivity increaseing glucose uptake in peripheral tissues; biguanides are ineffective in the absence of insulin Rare complications are hypoglycaemia and lactic acidosis Secondary failure is not a problem Metformin can be used in combination with either insulin or other oral hypoglycaemic agents Thiazolidinediones Pioglitazone and rosiglitazone reduce peripheral insulin resistance, leading to a reduction of blood glucose concentration These drugs stimulate the nuclear hormone receptor, peroxisome proliferator-activated receptor (PPARy), which causes differentation of adipocytes.8 They should be initiated only by a physician experienced in treating Type diabetes and should always be used in combination with metformin or with a sulphonylurea (if metformin is inappropriate) The drugs can cause 3-4 kg weight gain in the first year of use, with peripheral oedema in 3-4% of patients Other adverse effects of the class have included abnormal liver function, and relevant tests should be monitored during the first year The importance of PPARyin insulin sensitivity was confirmed with the finding, in Cambridge, of two families presenting with severe insulin resistance in whom rare mutations of the PPARy gene caused loss of PPARy activity (Barroso I, Gurnell M, Crowley VE, et al 1989 Dominant negative mutations in human PPARy associated with severe insulin resistance, diabetes mellitus and hypertension Nature 402: 880-882.) 688 INDIVIDUAL DRUGS Absorption from the alimentary tract is good for all the oral agents It is advisable to take drugs -30 before a meal These three groups of drugs are effective only in the presence of insulin If a patient fails to respond to one drug, response to another as single treatment is unlikely Proceeding to a combination of drugs from different classes may then be effective Sulphonylureas (see also Table 35.1) Several sulphonylureas are available Choice is determined by the duration of action as well as the patient's age and renal function, and unwanted effects The long-acting sulphonylureas, e.g glibenclamide, are associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly for whom the shorter-acting alternatives, such as gliclazide or tolbutamide, should be used As chlorpropamide is both longacting and has more unwanted effects than the other sulphonylureas (see below) it is no longer recommended In patients with impaired renal function, gliclazide, glipizide or tolbutamide are preferred since they are not excreted by the kidney Generally, it is prudent to start at the lowest recommended dose in order to minimise risk of hypoglycaemia TABLE 35.1 Principal oral antidiabetes drugs Drug Sulphonylureas glibeclamide gliclazide glipizide glimepiride Biguanide metformin Thiazolidinedione rosiglitazone pioglitazone Meglitinide repaglinide nateglinide a-glucosidase inhibitor acarbose Total Duration Dosing daily schedule of action dose (mg) (doses/day) (h) 2.5-20 40-320 2.5^tO 1-6 1-2 1-2 1-2 12-24 12-24 12-24 16-24 500-3000 2-3 8-12 2-8 15-30 1-2 12-24 16-24 0.5-16 60-180 3 3^t 2-3 50-300 3-4 Other sulphonylureas include tolbutamide,gliquidone, glibornuride, tolazamide TREATMENT Sulphonamides, as expected, potentiate sulphonylureas by direct action and by displacement from plasma proteins Gliclazide is a commonly used second generation sulphonylurea If more than 80 mg is prescribed, the drug should be taken twice daily before meals Glimepiride is designed to be used once daily and to provoke less hypoglycaemia than glibenclamide Repaglinide is a very short-acting oral hypoglycaemic agent whose action, like the sulphonylureas, is mediated through blockade of ATP-dependent potassium channels It affects only postprandial insulin profiles, and should in theory reduce risk of hypoglycaemia Biguanides (see also Table 35.1) Metformin (il/2 h) is taken with or after meals Its chief use is in the obese patient with Type diabetes either alone or in combination with a sulphonylurea It has a mild anorexic effect which helps to reduce weight in the obese The action of metformin is terminated by excretion by the kidney and it should not be used in the presence of renal impairment Minor adverse gut reactions are common, including nausea, diarrhoea, and a metallic taste in the mouth These symptoms are usually transient or subside after reduction of dose Heavy prolonged use can cause vitamin B12 deficiency due to malabsorption With a biguanide, ketonuria may occur in the presence of normal blood sugar This is not generally severe and responds to reduction of dose More serious, but rare, is lactic acidosis, which occurs in 0.03 cases per 1000 patient years When this condition does occur, it is usually against the background of a serious underlying medical state such as renal impairment, liver failure or cardiogenic or septic shock Lactic acidosis is treated with large (i.v.) doses of isotonic sodium bicarbonate Thiazolidinediones (see also Table 35.1) Pioglitazone, is indicated once daily in patients not controlled by metformin alone It is contraindicated by cardiac or hepatic failure Weight gain and oedema are the main adverse effects OF DIABETES MELLITUS 35 Rosiglitazone is similar and is administered once or twice daily PRECAUTIONS WITH ORAL AGENTS Hypoglycaemia is the most common adverse effect with sulphonylureas, but is less common than with insulin therapy It can be severe, and prolonged (for days), and may be fatal in 10% of cases, especially in the elderly and in patients with heart failure Erroneous alternate diagnoses such as stroke may be made Renal and hepatic disease A biguanide should not be used in patients with either condition as the risk of lactic acidosis is too great Sulphonylureas are potentiated in these diseases and a drug with a short tl/2 (i.e not glibenclamide) should be used in low dose Age adds to the hazard of oral agents Other adverse effects are rare but include skin rashes, gastrointestinal upset, minor derangement of haematological and hepatic indices OTHER ORAL AGENTS Acarbose is an a-glucosidase inhibitor which reduces digestion of complex carbohydrates and slows their absorption from the gut; in high doses it may cause actual malabsorption Acarbose reduces glycaemia after meals, and may improve overall glycaemic control The usual dose is 50-300 mg daily Adverse effects are mainly flatulence and diarrhoea, which lead to a high discontinuation rate The drug may be combined with a sulphonylurea Dietary fibre and diabetes The addition of gelforming (soluble) but unabsorbable fibre (guar gum, a hydrocolloidal polysaccharide of galactose and mannose from seeds of the 'cluster bean') to the diet of diabetics reduces carbohydrate absorption and flattens the postprandial blood glucose curve Reduced need for insulin and oral agents are reported, but adequate amounts (taken with lots of water) are unpleasant (flatulence) and patient compliance is therefore poor 689 35 D I A B E T E S M EL L I T U S, I N S U L I N , O R A L A N T I D I A BET ES A G E N T S, O BES I T Y Treatment of diabetes mellitus Doctor, nurse and patient are faced with a lifetime of collaboration Compliance is not a one-sided process, and the patients need all the consideration and support they can get They should learn about their disease and its management, including home monitoring of blood glucose, and about the need for appropriate diet, exercise and avoidance of smoking All Type patients need immediate insulin therapy Initial therapy in Type patients should be by dietary means alone, for 2-3 months but most patients will need oral antidiabetes drugs in addtion The aims of treatment are: • to alleviate symptomatic hyperglycaemia and improve quality of life, while avoiding hypoglycaemia • to avoid ketosis and infections • to keep • the fasting blood glucose < mmol/1 • the 1-hour postprandial concentration < mmol/1 • the glycosylated haemoglobin HbAlc as close to normal as possible • In addition to optimal glycaemic control other cardiovascular risk factors should be corrected: • optimal blood pressure control < 130/80 mmHg • cholesterol < 5.2 mmol/1 • triglycerides < 2.0 mmol/1 • by this regimen to avoid or delay long-term microvascular and macrovascular complications, and reduce mortality Each patient must be assessed individually; only an outline of the general principles involved can be given here Diet Patients should be allowed to follow their own preferences as far as is practicable They should receive dietary advice on a high complex carbohydrate diet (~65% of total calories) with low fat (< 30% of calories) with emphasis on reduction in saturated fat in favour of mono- and polyunsaturates Calories should be restricted and 690 patients encouraged to achieve an ideal body weight Diet should contain -40 g of fibre/day, with plenty of fresh fruit and vegetables The way in which carbohydrate is distributed through the day should correspond with the type of drug treatment, and especially the type of insulin in Type patients Type patients are initially underweight, whereas the reverse is true of Type While carbohydrate intake needs to be controlled in both types, overall energy intake is restricted initially only in the obese Type patients Other general factors which influence the diet, in both Types and 2, are the • High incidence of ischaemic heart disease in diabetics, requiring restriction of saturated fat intake • Need to reduce protein intake in patients with established nephropathy Weight Older overweight diabetics (70% of Type 2) have a relative deficiency of insulin but seldom develop ketosis In these patients, a hypocaloric (weight-reducing) diet is vital, as weight loss dramatically improves glycaemic control and indeed, glycosuria may cease when their weight is reduced It is also likely that effective dieting helps to prevent macrovascular disease through improved control of blood lipids and blood pressure Exercise is similarly, beneficial Biguanide treatment particularly helps weight reduction Weight loss is associated with an increase in numbers of insulin receptors and so an increase in responsiveness to insulin The use of anorectic agents is discussed later in the chapter (p 696) Young patients with Type diabetes are often underweight and need insulin to restore normal weight Calorie restriction is not initially required in these patients The blood of these young diabetics contains negligible insulin and they readily become ketotic SELECTION OFTHERAPY FOR DIABETES Patients are treated with: • Diet alone • Diet plus oral agent(s) T R E A T M E N T OF • Diet plus insulin • Diet plus oral agent (metformin) plus insulin • For ketoacidosis: soluble insulin, urgently Diabetic patients under 30 years: almost all need insulin; the exception is the rare single-gene disorder of Maturity Onset Diabetes of the Young (MODY) due usually to mutations in the glucokinase gene Diabetic patients over 30 years: approximately onethird need insulin, one-third oral agents and onethird diet only Type diabetes: human insulin is preferred for new patients (for regimen see below) Type diabetes: careful trial is the only sure way of deciding who can be maintained on oral therapy rather than on insulin About 30% of patients will be adequately managed without oral therapy When diet alone has failed to control Type diabetes, it is necessary to add an oral agent; the choice should fall first on • metformin for the obese patient: the usual regimen is metformin 500 mg once or twice daily after meals, increasing at 2-4-weekly intervals to a maximum of g daily • a sulphonylurea for the nonobese: an example regimen would be gliclazide 80 mg orally (or 40 mg in the small or aged) before the main meal of the day The dose is adjusted, according to response, at 2-4-weekly intervals by increments of 40-80 mg, to a maximum of 320 mg If control is incomplete, metformin may be added Insulin treatment in Type diabetes When oral therapy fails, insulin treatment should be used alone or in combination with metformin There is little advantage from adding insulin to a sulphonylurea The advent of thiazolidinediones offers an alternative to combining metformin with insulin, but more experience of these drugs is required before their combination with metformin can be routinely recommended It is important to stop the thiazolidinedione, if not effective, before progressing to insulin Definitive evidence that institution of insulin will reduce complications is lacking; however, there is an improvement in quality of life, with few patients requesting to stop insulin once they have D I A B E T E S M E L L I T US 35 started, and the improved glycaemic control can be assumed also to improve outcome Initial treatment with a single injection of intermediate-acting insulin (see Fig 35.1) at night, or twice daily, may control hyperglycaemia Fluctuations in blood glucose levels may be controlled with twice daily mixed insulin or by multiple injections Re-evaluation of the requirement for drugs can be made after the patient has been controlled and stable for 3-6 months, but complete withdrawal of oral agents is unusual Monitoring of patients taking oral agents should be as close as those on insulin The prognosis of poorly controlled type diabetes is serious Prevention of complications in Type diabetes: the United Kingdom Prospective Diabetes Study (UKPDS)9,10 This landmark study in Type diabetes confirmed that good glycaemic control and aggressive blood pressure reduction independently improve outcome For every 1% reduction in HbAlc there was a 21% reduction in diabetes related deaths, and 37% reduction in microvascular disease The study disproved concerns about long-term safety of sulphonylureas, but suggested that metformin might be the preferred first-line pharmacological therapy in obese patients Of highest importance was the finding that effective blood pressure control — regardless of type of antihypertensive drug — was more influential than glycaemic control in preventing macrovascular complications Reduction of blood pressure in 758 patients to a mean of 144/82 mmHg achieved 32% reduction in deaths related to diabetes and 37% reduction in microvascular end points, compared to 390 patients treated to a blood pressure of 154/87 mmHg Type treatment The range of insulin formulations available allows flexible adjustment of the UK Prospective Diabetes Study (UKPDS) Group 1998 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type diabetes (UKPDS 34) Lancet 352: 854-865 10 UK Prospective Diabetes Study (UKPDS) Group 1998 Tight blood pressure control and risk of macrovascular and microvascular complications in type diabetes British Medical Journal 317: 703-713 691 35 D I A B E T E S M E L L I T U S , I N S U L I N , O R A L A N T I D I A B ET ES A G E N T S , O B E S I T Y regimen to the patient's way of life No single regimen suits all patients but one of the following regimens can suit most patients (see Fig 35.1): • Three doses of soluble insulin (before the main meals) plus an intermediate-acting insulin at bedtime • A biphasic or intermediate-acting insulin (see Fig 35.1) twice a day before morning and evening meals • A single morning dose of a biphasic or intermediate-acting insulin before breakfast may suffice for some patients Injection technique has pharmacokinetic consequences according to whether the insulin is delivered into the subcutaneous tissue or (inadvertently) into muscle The introduction of a range of appropriate length needles and pen-shaped injectors has enabled patients to inject perpendicularly to the skin without risk of intramuscular injection The absorption of insulin is as much as 50% more rapid from shallow i.m injection Clearly factors such as heat or exercise which alter skin or muscle blood flow can markedly alter the rate of insulin absorption Patients should standardise their technique to ensure injection is s.c Inadvertent i.m injection of an overnight dose of an extended duration insulin can lead to inadequate early morning control of blood glucose Sites of injection should be rotated to minimise the now rare local complications (lipodystrophy) Absorption is faster from arm and abdomen than it is from the thigh and buttock Complications of diabetes A well-controlled diabetic is less liable to ketosis and infections It is now certain that good control of glycaemia mitigates the serious microvascular complications, retinopathy, nephropathy, neuropathy and cataract Too tight control of glycaemia can increase the frequency of attacks of hypoglycaemia SOME FACTORS AFFECTING CONTROL OF DIABETES Intercurrent illnesses cause fluctuations in the patient's metabolic needs If these are severe, e.g myocardial infarction, it is prudent to substitute 692 insulin for oral agents An appropriate starting dose is biphasic (mixtard) insulin 10-15 units twice daily Infections cause an increase in insulin need (about 20%), which may drop briskly on recovery In patients with poor glycaemic control, it is preferable to use an insulin infusion and sliding scale, as described below for diabetic ketosis Surgery, see later Menstruation and oral contraception: insulin needs may rise slightly Use of glucocorticoids: insulin needs are increased In pregnancy close control of diabetes is of the first importance to avoid fetal loss at all stages, and in the first trimester to reduce fetal malformations Insulins requirements increase steadily after the third month Ideally, women of childbearing age should be advised to conceive during a period of stable, euglycaemic control During labour soluble insulin should be given by continuous infusion at about l-2unit/h with i.v infusion of 5% glucose 1.0 litre in h) Substantially less, e.g 25%, insulin is likely to be needed immediately after delivery, when timing and dose of insulin injections should be carefully reconsidered lest hypoglycaemia occurs Insulin need remains lower during the first weeks of lactation Blood glucose estimations are necessary during pregnancy, for glycosuria is not then a reliable guide The renal threshold for glucose (also of lactose) falls, so that glycosuria and lactosuria may occur in the presence of a normal blood glucose Maternal hyperglycaemia leads to fetal hyperglycaemia with consequent fetal islet cell hyperplasia, high birthweight babies, and postnatal hypoglycaemia Premature labour: use of P2-adrenoceptor agonists and of dexamethasone (to prevent respiratory distress syndrome in the prematurely newborn) causes hyperglycaemia and increased insulin (and potassium) need Current practice for women on oral hypoglycaemic agents who are planning, or starting, a pregnancy is to change to insulin and continue on it DIABETIC throughout pregnancy There is no definitive evidence that oral drugs are associated with fetal malformations INTERACTIONS WITH NONDIABETES DRUGS The subject is ill-documented, but whenever a diabetic under treatment takes other drugs it is prudent to be on the watch for disturbance of control ft-adrenoceptor blocking drugs impair the sympathetic mediated (P2-receptor) release of glucose from the liver in response to hypoglycaemia and also reduce the adrenergic-mediated symptoms of hypoglycaemia (except sweating) Insulin hypoglycaemia is thus both more prolonged and less noticeable A diabetic needing (3-adrenoceptor blocker should be given a P^selective member, e.g bisoprolol Thiazide diuretics at a higher dose than generally now used in hypertension can precipitate diabetes, and it is wise to use low doses especially in established diabetes Hepatic enzyme inducers may enhance the metabolism of sulphonylureas that are metabolised in the liver (tolbutamide) Cimetidine, an inhibitor of drug metabolising enzymes, increases metformin plasma concentration and effect Monoamine oxidase inhibitors potentiate oral agents and perhaps also insulin They can also reduce appetite and so upset control Interaction may occur with alcohol (hypoglycaemia with any antidiabetes drug) Salicylates and fibrates can increase insulin sensitivity The action of sulphonylureas is intensified by heavy sulphonamide dosage and some sulphonamides increase free tolbutamide concentrations, probably by competing for plasma protein binding sites These examples suffice to show that the possibility of interactions of practical clinical importance is a real one DRUG-INDUCED DIABETES Diazoxide (see p 470) is chemically similar to thiazide diuretics, but stimulates the ATP dependent K+ KETOACIDOSIS 35 channel that is blocked by the sulphonylureas Therefore its chronic use as an antihypertensive agent is precluded by the development of diabetes Indeed its use in therapeutics should now be confined to the rare indication of treating hypoglycaemia due to islet-cell tumour (insulinoma) Adrenocortical steroids are also diabetogenic Diabetic ketoacidosis The condition is discussed in detail in medical texts and only the more pharmacological aspects will be dealt with here Nevertheless, it should be emphasised that the patients are always severely dehydrated and that fluid replacement is the first priority In severe ketoacidosis the patient urgently needs insulin to stop ketogenesis The objective is to supply, as continuously as possible, a moderate amount of insulin Soluble insulin, preferably from the same species the patient has been using (never a sustained-release form), should be given by continuous i.v infusion of a unit/ml solution of insulin in isotonic sodium chloride It is best to use a pump, which allows independent control of insulin and electrolyte administration more readily than an i.v drip If a pump is not available, the insulin should be added in a concentration of unit/ml to 50-100 ml of sodium chloride in a burette The infusion rate is determined by a sliding scale, as illustrated in Table 35.2 The rate is adjusted hourly using the same scale If an i.v drip is used instead of a pump the concentration should be lower (40 units/I) Stringent precautions against septicaemia are necessary in these patients Continuous infusion i.m (not s.c.) can also be equally effective, provided the patient is not in shock and provided there is not an important degree of peripheral vascular disease Intermittent doses i.v or i.m may be used when circumstances demand If the i.m route is used, a priming dose of 10 units should be given at the outset and then 6-10 units hourly 693 35 DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY TABLE 35.2 Sliding scale of insulin doses according to blood glucose concentrations in ketoacidosis (see text) Blood glucose (mmol/l) Infusion rate (ml/h = units/hour for 50 ml syringe containing 50 units of insulin) >22.0 19-21.9 16-18.9 12-15.9 8-11.9 10.0 (+ check pump and connections) 8.0 6.0 4.0 2.0 (+ change from saline to glucose infusion if blood glucose < Ommol/l) 1.0 0.5 (+ increase glucose infusion) 4-7.9 5.0 mmol/l none Bicarbonate (isotonic) should be used only if plasma pH is < 7.0 and peripheral circulation is good; insulin corrects acidosis Success in treatment of diabetic ketoacidosis and its complications (hypokalaemia, aspiration of stomach contents, infection, shock, thromboembolism, cerebral oedema) depends on close, constant, informed supervision Mild diabetic ketosis If the patient is fully conscious and there has been no nausea or vomiting for at least 12 h, intravenous therapy is unnecessary It is reasonable to give small doses of insulin s.c 4-6-hourly and fluids by mouth Hyperosmolar diabetic coma occurs chiefly in noninsulin-dependent diabetics who fail to compensate for their continuing, osmotic glucose diuresis It is characterised by severe dehydration, a very high blood sugar (> 33 mmol/l: 600 mg/100 ml) and lack of ketosis and acidosis Treatment is with isotonic (0.9%) saline, at half the rate recommended for ketoacidotic coma, and with less potassium than in severe ketoacidosis Insulin requirements are less than in ketoacidosis, where the acidosis causes resistance to the actions of insulin, and should generally be half those shown in Table 35.2 Patients are more liable to thrombosis and prophylactic heparin is used MISCELLANOUS Surgery in diabetes patients Principles of management: • • • • Surgery constitutes a major stress Insulin needs increase with surgery Avoid ketosis Avoid hypoglycaemia High blood glucose concentration matters little over short periods, except in the critically ill The programme for control should be agreed between anaesthetist and physician whenever diabetic patients must undergo general anaesthesia or modify their diets There are many different techniques that can give satisfactory results TYPE I DIABETES (IDDM) Elective major surgery • Admit to hospital the day before surgery • Arrange operation for morning • Evening before surgery: give patient's usual insulin • Day of operation: omit morning s.c dose; set up i.v infusion: glucose 5-10% + KC120 mmol/1, infuse at 100 ml/h; insulin 20 units may be added to litre of infusate or infused by pump at a basal rate of 2-3 units/h and adjusted according to a sliding scale • Modify regimen during and after surgery according to monitoring; insulin doses should be adjusted according to similar scale as in Table 35.2 • Stop i.v infusion one hour after first postsurgical s.c insulin • Insulin requirements may be high, 10-15 units/h, in cases of serious infection, corticosteroid use, obesity, liver disease Minor surgery For example, simple dental extractions (for multiple extractions or when there is infection the patient should be admitted to hospital) A suitable postoperative diet of appropriate calorie and carbo- 35 hydrate content must be arranged Plan the operation for between 12 noon and pm (17.00 h) Omit the usual dose of long-acting insulin on the morning of the operation and substitute soluble insulin, onequarter of the usual total daily dose, before a light breakfast 6h preceding the operation Arrange a light evening meal after the operation and soluble insulin, 10-20 units s.c., according to the blood glucose Return to the normal routine the next day Emergency surgery When a surgical emergency is complicated by diabetic ketosis, an attempt should be made to control the ketosis before the operation Management during the operation will be similar to that for major surgery except that more insulin will be needed In other cases small doses of soluble insulin are given 2-4-hourly (where pumps are not available), keeping the blood glucose between and mmol/1 TYPE DIABETES (NIDDM) Elective and emergency surgery, and minor surgery if NIDDM is poorly controlled: use the same regimen as for IDDM Minor surgery: If NIDDM is well controlled, omit the oral hypoglycaemic agent on the morning of surgery If the surgery is more than trivial, monitor blood glucose carefully, and use soluble insulin s.c or by infusion if blood glucose rises If vomiting is likely, use insulin Miscellaneous Most patients with both Type and Type succumb to either the macrovascular or microvascular complications — especially ischaemic heart disease and diabetic nephropathy, respectively Indeed diabetes is the major indication for dialysis and transplantation As discussed in other chapters, the treatment of hypertension and hyperlipidaemia is particularly important in patients with diabetes Patients with diabetic nephropathy should receive either an ACE inhibitor or angiotensin receptor 695 35 • D I A B E T E S M E L L I T U S , I N S U L I N , O R A L A N T I D I A B ET ES A G E N T S , O B E S I T Y Diabetes mellitus is important in global terms because of its chronicity, and high incidence and frequency of major complications It is of two kinds:Type I (previously, insulin dependent diabetes mellitus) and Type (previously, non-insulin dependent diabetes) • Type I diabetes is commoner among young, thin patients with diabetes Insulin may also be required when glycaemic control is not achieved by oral drugs in Type pateints • Insulin is given s.c to stable patients, usually as a biphasic mixture of soluble, short-acting human insulin, and a longer-acting suspension of insulin with protamine or zinc • In the treatment of diabetic ketoacidosis, in the perioperative patient, and at other times of changing insulin requirement, insulin is best given by i.v infusion of the soluble form • Diet plays a major role in the treatment of Type diabetes with obesity • There is now a clear difference in the choice of first- 12.0% to 17.9% in the USA Obesity predisposes to several chronic diseases including hypertension, hyperlipidaemia, diabetes mellitus, cardiovascular disease and osteoarthritis, and aspects of these are discussed in the relevant sections of this book The body mass index15 (BMI) correlates highly with the amount of body fat; individuals whose BMI lies between 25 and 30 kg/m are considered overweight and those in whom it exceeds 30 kg/m2 are defined as obese Management of the condition involves a variety of approaches from nutritional advice to lifestyle alteration, drugs and, in extreme instances, gastric surgery An evidence-based algorithm coordinates these.16 The present account concentrates on pharmacological interventions Drugs for obesity act either on the gastrointestinal tract to lower nutrient absorption or centrally to reduce food intake by decreasing appetite or increasing satiety (appetite suppressants) line drug, if a drug is required, in Type diabetes A sulphonylurea is used for the nonobese, and metformin (a biguanide) for the obese • Aggressive treatment of Type I, and probably Type 2, successfully reduces microvascular complications Close attention to associated risk factors, especially hyperlipidaemia and hypertension, is important in reducing risk of macrovascular disease antagonist, with the evidence for the latter being particularly strong that they are superior to other antihypertensive agents in reducing progression to renal failure.12 Addition of an ACE inhibitor to other drugs may also improve overall outcome in patients with diabetes.13 Most impressively, the Heart Protection Study showed that addition of simvastatin 40 mg daily to the treatment of 4000 patients with diabetes reduced all cardiovascular complications by 30%14 (see p 486) Obesity and appetite control Overweight and obesity are the commonest nutritional disorders in developed countries Between 1991 and 1998 the incidence of obesity rose from 696 12 Three trials compared an angiotensin blocker with other blood pressure lowering drugs, and found a 20% reduction in the proportion of patients in whom proteinuria worsened or serum creatinine doubled during follow-up: Parving H H, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P 2001 The effect of irbesartan on the development of diabetic nephropathy in patients with type diabetes New England Journal of Medicine 345: 870-878 Brenner B M, Cooper M E, de Zeeuw D et al 2001 Effects of losartan on renal and cardiovascular outcomes in patients with type diabetes and nephropathy New England Journal of Medicine 345: 861-869 Lewis E J, Hunsicker L G, Clarke W R et al 2001 Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type diabetes New England Journal of Medicine 345: 851-860 13 The HOPE study included patients with diabetes as one of its high risk group of cardiovascular patients, in whom ramipril reduced further coronary heart disease endpoints by about 30% Yusuf S, Sleight P, Pogue J et al 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients The Heart Outcomes Prevention Evaluation Study Investigators New England Journal of Medicine 342:145-153 14 Heart Protection Study Collaborative Group 2002 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals Lancet 360: 7-22 15 The weight in kilograms divided by the square of the height in metres 16 http//wwv^.nhlbi.nih.gov/guidelines/obesity/practgde.hrrn OBESITY AND APPETITE ORLISTAT Orlistat is a pentanoic acid ester that binds to and inhibits gastric and pancreatic lipases; the resulting inhibition of their activity prevents the absorption of about 30% of dietary fat compared with a normal 5% loss Weight loss is due to calorie loss but drugrelated adverse effects also contribute by diminishing food intake The drug is not absorbed from the alimentary tract Clinical trials show that patients who adhere to a low-calorie diet and take orlistat lost on average 9-10 kg after one year (compared to 6kg in those who took placebo); in the following year those who remained on orlistat regained 1.5-3.0 kg (4-6 kg with placebo) Orlistat has found a place in the management of obesity in the UK but, not surprisingly, this is subject to stringent guidance from the National Institute for Clinical Excellence, namely that it be initiated only in individuals: • aged 18-75 years • with BMI28 kg/m or more who also have cardiovascular risk factors or 30 kg/m2 or more without such comorbidity and • who have lost at least 2.5 kg body weight by dieting and increasing physical activity in the previous month The dose is 120mg, taken immediately before, during or h after each main meal, up to thrice daily If a meal is missed, or contains no fat, the dose of orlistat should be omitted Treatment should be accompanied by counselling advice and proceed beyond months only in those who have lost > 5% of their initial weight, beyond months in those who have lost > 10%, should not normally exceed year, and never more than years Adverse effects include flatulence and liquid, oily stools, leading to faecal urgency, abdominal and rectal pain Symptoms may be reduced by adhering to a reduced-fat diet Low plasma concentrations of the fat-soluble vitamins A, D and E have been found Orlistat is contraindicated where there is chronic intestinal malabsorption or cholestasis SIBUTRAMINE Sibutramine was originally developed as an anti- CONTROL 35 depressant and it inhibits the reuptake of noradrenaline and serotonin at nerve endings, increasing the concentration of these neurotransmitters at postsynaptic receptors in the brain that affect food intake It is also thought to stimulate energy expenditure The drug is rapidly absorbed from the gastrointestinal tract and extensively metabolised in the liver by cytochrome P450 3A4 These metabolites have a tl/2 of 14-16 h and are responsible for its effects When taken with dietary advice, sibutramine can be expected to cause a loss of 5-7% of initial body weight but this tends to be regained once the drug is stopped Sibutramine should be prescribed only for individuals with BMI 27 kg/m2 or more who have other cardiovascular risk factors or 30 kg/m2 or more in their absence It should be discontinued if weight loss after months is < 5% of initial weight, if weight stabilises at 10% of users Less commonly, nausea, tachycardia, palpitations, raised blood pressure, anxiety, sweating and altered taste may occur Blood pressure should be monitored closely throughout its use (twice weekly in the first months) Contraindications include severe hypertension, peripheral occlusive arterial or coronary heart disease, cardiac arrhythmia, prostatic hypertrophy and those with severe hepatic or renal impairment It should not be used to treat obesity of endocrine origin or those with a history of major eating disorder or psychiatric disease Concomitant use with tricyclic antidepressants should be avoided (CNS toxicity) The noradrenergic drugs fenfluramine, dexfenfluramine and phenteramine were formerly prescribed as appetite suppressants but were withdrawn when their use was associated with cardiac valve disease and pulmonary hypertension Considerable interest continues to surround the adipocyte-derived hormone leptin (Greek, leptos, thin) which acts on the hypothalamus to control 697 35 D I A B E T E S M E L L I T U S, I N S U L I N, O R A L A N T I D I A B E T E S A G E N T S, O B E S I T Y appetite and energy expenditure by informing neuroendocrine pathways of the state of energy stores in adipose tissue Plasma leptin correlates with indices of obesity in humans, with most obese patients being resistant to their elevated levels of leptin, rather than deficient in leptin production The use of therapeutic doses of leptin is under evaluation; physiological doses are effective in rare patients with inherited leptin deficiency Further understanding of the leptin pathway may open avenues for new agents to control appetite and obesity GUIDETO FURTHER READING Atkinson M A, Eisenbarth G S 2001 Type diabetes: new perspectives on disease pathogenesis and treatment Lancet 358: 221-229 Boyle P J et al 1995 Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus New England Journal of Medicine 333:1726-1731 Clark C M Jr, Lee D A1995 Prevention and treatment of the complications of diabetes mellitus New England Journal of Medicine 332:1210-1217 Dornhorst A 2001 Insulinotropic meglitinide analogues Lancet 358:1709-1716 Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of 698 long-term complications in insulin-dependent diabetes mellitus New England Journal of Medicine 329: 977-986 Fajans S S, Bell G I, Polonski K S 2001 Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes in the young New England Journal of Medicine 345: 971-980 Garner P 1995 Type I diabetes mellitus and pregnancy Lancet 346:157-161 Owens D R, Zinman B, Bolli G B 2001 Insulins today and beyond Lancet 358: 739-746 Report 1998 Clinical management of overweight and obese patients with particular reference to the use of drugs Royal College of Physicians of London: London Stevens A B et al 1989 Motor vehicle driving amongst diabetics taking insulin and non-diabetics British Medical Journal 299: 591 Stumvoll M et al 1995 Metabolic effects of metformin in non-insulin-dependent diabetes mellitus New England Journal of Medicine 333: 550-554 Willett W C, Dietz W H, Colditz G A1999 Guidelines for healthy weight New England Journal of Medicine 341: 427-434 Williams G 1994 Management of non-insulindependent diabetes mellitus Lancet 343: 95-100 Wright J R 2002 From ugly fish to conqueror of death: J J R Macleod's fish insulin research, 1922-24 Lancet 359:1238-1242 Yanovski S Z, Yanovski J A 2002 Obesity New England Journal of Medicine 346: 591-602 ... and crystalline suspension, it is not expected that doctors or patients would vary the formulation prescribed The important thing is for the doctor to get to know well a range that will serve... glucose uptake in the brain during episodes of hypoglycaemia that trigger a symptomatic and neuroendocrine response in patients with elevated levels of HbAlc (see Boyle et al 1995, in Guide to Further... and other peripheral organs receive the same concentration INSULIN 35 This difference may have clinical importance and this is why some continous infusion pumps (see below) deliver insulin intraperitoneally