CLINICAL PHARMACOLOGY 2003 (PART 36)

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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. ...

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35 Diabetes mellitus, insulin, oral antidiabetes agents, obesity SYNOPSIS Many doctors, after they have developed a disease, take up the speciality in it... But that was not so Diabetes mellitus affects 1-2% of many with me. I was studying for surgery when diabetes national populations. Its successful management took me up. The great book of Joslin said that by requires close collaboration between the starving you might live four years with luck. [He patient and the doctor. went to Italy and, whilst his health was declining • Diabetes mellitus and insulin there, he received a letter from a biochemist friend • Insulins in current use (including choice, which said] there was something called 'insulin' formulations, adverse effects, hypoglycaemia, appearing with a good name in Canada, what insulin resistance) about going there and getting it. I said 'No thank Oral antidiabetes drugs you; I've tried too many quackeries for diabetes; Treatment of diabetes mellitus I'll wait and see'. Then I got peripheral neuritis ... Diabetic ketoacidosis So when [the friend] cabled me and said, 'I've got Surgery in diabetic patients insulin — it works — come back quick', I Obesity and overweight 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 Diabetes mellitus and Bunsen. I hadn't eaten bread for months and insulin months ... by 3 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 HISTORY Best.1 But at 4 pm I had a terrible shaky feeling and a Insulin (as pancreatic islet cell extract) was first ad- terrible sweat and hunger pain. That was my first ministered to a 14-year-old insulin-deficient patient experience of hypoglycaemia. We remembered that 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 1 F G Banting and C H Best of Toronto, Canada (see also 1968, has told how: Journal of Laboratory and Clinical Medicine 1922 7: 251). 679
DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY 35 Banting and Best had described an overdose of as insulin emp (Enzyme Modified Porcine), prb insulin in dogs. So I had some sugar and a biscuit (Proinsulin Recombinant in Bacteria) and pyr and soon got quite well, thank you.2 (Precursor insulin Yeast Recombinant). Although one of the incentives for introducing human insulin was avoidance of insulin antibody production, the Type I (formerly, insulin dependent diabetes mellitus, allergies to older insulins were largely caused by IDDM) which typically occurs in younger people who impurities in the preparations, and are avoided cannot secrete insulin equally well by using the highly purified, mono- Type 2 (formerly, non-insulin dependent diabetes mellitus, component porcine and bovine insulins. Other NIDDM), which typically occurs in older, often obese preparations have been withdrawn. There is no people who retain capacity to secrete insulin but who are resistant to its action.These terms and abbreviations are systematic difference in activity between human used in this chapter. 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 Insulin receptors granules in the (Hslet cells of the pancreas. Daily Insulin binds to the a subunit of its receptor. The (3 secretion amounts to 30-40 units, which is about subunit is a tyrosine kinase which is activated by 25% of total pancreatic insulin content. The principal insulin binding and is autophosphorylated. Tyrosine factor that evokes insulin secretion is a high blood kinase also phosphorylates other substrates so that glucose concentration. a signalling cascade is initiated and biological Insulin is a polypeptide with two peptide chains response ensues. Insulin receptors are present on (A chain, 21 amino acids and B chain, 30) linked by the surface of the target cells (mostly liver, muscle, two disulphide bridges. The basic structure having fat). Receptors vary in number inversely with the metabolic activity is common to all mammalian insulin concentration to which they are exposed, i.e. species but there are minor species differences, with high insulin concentration the number of which result in the development of antibodies in all receptors declines (down-regulation) and responsive- patients treated with animal insulins, as well as to ness to insulin also declines (insulin resistance); unavoidable impurities in the preparations, minimal with low insulin concentration the number of though these now are. receptors increases (up-regulation) and responsive- • Bovine insulin differs from human insulin by ness to insulin increases. Type 2 diabetes patients three amino acids and is more antigenic to man have insulin resistance. than is Hyperinsulinaemia predates the onset of diabetes • Porcine insulin differs from human by only one and the resistance is thought to be secondary to amino acid down-regulation of insulin receptors as well as • Human insulin (1980) is made either by enzyme postreceptor, intracellular events. Obesity is a major modification of porcine insulin, or by using factor in the development of insulin resistance. recombinant DNA to synthesise the proinsulin, Patients may recover insulin responsiveness as precursor molecule for insulin. This is done by a result of dieting so that the insulin secretion artificially introducing the DNA into either decreases, cellular receptors increase and insulin Escherichia coli or yeast. sensitivity is restored. The three forms of human insulin have the same amino acid sequence, but are separately designated Actions of insulin 2 Abbreviated from Lawrence R D 1961 King's College The effects of stimulation of the insulin receptors Hospital Gazette 40: 220. Transcript from a recorded after include activation of glucokinase and glucose phos- dinner talk to students' Historical Society. phatase. Insulin also increases glucose transport 680
DIABETES MELLITUSAND INSULIN 35 as well as its utilisation, especially by muscle and This difference may have clinical importance and adipose tissue. Its effects include: this is why some continous infusion pumps (see below) deliver insulin intraperitoneally rather than • Reduction in blood glucose due to increased subcutaneously. glucose uptake in the peripheral tissues (which In conventional use, insulin is injected (s.c., i.m. convert it into glycogen or fat), and reduction of or i.v.) as it is digested if swallowed. It is absorbed hepatic output of glucose (diminished into the blood3 and is inactivated in the liver and breakdown of glycogen and diminished kidney; about 10% appears in the urine. The t1/, is gluconeogenesis). When the blood glucose 5 min. concentration falls below the renal threshold (10 In addition to needles and syringes, alternative mmol/1 or 180 mg/100 ml) glycosuria ceases, as techniques for insulin administration have been does the osmotic diuresis of water and developed, some availing themselves of the kinetics electrolytes. Polyuria with dehydration and of insulin: insulin pens (supplied preloaded or excessive thirst are thus alleviated. As the blood with replaceable cartridges), external infusions and glucose falls, appetite is stimulated. implantable pumps. These latter are convenient for • Other metabolic effects. In addition to enabling an accurately controlled continuously functioning glucose to pass across cell membranes, the biofeedback system, but pose difficulties for rou- transit of amino acids and potassium into the cell tine replacement in insulin deficiency. Therefore is enhanced. Insulin regulates carbohydrate sustained-release (depot) formulations are used to utilisation and energy production. It enhances provide an approach reasonably near to natural protein synthesis. It inhibits breakdown of fats function and compatible with the convenience of (lipolysis). An insulin-deficient diabetic (Type 1) daily living. An even closer approach is provided by becomes dehydrated due to osmotic diuresis, the development of (at present inevitably expensive) and is ketotic because fats break down faster miniaturised infusion pumps which can be used by than the ketoacid metabolites can be reliable patients. metabolised. Uses DIFFERENCES BETWEEN HUMAN • Diabetes mellitus is the main indication. AND ANIMAL INSULINS • Insulin promotes the passage of potassium Human insulin is absorbed from subcutaneous simultaneously with glucose into cells, and this tissue slightly more rapidly than animal insulins effect is utilised to correct hyperkalaemia (see and it has a slightly shorter duration of action. p. 537). Human insulin is less immunogenic than bovine, • Insulin-induced hypoglycaemia can also be used but not porcine, insulin. When changing from as a test of anterior pituitary function (growth animal to human insulin, patients taking < 100 units hormone and corticotropin are released). of animal insulin are likely to require 10% less human insulin, and if taking > 100 units animal insulin, 25% less human insulin. Pharmacokinetics There has been concern that patients taking • Insulin, naturally secreted by the pancreas, human insulin may experience more frequent and enters the portal vein and passes straight to the more severe hypoglycaemic attacks, especially when liver, where half of it is taken up. The rest enters and is distributed in the systemic circulation so 3 that its concentration (in fasting subjects) is only Peak plasma insulin (s.c.) concentration is attained in about 15% of that entering the liver. 60-90 min. Absorption is slower if there is peripheral vascular disease or smoking, and faster if the patient takes a • When insulin is injected s.c. it enters the systemic hot bath or uses an ultraviolet light sunbed (which may circulation and both liver and other peripheral induce a hypoglycaemic fit) or exercises. The effects are due organs receive the same concentration. to changes in peripheral blood flow. 681
_35_ DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY transferring from animal insulins. Such occurrences resulted in a very rapid onset of action (within are likely to be due to management problems rather 15 minutes of injection). Insulin aspart is similar. than to pharmacological differences. 2. Intermediate duration of action (and slower There is some evidence of a lessened aware- onset): Isophane Insulin, a suspension with ness of hypoglycaemia with human insulin, i.e. protamine; Insulin Zinc Suspensions, the counter-regulatory physiological responses to amorphous or a mixture of amorphous and animal and human insulin may differ. It is claimed crystalline that with human insulin patients experience less 3. Longer duration of action: Insulin Zinc adrenergic symptoms (sweating, tremor, palpita- Suspension, crystalline, or Protamine Zinc tions), which are such a useful warning, although Insulin (insulin in suspension with both zinc the neurological (neuroglycopenic) symptoms and protamine). (dizziness, headache, inability to concentrate) are 4. A mixture of soluble and isophane insulins, unchanged. It now seems likely that the reduced officially called biphasic insulins. The short- awareness is a paradoxical response to improved acting analogue insulins are now also available glycaemic control. Thus patients with a normal in mixtures. Other mixtures are available, but level of glycosylated haemoglobin (HbAlc) show infrequently used. no reduction in glucose uptake in the brain during episodes of hypoglycaemia that trigger a sympto- matic and neuroendocrine response in patients with Insulin nomenclature elevated levels of HbAlc (see Boyle et al 1995, in This is potentially confusing. The problems have Guide to Further Reading). arisen because insulin is a naturally occuring mol- ecule (differing slightly among species), which has PREPARATIONS OF INSULIN (Fig. 35.1) been formulated in many ways — partly catering for differing patient requirements, and partly reflect- There are three major factors: ing a variety of manufacturing processes used by • Strength (concentration) pharmaceutical companies. Fortunately, there has • Source (human, porcine, bovine) been considerable rationalisation of the preparations • Formulation but it may be helpful to explain some remaining — short-acting solution of insulin for use s.c., ambiguities. i.m. or i.v. • Soluble and neutral insulin are the same; the — intermediate and longer acting (sustained British National Formulary favours the former release) preparations in which the insulin has term, but neutral is the INN (internationally been physically modified by combination with approved) name, dating back to when there were protamine or zinc to give an amorphous or acid and neutral pH formulations of soluble crystalline suspension; this is given s.c. and insulin. Human, porcine and beef are available. slowly dissociates to release insulin in its • Isophane insulin is the only approved name for soluble form (given i.m., which is not advised, suspensions of insulin with protamine. Human, the time course of release would be different). porcine and beef are available; the latter is rarely Dosage is measured in international units now used. standardised by chemical assay. • Biphasic insulins are, with one exception, Diabetes mellitus may be managed from a choice proprietary mixtures of soluble (neutral) insulin of four types of insulin (animal or human) prep- and isophane insulin, which provide soluble arations, having: (neutral) insulin at concentrations between 10% 1. Short duration of action (and rapid onset): and 50% of the total insulin concentration. Soluble Insulin (neutral insulin). The most Human, porcine and beef are available, but most recent addition to this class of insulin, insulin preparations in this group are of human insulin. lispro (Humalog), is a modified human insulin These preparations remove the need for patients in which the reversing of two amino acids has to mix soluble and isophane insulins, without 682
DIABETES MELLITUSAND INSULIN 35 Preparation Onset, peak activity and duration of action in hours (approx) Species 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Neutral insulin Humalog injection (insulin lispro) Human actrapid (pyr) Human velosulin (emp) Humulin S (prb) Hypurin neutral Pork velosulin Biphasic insulin Human mixtard injection 10, 20, 30, 40, or 50 (pyr) The numbers refer to Humulin the proportion of Ml, 2. 3, 4 or 5 {pyr) soluble insulin in the mixture, between Pork mixtard 30 10 and 50% Rapitard MC Insulin zinc suspension . Semitard MC (amorphous) Isophane insulin Human insulatard injection (pry) Humulin 1 (prb) Hypurin isophane Pork insulatard Insulin zinc Human monotard suspension (mixed) (pyr) Humulin lente (prb) Hypurin lente Lentard MC Insulin zinc suspension Human ultratard (cystalline) (pry) Humulin zn (prb) Protamine zinc Hypurin protamine insulin injection 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
DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY 35 losing the flexible administration of the right Compatibility. Soluble insulin may be mixed in the amount of soluble (neutral) insulin to cover the syringe with insulin zinc suspensions (amorphous, meal following the dose. crystalline) and with isophane and mixed (biphasic) • Mixed insulin zinc suspension is, confusingly, the insulin, and used at once: but there are insulins in approved name for proprietary mixtures of which protamine is used as a carrier, and spare crystalline and amorphous zinc suspension. protamine will bind some of the short-acting neutral Mixed insulins are not, therefore, the same as insulin, thus blunting its effects. biphasic insulins. While the different proprietary formulations in this group do have differing time Intravenous insulin. Only Soluble (neutral, clear) courses of action (see Fig. 35.1) depending on Insulin Inj. should be used. their (unstated) proportions of amorphous and The standard strength of insulin preparations is crystalline suspension, it is not expected that 100 units per ml in a large and growing number of doctors or patients would vary the formulation countries. Even very low doses can be accurately prescribed. measured with modern special syringes. Solutions of 40 units and 80 units remain available in many The important thing is for the doctor to get to countries, and healthcare providers should be know well a range that will serve most patients. aware of this. (For insulin regimens and injection techniques, see p. 691.) NOTES FOR PRESCRIBING INSULIN Insulins in current use There is no need to change a stabilised diabetic from animal to human insulin. Unexplained require- CHOICE OF PREPARATION ment of above 100 units/d is usually due to non- That insulin preparations should be both precise compliance and less often to antibodies since the and of uniform strength all over the world is vital withdrawal of the older insulin preparations. to the health and safety of millions of diabetics. Allergy still occurs to additives (protamine), to the Advances in technology now allow biological standardisation in animal insulin to be replaced by preservative, e.g. phenol, cresol, or to insulin itself. It may take the form of local reactions (inflam- physicochemical methods (high performance liquid matory or fat atrophy) or of insulin resistance. chromatography: HPLC). Soluble insulin inj. (neutral, regular insulin) is an Antibodies to insulin, provided they are moderate in amount, may be actually advantageous. They act aqueous solution of insulin. It is simple to use, as a carrier or store, binding insulin after injection being given s.c. 2-3 times a day, 30 min before meals. and releasing it slowly as the free insulin in the There is little risk of serious hypoglycaemic reaction if it is used sensibly. If a meal must be delayed, then plasma declines. In this way they smooth and pro- long insulin action. But too high antibody concen- the insulin injection should be delayed. The dose can easily be adjusted according to self-performed trations cause insulin resistance. blood glucose measurements.4 For these reasons it 4 is often used initially to balance diabetics needing An adverse effect of easy self-monitoring is that a minority of obsessional patients, told of the desirability of blood insulin and always for the treatment of diabetic glucose concentrations being kept in the normal range to ketoacidosis. The biggest disadvantages of soluble prevent diabetic complications, become obsessed with insulin for long-term use are the need for frequent monitoring, and experience great anxiety when they find injections, and the occurrence of high blood glucose what are, in fact, normal fluctuations. They then anxiously before breakfast. change their insulin doses daily and as a result induce frequent hypoglycaemia, e.g. one patient had 33 episodes in Soluble insulin is neutral, adjusted to pH 7.0. 44 days, many with loss of consciousness (Beer S F et al 1989 Acid formulations of soluble insulin are no longer British Medical Journal 298: 362). available. 684
INSULINS IN CURRENT USE _35_ Intravenous soluble (neutral) insulin is used in and an intermediate-acting insulin at bedtime, can diabetic ketoacidosis. It may be given intermittently follow later. The following is a guide to initial daily (i.v. or i.m.) but continous infusion is preferred. If dose requirements: the insulin is infused by drip in physiological saline • 0.3 units/kg (16-20 units daily) (40 units/1) as much as 60-80% can be lost due • increasing to 0.5 units/kg. to binding to the fluid container and tubing. It is necessary to take this into account in dosing. The dose is adjusted according to the usual moni- Polygeline (Haemaccel) may be added to bind the toring of blood5 glucose (or urine, if glucose meters insulin in competition with the apparatus and so are unavailable). Daily (total) dose increments should carry it into the body. be 4 units at 3-4-day intervals. Use of a slow-infusion pump with a concen- If it is decided to give the patient only one injection trated solution (insulin 1.0 unit/ml) is recommended. per day, then 10-14 units of an intermediate-acting Insulin loss is minimised and control of dose is isophane suspension may be given. Dose increments more accurate than when more dilute solutions are (4 units) may be made on alternate days. Soluble used. (For i.v. doses see diabetic ketoacidosis, below.) insulin (neutral) may be added, or mixed (biphasic) Insulin is suitable for adimistration by continuous insulins may be used, according to the patient's i.v. infusion because its short il/2 (5 min) means that response. the plasma concentration rapidly reaches steady When stable, patients usually receive either a state after initiating the infusion or altering its rate biphasic insulin or a mixture of soluble, short-acting (5 x t1/,, see p. 101). Long-acting (sustained-release) human insulin, and a longer-acting suspension of preparations must not be given i.v. insulin with protamine or zinc. Excessive dose of insulin leads to overeating and Insulin zinc suspensions and isophane insulin obesity; it also leads to hypoglycaemia (especially (see Fig. 35.1) are sustained-release formulations in nocturnal), that may be followed by rebound which rate of release is controlled by modifying morning hyperglycaemia that is mistakenly treated particle size. Neutral pH, soluble insulin can be by increased insulin, thus establishing a vicious mixed with them without altering the time course cycle (Somogyi effect). of effect of either and these formulations can be a Physical activity increases carbohydrate utilis- great convenience. ation and insulin sensitivity, so that hypoglycaemia is likely if a well-stabilised patient changes suddenly Duration of action. Patients live by a 24-hour cycle from an inactive existence to a vigorous life. If this and plainly insulins having a duration of action is likely to happen the carbohydrate in the diet may exceeding 24 hours can cause problems, especially be increased and/or the dose of insulin reduced by early morning hypoglycaemia. 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 DOSE AND USAGE (below). The total daily output of endogenous insulin from pancreatic islet cells is 30-40 units (determined ADVERSE EFFECTS OF INSULIN by the needs of completely pancreatectomised patients), and most insulin-deficient diabetics will Adverse effects of insulin are mainly those of need 30-50 unit/day (0.5-0.8 units/kg) of insulin overdose.6 Because the brain relies on glucose as its (two-thirds in the morning and one-third in the evening). 5 Initial treatment for a Type 1 (IDDM) patient, who The normal (fasting) blood glucose range is 3.9-5.8 mmol/1 does not present with ketoacidosis, will usually be (70-105 mg/100 ml). 6 Suicidal overdose (in diabetics) is well recorded. Surgical outside hospital with two injections of intermediate- excision of the skin and subcutaneous tissue at the injection acting insulin, or a mixed insulin. Other permu- site of an enormous dose of long-acting insulin has been tations, including soluble insulin before each meal, 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 con- to give sugar, either by mouth if the patient can still centration is just as essential as an adequate supply swallow or glucose (dextrose) i.v. (20-50 ml of 50% of oxygen, and hypoglycaemia may lead to coma, solution, i.e. 10-25 g; this concentration is irritant convulsions and even death (in 4% of diabetics especially if extravasation occurs and the veins of under 50 years of age). diabetics are precious, so compress the vein It is usually easier to differentiate hypogly- immediately after completion of injection; adminis- caemia from severe diabetic ketosis than from other tration of 50-125 ml of 20% glucose is less throm- causes of coma, which are as likely in a diabetic as botic, if available. The response is usually dramatic. in anyone else. It is unsound to advocate blind The patient should be given a meal to avoid relapse. administration of i.v. glucose to comatose diabetics But if the patient does not respond within 30 min, on the basis that it will revive them if they are it may be because of cerebral oedema, which re- hypoglycaemic and do no harm if they are hyper- covers slowly and may require treatment with i.v. glycaemic. A minority of comatose insulin-dependent dexamethasone. If the patient has been severely diabetics have hyperkalaemia and added glucose hypoglycaemic or if very large amounts of insulin can cause a brisk and potentially hazardous rise in or sulphonylurea have been taken, then 20% glucose serum potassium (mechanism uncertain), in contrast should be given by i.v. infusion. Very severe attacks to nondiabetics in whom glucose causes a fall in sometimes damage the central nervous system serum potassium. permanently. (See also use of glucagon, below.) Hypoglycaemia may manifest itself as disturbed After recovery from a severe attack and eluci- sleep (nightmares) and morning headache. For dation of the cause, the patient's treatment regimen details of treatment see below. should be carefully reviewed with appropriate Other adverse reactions to insulin are lipodystrophy educational input. (atrophy or hypertrophy) at the injection sites (rare Hypoglycaemia due to other causes, e.g. alcohol, with purified pork and human insulin), after they is treated similarly. have been used repeatedly. These are unsightly, but otherwise harmless. The site should not be used INSULIN RESISTANCE AND further, for absorption can be erratic, but the patient HORMONES THAT INCREASE BLOOD may be tempted to continue if local anaesthesia has GLUCOSE developed, as it sometimes does. Lipoatrophy is probably allergic and lipohypertrophy is due to a Insulin resistance may be due to a decline in number local metabolic action of insulin. Local allergy also and/or affinity of receptors (see above) or to defects is manifested as itching or painful red lumps. in postreceptor mechanisms. Generalised allergic reactions are very rare, but A diabetic patient requiring more than 200 may occur to any insulin (including human) and to units/day is rare and regarded as insulin resistant any constituent of the formulation. Change of brand (occasional patients have needed as much as 5000 of insulin, especially to highly purified preparations units/day). Insulin resistance has become much (or to one with a different mode of manufacture) less frequent with the wide availability of purified, may rectify allergic problems. But zinc occurs in all mono-component and human insulins. If the insulins (though very little in soluble insulin) and requirement is acquired and genuine, it is due to can be the allergen. antibodies binding insulin in a biologically inactive complex (though it can dissociate as with protein binding of drugs). De novo insulin resistance occurs TREATMENT OF A HYPOGLYCAEMIC in a small number of genetic syndromes, e.g. in ATTACK combination with the skin condition acanthosis Prevention depends very largely upon patient nigricans. education, but it is an unavoidable aspect of inten- sive glycaemic control. Patients should not miss 7 In the early stages of insulin treatment, it can be very useful meals, must know the early symptoms of an attack, training to allow a patient to experience hypoglycaemia once and always carry glucose with them.7 Treatment is by delaying a meal. 686
ORAL ANTI DIABETES DRUGS 35. Where animal insulins are still in use, change to may be resistant to insulin. Patients with Addison's a highly purified pork or human insulin may be disease, hypothyroidism and hypopituitarism are successful in reducing resistance. Responsiveness abnormally sensitive to insulin action. to insulin may sometimes be restored by immuno- suppression, e.g. an adrenocortical steroid (pred- Oral contraceptives can impair carbohydrate nisolone 20-40 mg/d) over weeks (or a few months), tolerance. to suppress antibody production. Obviously, if this is successful, insulin dosage will have to be reduced Growth hormone antagonises the actions of insulin in accordance with the unpredictable reduction in in the tissues. Acromegalic patients may develop antibodies. Patients need to be carefully monitored insulin-resistant diabetes. to avoid severe hypoglycaemia. Ketoacidosis also reduces the effect of insulin. Thyroid hormone increases the requirements for insulin. Glucagon (il/2 4min) is a polypeptide hormone (29 amino acids) from the a-islet cells of the pan- creas. It is released in response to hypoglycaemia and is a physiological regulator of insulin effect, Oral antidiabetes drugs acting by causing the release of liver glycogen as glucose. Glucagon has been used to treat insulin- Oral antidiabetes drugs are of two kinds: sulphon- induced hypoglycaemia, but in about 45 min from amide derivatives (sulphonylureas) and guanidine onset of coma the hepatic glycogen will anyway be derivatives (biguanides). They are used by 30% of exhausted and glucagon will be useless. Its chief all diabetics. Unlike insulin they are not essential advantage is that, as it can be given s.c. or i.m. for life. (1.0 mg), glucagon can be used in a severe Following the observation in 1918 that guanidine hypoglycaemic attack by somebody, e.g. a member had hypoglycaemic effect, guanides were tried in of the patient's family, who is unable to give an i.v. diabetes in 1926, but were abandoned a few years injection of glucose. If a comatose patient does not later for fear of hepatic toxicity. recover sufficiently in 20 min to allow oral therapy, In 1930 it was noted that sulphonamides could i.v. glucose is essential. Glucagon is ineffective in cause hypoglycaemia, and in 1942 severe hypo- substantial hepatic insufficiency. glycaemia was found in patients with typhoid fever Glucagon has a positive cardiac inotropic effect during a therapeutic trial of sulphonamide. In the by stimulating adenylyl cyclase; it appears to have 1950s a similar observation was made during a value in acute overdose of (3-adrenoceptor blockers chemotherapeutic trial in urinary infections. This (see Index). was followed up and effective drugs soon resulted. The first sulphonylureas were introduced into clinical practice in 1954. Adrenaline (epinephrine) raises the blood sugar by mobilising liver and muscle glycogen; it does not antagonise the peripheral actions of insulin. MODE OF ACTION Glycosuria and diabetic symptoms may occur in patients with phaeochromocytoma. Sulphonylureas block the ATP-sensitive potassium channels on the p-islet cell plasma membrane. This Adrenal steroids, either endogenous or exogenous, results in the release of stored insulin in response to antagonise the actions of insulin, although this effect glucose. They do not increase insulin formation. is only slight with the primarily mineralocorticoid Sulphonylureas appear to enhance insulin action on group; the glucocorticoid hormones increase gluco- liver, muscle and adipose tissue by increasing in- neogenesis and reduce glucose uptake and util- sulin receptor number and by enhancing the post- isation by the tissues. Patients with Cushing's receptor complex enzyme reactions mediated by syndrome thus develop diabetes very readily and insulin. The principal result is decreased hepatic 687
DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY 35. glucose output and increased glucose uptake in INDIVIDUAL DRUGS muscle. They are ineffective in totally insulin- Absorption from the alimentary tract is good for all deficient patients and for successful therapy prob- the oral agents. It is advisable to take drugs -30 min ably require about 30% of normal [3-cell function to before a meal. These three groups of drugs are be present. Their main adverse effects are hypo- effective only in the presence of insulin. If a patient glycaemia and weight gain. fails to respond to one drug, response to another as Secondary failure (after months or years) occurs single treatment is unlikely. Proceeding to a com- due to declining f}-cell function and to insulin bination of drugs from different classes may then be resistance. effective. Biguanides. These agents have been in use since Sulphonylureas (see also Table 35.1) 1957. Metformin is the only biguanide in current use, and is a major agent in the management of Type 2 Several sulphonylureas are available. Choice is diabetes. Its cellular mode of action is uncertain but determined by the duration of action as well as the the most important effect is reduction of hepatic patient's age and renal function, and unwanted glucose production. Other effects include enhance- effects. The long-acting sulphonylureas, e.g. gliben- ment of peripheral insulin sensitivity increaseing clamide, are associated with a greater risk of glucose uptake in peripheral tissues; biguanides are hypoglycaemia; for this reason they should be ineffective in the absence of insulin. Rare com- avoided in the elderly for whom the shorter-acting plications are hypoglycaemia and lactic acidosis. alternatives, such as gliclazide or tolbutamide, Secondary failure is not a problem. Metformin can should be used. As chlorpropamide is both long- be used in combination with either insulin or other acting and has more unwanted effects than the oral hypoglycaemic agents. other sulphonylureas (see below) it is no longer recommended. In patients with impaired renal Thiazolidinediones. Pioglitazone and rosiglitazone function, gliclazide, glipizide or tolbutamide are reduce peripheral insulin resistance, leading to a preferred since they are not excreted by the kidney. reduction of blood glucose concentration. These Generally, it is prudent to start at the lowest drugs stimulate the nuclear hormone receptor, per- recommended dose in order to minimise risk of oxisome proliferator-activated receptor (PPARy), hypoglycaemia. which causes differentation of adipocytes.8 They should be initiated only by a physician experienced in treating Type 2 diabetes and should always be TABLE 35.1 Principal oral antidiabetes drugs used in combination with metformin or with a Drug Total Dosing Duration daily schedule of action sulphonylurea (if metformin is inappropriate). The dose (mg) (doses/day) (h) drugs can cause 3-4 kg weight gain in the first year Sulphonylureas of use, with peripheral oedema in 3-4% of patients. glibeclamide 2.5-20 1-2 12-24 Other adverse effects of the class have included gliclazide 40-320 1-2 12-24 abnormal liver function, and relevant tests should glipizide 2.5^tO 1-2 12-24 glimepiride 1-6 1 16-24 be monitored during the first year. Biguanide metformin 500-3000 2-3 8-12 Thiazolidinedione rosiglitazone 2-8 1-2 12-24 pioglitazone 15-30 1 16-24 8 The importance of PPARyin insulin sensitivity was Meglitinide confirmed with the finding, in Cambridge, of two families repaglinide 0.5-16 3 3^t presenting with severe insulin resistance in whom rare nateglinide 60-180 3 2-3 mutations of the PPARy gene caused loss of PPARy activity a-glucosidase inhibitor (Barroso I, Gurnell M, Crowley VE, et al 1989 Dominant acarbose 50-300 3 3-4 negative mutations in human PPARy associated with severe insulin resistance, diabetes mellitus and hypertension. Other sulphonylureas include tolbutamide,gliquidone, Nature 402: 880-882.) glibornuride, tolazamide. 688
TREATMENT OF DIABETES MELLITUS 35 Sulphonamides, as expected, potentiate sul- Rosiglitazone is similar and is administered once phonylureas by direct action and by displacement or twice daily. from plasma proteins. PRECAUTIONS WITH ORAL AGENTS Gliclazide is a commonly used second generation sulphonylurea. If more than 80 mg is prescribed, Hypoglycaemia is the most common adverse effect the drug should be taken twice daily before meals. with sulphonylureas, but is less common than with insulin therapy. It can be severe, and prolonged (for Glimepiride is designed to be used once daily and days), and may be fatal in 10% of cases, especially to provoke less hypoglycaemia than glibenclamide. in the elderly and in patients with heart failure. Erroneous alternate diagnoses such as stroke may Repaglinide is a very short-acting oral hypogly- be made. caemic agent whose action, like the sulphonylureas, is mediated through blockade of ATP-dependent Renal and hepatic disease. A biguanide should potassium channels. It affects only postprandial not be used in patients with either condition as the insulin profiles, and should in theory reduce risk of risk of lactic acidosis is too great. Sulphonylureas hypoglycaemia. are potentiated in these diseases and a drug with a short tl/2 (i.e. not glibenclamide) should be used in Biguanides (see also Table 35.1) low dose. Metformin (il/2 5 h) is taken with or after meals. Its Age adds to the hazard of oral agents. chief use is in the obese patient with Type 2 diabetes either alone or in combination with a sulphonylurea. Other adverse effects are rare but include skin It has a mild anorexic effect which helps to reduce rashes, gastrointestinal upset, minor derangement weight in the obese. The action of metformin is of haematological and hepatic indices. terminated by excretion by the kidney and it should not be used in the presence of renal impairment. Minor adverse gut reactions are common, OTHER ORAL AGENTS including nausea, diarrhoea, and a metallic taste in the mouth. These symptoms are usually transient Acarbose is an a-glucosidase inhibitor which or subside after reduction of dose. Heavy pro- reduces digestion of complex carbohydrates and longed use can cause vitamin B12 deficiency due to slows their absorption from the gut; in high doses it malabsorption. With a biguanide, ketonuria may may cause actual malabsorption. Acarbose reduces occur in the presence of normal blood sugar. This is glycaemia after meals, and may improve overall not generally severe and responds to reduction of glycaemic control. The usual dose is 50-300 mg dose. More serious, but rare, is lactic acidosis, which daily. Adverse effects are mainly flatulence and occurs in 0.03 cases per 1000 patient years. When diarrhoea, which lead to a high discontinuation rate. this condition does occur, it is usually against the The drug may be combined with a sulphonylurea. background of a serious underlying medical state such as renal impairment, liver failure or cardiogenic Dietary fibre and diabetes. The addition of gel- or septic shock. Lactic acidosis is treated with large forming (soluble) but unabsorbable fibre (guar (i.v.) doses of isotonic sodium bicarbonate. gum, a hydrocolloidal polysaccharide of galactose and mannose from seeds of the 'cluster bean') to the Thiazolidinediones (see also Table 35.1) diet of diabetics reduces carbohydrate absorption and flattens the postprandial blood glucose curve. Pioglitazone, is indicated once daily in patients Reduced need for insulin and oral agents are not controlled by metformin alone. It is reported, but adequate amounts (taken with lots of contraindicated by cardiac or hepatic failure. Weight water) are unpleasant (flatulence) and patient com- gain and oedema are the main adverse effects. pliance 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 patients encouraged to achieve an ideal body Treatment of diabetes weight. Diet should contain -40 g of fibre/day, with plenty of fresh fruit and vegetables. mellitus The way in which carbohydrate is distributed through the day should correspond with the type of Doctor, nurse and patient are faced with a lifetime drug treatment, and especially the type of insulin in of collaboration. Compliance is not a one-sided Type 1 patients. process, and the patients need all the consideration Type 1 patients are initially underweight, where- and support they can get. They should learn about as the reverse is true of Type 2. While carbohydrate their disease and its management, including home intake needs to be controlled in both types, overall monitoring of blood glucose, and about the need energy intake is restricted initially only in the obese for appropriate diet, exercise and avoidance of Type 2 patients. Other general factors which in- smoking. fluence the diet, in both Types 1 and 2, are the All Type 1 patients need immediate insulin therapy. Initial therapy in Type 2 patients should be • High incidence of ischaemic heart disease in by dietary means alone, for 2-3 months but most diabetics, requiring restriction of saturated fat patients will need oral antidiabetes drugs in addtion. intake The aims of treatment are: • Need to reduce protein intake in patients with established nephropathy. • to alleviate symptomatic hyperglycaemia and improve quality of life, while avoiding Weight. Older overweight diabetics (70% of Type 2) hypoglycaemia have a relative deficiency of insulin but seldom • to avoid ketosis and infections develop ketosis. In these patients, a hypocaloric • to keep (weight-reducing) diet is vital, as weight loss dra- • the fasting blood glucose < 6 mmol/1 matically improves glycaemic control and indeed, • the 1-hour postprandial concentration glycosuria may cease when their weight is reduced. < 9 mmol/1 It is also likely that effective dieting helps to prevent • the glycosylated haemoglobin HbAlc as close macrovascular disease through improved control of to normal as possible blood lipids and blood pressure. Exercise is similarly, • In addition to optimal glycaemic control other beneficial. Biguanide treatment particularly helps cardiovascular risk factors should be corrected: weight reduction. Weight loss is associated with an • optimal blood pressure control increase in numbers of insulin receptors and so an < 130/80 mmHg increase in responsiveness to insulin. The use of • cholesterol < 5.2 mmol/1 anorectic agents is discussed later in the chapter • triglycerides < 2.0 mmol/1 (p. 696). • by this regimen to avoid or delay long-term Young patients with Type 1 diabetes are often microvascular and macrovascular complications, underweight and need insulin to restore normal and reduce mortality. weight. Calorie restriction is not initially required in Each patient must be assessed individually; only these patients. The blood of these young diabetics an outline of the general principles involved can be contains negligible insulin and they readily become given here. ketotic. Diet. Patients should be allowed to follow their own preferences as far as is practicable. They SELECTION OFTHERAPY FOR should receive dietary advice on a high complex DIABETES carbohydrate diet (~65% of total calories) with low Patients are treated with: fat (< 30% of calories) with emphasis on reduction in saturated fat in favour of mono- and poly- • Diet alone unsaturates. Calories should be restricted and • Diet plus oral agent(s) 690
T R E A T M E N T OF D I A B E T E S M E L L I T US 35 • Diet plus insulin started, and the improved glycaemic control can be • Diet plus oral agent (metformin) plus insulin assumed also to improve outcome. Initial treatment • For ketoacidosis: soluble insulin, urgently. with a single injection of intermediate-acting insulin (see Fig. 35.1) at night, or twice daily, may control Diabetic patients under 30 years: almost all need hyperglycaemia. Fluctuations in blood glucose insulin; the exception is the rare single-gene dis- levels may be controlled with twice daily mixed order of Maturity Onset Diabetes of the Young insulin or by multiple injections. (MODY) due usually to mutations in the glucoki- nase gene. Re-evaluation of the requirement for drugs can be Diabetic patients over 30 years: approximately one- made after the patient has been controlled and third need insulin, one-third oral agents and one- stable for 3-6 months, but complete withdrawal of third diet only. oral agents is unusual. Type 1 diabetes: human insulin is preferred for Monitoring of patients taking oral agents should new patients (for regimen see below). be as close as those on insulin. The prognosis of poorly controlled type 2 diabetes is serious. Type 2 diabetes: careful trial is the only sure way of deciding who can be maintained on oral therapy Prevention of complications in Type 2 diabetes: rather than on insulin. About 30% of patients will the United Kingdom Prospective Diabetes Study be adequately managed without oral therapy. When (UKPDS)9,10 This landmark study in Type 2 diabetes diet alone has failed to control Type 2 diabetes, it is confirmed that good glycaemic control and ag- necessary to add an oral agent; the choice should gressive blood pressure reduction independently fall first on improve outcome. For every 1% reduction in HbAlc • metformin for the obese patient: the usual there was a 21% reduction in diabetes related deaths, regimen is metformin 500 mg once or twice daily and 37% reduction in microvascular disease. The after meals, increasing at 2-4-weekly intervals to study disproved concerns about long-term safety a maximum of 3 g daily. of sulphonylureas, but suggested that metformin • a sulphonylurea for the nonobese: an example might be the preferred first-line pharmacological regimen would be gliclazide 80 mg orally (or therapy in obese patients. Of highest importance 40 mg in the small or aged) before the main meal was the finding that effective blood pressure control of the day. The dose is adjusted, according to — regardless of type of antihypertensive drug — response, at 2-4-weekly intervals by increments was more influential than glycaemic control in pre- of 40-80 mg, to a maximum of 320 mg. If control venting macrovascular complications. Reduction is incomplete, metformin may be added. of blood pressure in 758 patients to a mean of 144/82 mmHg achieved 32% reduction in deaths Insulin treatment in Type 2 diabetes. When oral related to diabetes and 37% reduction in micro- therapy fails, insulin treatment should be used alone vascular end points, compared to 390 patients treated or in combination with metformin. There is little to a blood pressure of 154/87 mmHg. advantage from adding insulin to a sulphonylurea. The advent of thiazolidinediones offers an alter- Type 1 treatment. The range of insulin formu- native to combining metformin with insulin, but lations available allows flexible adjustment of the more experience of these drugs is required before their combination with metformin can be routinely 9 UK Prospective Diabetes Study (UKPDS) Group 1998 Effect recommended. It is important to stop the thiazo- of intensive blood-glucose control with metformin on lidinedione, if not effective, before progressing to complications in overweight patients with type 2 diabetes insulin. Definitive evidence that institution of insulin (UKPDS 34). Lancet 352: 854-865. 10 UK Prospective Diabetes Study (UKPDS) Group 1998 Tight will reduce complications is lacking; however, there blood pressure control and risk of macrovascular and is an improvement in quality of life, with few microvascular complications in type 2 diabetes. British patients requesting to stop insulin once they have Medical Journal 317: 703-713. 691
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 35 regimen to the patient's way of life. No single insulin for oral agents. An appropriate starting dose regimen suits all patients but one of the following is biphasic (mixtard) insulin 10-15 units twice daily. regimens can suit most patients (see Fig. 35.1): Infections cause an increase in insulin need (about 20%), which may drop briskly on recovery. In • Three doses of soluble insulin (before the main patients with poor glycaemic control, it is prefer- meals) plus an intermediate-acting insulin at able to use an insulin infusion and sliding scale, as bedtime described below for diabetic ketosis. • A biphasic or intermediate-acting insulin (see Fig. 35.1) twice a day before morning and Surgery, see later. evening meals • A single morning dose of a biphasic or Menstruation and oral contraception: insulin needs intermediate-acting insulin before breakfast may may rise slightly. suffice for some patients. Injection technique has pharmacokinetic conse- Use of glucocorticoids: insulin needs are increased. quences according to whether the insulin is delivered into the subcutaneous tissue or (inadvertently) into In pregnancy close control of diabetes is of the first muscle. The introduction of a range of appropriate importance to avoid fetal loss at all stages, and in length needles and pen-shaped injectors has the first trimester to reduce fetal malformations. In- enabled patients to inject perpendicularly to the sulins requirements increase steadily after the third skin without risk of intramuscular injection. The month. Ideally, women of childbearing age should absorption of insulin is as much as 50% more rapid be advised to conceive during a period of stable, from shallow i.m. injection. Clearly factors such as euglycaemic control. heat or exercise which alter skin or muscle blood During labour soluble insulin should be given by flow can markedly alter the rate of insulin continuous infusion at about l-2unit/h with i.v. absorption. infusion of 5% glucose 1.0 litre in 8 h). Substantially Patients should standardise their technique to less, e.g. 25%, insulin is likely to be needed imme- ensure injection is s.c. Inadvertent i.m. injection of diately after delivery, when timing and dose of an overnight dose of an extended duration insulin insulin injections should be carefully reconsidered can lead to inadequate early morning control lest hypoglycaemia occurs. Insulin need remains of blood glucose. Sites of injection should be lower during the first 6 weeks of lactation. rotated to minimise the now rare local compli- Blood glucose estimations are necessary during cations (lipodystrophy). Absorption is faster from pregnancy, for glycosuria is not then a reliable arm and abdomen than it is from the thigh and guide. The renal threshold for glucose (also of buttock. lactose) falls, so that glycosuria and lactosuria may occur in the presence of a normal blood Complications of diabetes. A well-controlled dia- glucose. betic is less liable to ketosis and infections. It is now Maternal hyperglycaemia leads to fetal hyper- certain that good control of glycaemia mitigates the glycaemia with consequent fetal islet cell hyper- serious microvascular complications, retinopathy, plasia, high birthweight babies, and postnatal nephropathy, neuropathy and cataract. Too tight hypoglycaemia. control of glycaemia can increase the frequency of attacks of hypoglycaemia. Premature labour: use of P2-adrenoceptor agonists and of dexamethasone (to prevent respiratory dis- SOME FACTORS AFFECTING tress syndrome in the prematurely newborn) causes CONTROL OF DIABETES hyperglycaemia and increased insulin (and pot- assium) need. Intercurrent illnesses cause fluctuations in the Current practice for women on oral hypogly- patient's metabolic needs. If these are severe, e.g. caemic agents who are planning, or starting, a preg- myocardial infarction, it is prudent to substitute nancy is to change to insulin and continue on it 692
DIABETIC KETOACIDOSIS 35 throughout pregnancy. There is no definitive evi- channel that is blocked by the sulphonylureas. dence that oral drugs are associated with fetal Therefore its chronic use as an antihypertensive malformations. agent is precluded by the development of diabetes. Indeed its use in therapeutics should now be confined to the rare indication of treating hypo- glycaemia due to islet-cell tumour (insulinoma). INTERACTIONS WITH NONDIABETES Adrenocortical steroids are also diabetogenic. 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. Diabetic ketoacidosis ft-adrenoceptor blocking drugs impair the sympa- The condition is discussed in detail in medical texts thetic mediated (P2-receptor) release of glucose and only the more pharmacological aspects will from the liver in response to hypoglycaemia and be dealt with here. Nevertheless, it should be also reduce the adrenergic-mediated symptoms of emphasised that the patients are always severely hypoglycaemia (except sweating). Insulin hypo- dehydrated and that fluid replacement is the first glycaemia is thus both more prolonged and less priority. noticeable. A diabetic needing (3-adrenoceptor blocker should be given a P^selective member, e.g. bisoprolol. In severe ketoacidosis the patient urgently needs Thiazide diuretics at a higher dose than generally insulin to stop ketogenesis. The objective is to supply, now used in hypertension can precipitate diabetes, as continuously as possible, a moderate amount of and it is wise to use low doses especially in estab- insulin. lished diabetes. Hepatic enzyme inducers may enhance the metab- Soluble insulin, preferably from the same species olism of sulphonylureas that are metabolised in the the patient has been using (never a sustained-release liver (tolbutamide). Cimetidine, an inhibitor of drug form), should be given by continuous i.v. infusion metabolising enzymes, increases metformin plasma of a 1 unit/ml solution of insulin in isotonic sodium concentration and effect. chloride. It is best to use a pump, which allows Monoamine oxidase inhibitors potentiate oral agents independent control of insulin and electrolyte and perhaps also insulin. They can also reduce administration more readily than an i.v. drip. If a appetite and so upset control. pump is not available, the insulin should be added Interaction may occur with alcohol (hypogly- in a concentration of 1 unit/ml to 50-100 ml of caemia with any antidiabetes drug). sodium chloride in a burette. The infusion rate is Salicylates and fibrates can increase insulin determined by a sliding scale, as illustrated in Table sensitivity. 35.2. The rate is adjusted hourly using the same The action of sulphonylureas is intensified by heavy scale. If an i.v. drip is used instead of a pump the sulphonamide dosage and some sulphonamides concentration should be lower (40 units/I). Stringent increase free tolbutamide concentrations, probably precautions against septicaemia are necessary in by competing for plasma protein binding sites. these patients. Continuous infusion i.m. (not s.c.) These examples suffice to show that the possibility can also be equally effective, provided the patient is of interactions of practical clinical importance is a not in shock and provided there is not an important real one. degree of peripheral vascular disease. Intermittent doses i.v. or i.m. may be used when DRUG-INDUCED DIABETES circumstances demand. If the i.m. route is used, a Diazoxide (see p. 470) is chemically similar to thiazide priming dose of 10 units should be given at the diuretics, but stimulates the ATP dependent K+ outset and then 6-10 units hourly. 693
DIABETES MELLITUS, INSULIN, ORAL ANTIDIABETES AGENTS, OBESITY 35 TABLE 35.2 Sliding scale of insulin doses according level falls to 10 mmol/l, the fluid replacement to blood glucose concentrations in ketoacidosis should be changed from saline to 5% glucose, at the (see text) same rate as detailed above. Blood glucose Infusion rate (mmol/l) (ml/h = units/hour for 50 ml syringe Potassium. Even if plasma potassium is normal or containing 50 units of insulin) high, patients have a substantial total body deficit, >22.0 10.0 (+ check pump and connections) and the plasma concentration will fall briskly with 19-21.9 8.0 16-18.9 6.0 i.v. saline (dilution) and insulin which draws 12-15.9 4.0 potassium into cells within minutes. Potassium 8-11.9 2.0 (+ change from saline to glucose chloride should be added to the second and infusion if blood glucose < 1 Ommol/l) 4-7.9 1.0 subsequent litres of fluid according to plasma 5.0 mmol/l none. insulin is restarted. The rate of fall of blood glucose/hour is proportional to the rate of infusion of insulin over the range of 1-10 units/h. A reason- Bicarbonate (isotonic) should be used only if plasma able rate of fall during treatment is 4-5.5 mmol/l pH is < 7.0 and peripheral circulation is good; (75-100 mg/100 ml) per hour. insulin corrects acidosis. Intravenous fluid and electrolytes.11 Patients are often more deficient in water than in saline and Success in treatment of diabetic ketoacidosis and its although initial replacement is by isotonic (0.9%) complications (hypokalaemia, aspiration of stomach sodium chloride solution, occurrence of hyper- contents, infection, shock, thromboembolism, cer- natraemia is an indication for half isotonic (0.45%) ebral oedema) depends on close, constant, informed solution. A patient with diabetic ketoacidosis may supervision. have a fluid deficit of above 5 litres and may be given: Mild diabetic ketosis. If the patient is fully con- • 1 litre in the first hour, scious and there has been no nausea or vomiting for • followed by 2 litres in 4 hours, at least 12 h, intravenous therapy is unnecessary. • then 4 litres in the next 24 hours, watching for It is reasonable to give small doses of insulin s.c. signs of fluid overload. 4-6-hourly and fluids by mouth. Note that fluid replacement causes a fall in blood glucose by dilution. Hyperosmolar diabetic coma occurs chiefly in non- insulin-dependent diabetics who fail to compensate Glucose should be given only when its concen- for their continuing, osmotic glucose diuresis. It is tration in blood falls below the renal threshold, in characterised by severe dehydration, a very high practice starting when the blood glucose falls to blood sugar (> 33 mmol/l: 600 mg/100 ml) and lack 10 mmol/l. If glucose is used at concentrations of ketosis and acidosis. Treatment is with isotonic above the renal threshold it merely increases the (0.9%) saline, at half the rate recommended for diabetic osmotic diuresis, causing further dehy- ketoacidotic coma, and with less potassium than in dration and potassium and magnesium loss (but see severe ketoacidosis. Insulin requirements are less Hypoglycaemia, above). When the blood glucose than in ketoacidosis, where the acidosis causes resistance to the actions of insulin, and should 11 In this situation glucose solution does not provide water generally be half those shown in Table 35.2. Patients replacement since the normal capacity to metabolise glucose are more liable to thrombosis and prophylactic is fully taken up. heparin is used. 694
MISCELLANOUS 35 hydrate content must be arranged. Plan the operation Surgery in diabetes for between 12 noon and 5 pm (17.00 h). Omit the usual dose of long-acting insulin on the morning of patients the operation and substitute soluble insulin, one- quarter of the usual total daily dose, before a light Principles of management: breakfast 6h preceding the operation. Arrange a • Surgery constitutes a major stress light evening meal after the operation and soluble • Insulin needs increase with surgery insulin, 10-20 units s.c., according to the blood • Avoid ketosis glucose. Return to the normal routine the next day. • Avoid hypoglycaemia High blood glucose concentration matters little Emergency surgery over short periods, except in the critically ill. The When a surgical emergency is complicated by programme for control should be agreed between diabetic ketosis, an attempt should be made to anaesthetist and physician whenever diabetic control the ketosis before the operation. Manage- patients must undergo general anaesthesia or ment during the operation will be similar to that for modify their diets. There are many different tech- major surgery except that more insulin will be niques that can give satisfactory results. needed. In other cases small doses of soluble insulin TYPE I DIABETES (IDDM) are given 2-4-hourly (where pumps are not avail- able), keeping the blood glucose between 5 and Elective major surgery 8 mmol/1. • Admit to hospital the day before surgery • Arrange operation for morning TYPE 2 DIABETES (NIDDM) • Evening before surgery: give patient's usual Elective and emergency surgery, and minor surgery if insulin NIDDM is poorly controlled: use the same regimen • Day of operation: omit morning s.c. dose; set up as for IDDM. i.v. infusion: glucose 5-10% + KC120 mmol/1, Minor surgery: If NIDDM is well controlled, omit infuse at 100 ml/h; insulin 20 units may be the oral hypoglycaemic agent on the morning of added to 1 litre of infusate or infused by pump at surgery. If the surgery is more than trivial, monitor a basal rate of 2-3 units/h and adjusted blood glucose carefully, and use soluble insulin s.c. according to a sliding scale. or by infusion if blood glucose rises. If vomiting is • Modify regimen during and after surgery likely, use insulin. 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 Miscellaneous s.c. insulin • Insulin requirements may be high, 10-15 units/h, Most patients with both Type 1 and Type 2 succumb in cases of serious infection, corticosteroid use, to either the macrovascular or microvascular obesity, liver disease. complications — especially ischaemic heart disease and diabetic nephropathy, respectively. Indeed Minor surgery diabetes is the major indication for dialysis and transplantation. As discussed in other chapters, the For example, simple dental extractions (for multiple treatment of hypertension and hyperlipidaemia is extractions or when there is infection the patient particularly important in patients with diabetes. should be admitted to hospital). A suitable post- Patients with diabetic nephropathy should receive operative diet of appropriate calorie and carbo- 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 12.0% to 17.9% in the USA. Obesity predisposes • Diabetes mellitus is important in global terms because to several chronic diseases including hypertension, of its chronicity, and high incidence and frequency of hyperlipidaemia, diabetes mellitus, cardiovascular major complications. It is of two kinds:Type I disease and osteoarthritis, and aspects of these are (previously, insulin dependent diabetes mellitus) and discussed in the relevant sections of this book. Type 2 (previously, non-insulin dependent diabetes). The body mass index15 (BMI) correlates highly • Type I diabetes is commoner among young, thin with the amount of body fat; individuals whose patients with diabetes. Insulin may also be required BMI lies between 25 and 30 kg/m 2 are considered when glycaemic control is not achieved by oral drugs in Type 2 pateints. overweight and those in whom it exceeds 30 kg/m2 • Insulin is given s.c. to stable patients, usually as a are defined as obese. Management of the condition biphasic mixture of soluble, short-acting human involves a variety of approaches from nutritional insulin, and a longer-acting suspension of insulin with advice to lifestyle alteration, drugs and, in extreme protamine or zinc. instances, gastric surgery. An evidence-based • In the treatment of diabetic ketoacidosis, in the algorithm coordinates these.16 The present account perioperative patient, and at other times of changing concentrates on pharmacological interventions. insulin requirement, insulin is best given by i.v. infusion of the soluble form. Drugs for obesity act either on the gastrointes- • Diet plays a major role in the treatment of Type 2 tinal tract to lower nutrient absorption or centrally diabetes with obesity. to reduce food intake by decreasing appetite or • There is now a clear difference in the choice of first- increasing satiety (appetite suppressants). line drug, if a drug is required, in Type 2 diabetes. A sulphonylurea is used for the nonobese, and metformin (a biguanide) for the obese. • Aggressive treatment of Type I, and probably Type 2, 12 successfully reduces microvascular complications. Three trials compared an angiotensin blocker with other Close attention to associated risk factors, especially blood pressure lowering drugs, and found a 20% reduction hyperlipidaemia and hypertension, is important in in the proportion of patients in whom proteinuria worsened or serum creatinine doubled during follow-up: reducing risk of macrovascular disease. 1. 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 2 diabetes. New England Journal of Medicine 345: 870-878. 2. Brenner B M, Cooper M E, de Zeeuw D et al 2001 Effects antagonist, with the evidence for the latter being of losartan on renal and cardiovascular outcomes in particularly strong that they are superior to other patients with type 2 diabetes and nephropathy. New antihypertensive agents in reducing progression to England Journal of Medicine 345: 861-869. renal failure.12 Addition of an ACE inhibitor to 3. Lewis E J, Hunsicker L G, Clarke W R et al 2001 Renoprotective effect of the angiotensin-receptor other drugs may also improve overall outcome in antagonist irbesartan in patients with nephropathy due to patients with diabetes.13 Most impressively, the type 2 diabetes. New England Journal of Medicine 345: Heart Protection Study showed that addition of 851-860. 13 simvastatin 40 mg daily to the treatment of 4000 The HOPE study included patients with diabetes as one of patients with diabetes reduced all cardiovascular its high risk group of cardiovascular patients, in whom ramipril reduced further coronary heart disease endpoints complications by 30%14 (see p. 486). 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 Obesity and appetite England Journal of Medicine 342:145-153. 14 Heart Protection Study Collaborative Group 2002 control MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals. Lancet 360: 7-22 Overweight and obesity are the commonest nu- 15 The weight in kilograms divided by the square of the tritional disorders in developed countries. Between height in metres. 1991 and 1998 the incidence of obesity rose from 16 http//wwv^.nhlbi.nih.gov/guidelines/obesity/practgde.hrrn 696
OBESITY AND APPETITE CONTROL 35 ORLISTAT depressant and it inhibits the reuptake of nor- adrenaline and serotonin at nerve endings, increasing Orlistat is a pentanoic acid ester that binds to and the concentration of these neurotransmitters at inhibits gastric and pancreatic lipases; the resulting postsynaptic receptors in the brain that affect food inhibition of their activity prevents the absorption intake. It is also thought to stimulate energy of about 30% of dietary fat compared with a normal expenditure. 5% loss. Weight loss is due to calorie loss but drug- The drug is rapidly absorbed from the gastro- related adverse effects also contribute by diminish- intestinal tract and extensively metabolised in the ing food intake. The drug is not absorbed from the liver by cytochrome P450 3A4. These metabolites alimentary tract. have a tl/2 of 14-16 h and are responsible for its Clinical trials show that patients who adhere to a effects. low-calorie diet and take orlistat lost on average When taken with dietary advice, sibutramine 9-10 kg after one year (compared to 6kg in those can be expected to cause a loss of 5-7% of initial who took placebo); in the following year those who body weight but this tends to be regained once the remained on orlistat regained 1.5-3.0 kg (4-6 kg with drug is stopped. placebo). Orlistat has found a place in the manage- Sibutramine should be prescribed only for ment of obesity in the UK but, not surprisingly, this individuals with BMI 27 kg/m2 or more who have is subject to stringent guidance from the National other cardiovascular risk factors or 30 kg/m2 or Institute for Clinical Excellence, namely that it be more in their absence. It should be discontinued if initiated only in individuals: weight loss after 3 months is < 5% of initial weight, • aged 18-75 years if weight stabilises at 10% of users. Less The dose is 120mg, taken immediately before, commonly, nausea, tachycardia, palpitations, raised during or 1 h after each main meal, up to thrice blood pressure, anxiety, sweating and altered taste daily. If a meal is missed, or contains no fat, the may occur. Blood pressure should be monitored dose of orlistat should be omitted. closely throughout its use (twice weekly in the first Treatment should be accompanied by coun- 3 months). Contraindications include severe hyper- selling advice and proceed beyond 3 months only tension, peripheral occlusive arterial or coronary in those who have lost > 5% of their initial weight, heart disease, cardiac arrhythmia, prostatic hyper- beyond 6 months in those who have lost > 10%, trophy and those with severe hepatic or renal should not normally exceed 1 year, and never more impairment. It should not be used to treat obesity of than 2 years. endocrine origin or those with a history of major eating disorder or psychiatric disease. Concomitant Adverse effects include flatulence and liquid, oily use with tricyclic antidepressants should be stools, leading to faecal urgency, abdominal and avoided (CNS toxicity). rectal pain. Symptoms may be reduced by adhering The noradrenergic drugs fenfluramine, dexfen- to a reduced-fat diet. Low plasma concentrations fluramine and phenteramine were formerly pre- of the fat-soluble vitamins A, D and E have been scribed as appetite suppressants but were withdrawn found. Orlistat is contraindicated where there is when their use was associated with cardiac valve chronic intestinal malabsorption or cholestasis. disease and pulmonary hypertension. Considerable interest continues to surround the SIBUTRAMINE adipocyte-derived hormone leptin (Greek, leptos, Sibutramine was originally developed as an anti- 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 long-term complications in insulin-dependent neuroendocrine pathways of the state of energy diabetes mellitus. New England Journal of stores in adipose tissue. Plasma leptin correlates Medicine 329: 977-986 with indices of obesity in humans, with most obese Fajans S S, Bell G I, Polonski K S 2001 Molecular patients being resistant to their elevated levels of mechanisms and clinical pathophysiology of leptin, rather than deficient in leptin production. maturity-onset diabetes in the young. New The use of therapeutic doses of leptin is under England Journal of Medicine 345: 971-980 evaluation; physiological doses are effective in rare Garner P 1995 Type I diabetes mellitus and pregnancy. patients with inherited leptin deficiency. Further Lancet 346:157-161 understanding of the leptin pathway may open Owens D R, Zinman B, Bolli G B 2001 Insulins today avenues for new agents to control appetite and and beyond. Lancet 358: 739-746 obesity. 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 GUIDETO FURTHER READING diabetics taking insulin and non-diabetics. British Atkinson M A, Eisenbarth G S 2001 Type 1 diabetes: Medical Journal 299: 591 new perspectives on disease pathogenesis and Stumvoll M et al 1995 Metabolic effects of treatment. Lancet 358: 221-229 metformin in non-insulin-dependent diabetes Boyle P J et al 1995 Brain glucose uptake and mellitus. New England Journal of Medicine 333: unawareness of hypoglycemia in patients with 550-554 insulin-dependent diabetes mellitus. New England Willett W C, Dietz W H, Colditz G A1999 Guidelines Journal of Medicine 333:1726-1731 for healthy weight. New England Journal of Clark C M Jr, Lee D A1995 Prevention and treatment Medicine 341: 427-434 of the complications of diabetes mellitus. New Williams G 1994 Management of non-insulin- England Journal of Medicine 332:1210-1217 dependent diabetes mellitus. Lancet 343: 95-100 Dornhorst A 2001 Insulinotropic meglitinide Wright J R 2002 From ugly fish to conqueror of death: analogues. Lancet 358:1709-1716 J J R Macleod's fish insulin research, 1922-24. Diabetes Control and Complications Trial Research Lancet 359:1238-1242 Group 1993 The effect of intensive treatment of Yanovski S Z, Yanovski J A 2002 Obesity. New diabetes on the development and progression of England Journal of Medicine 346: 591-602 698