Guidelines to therapy
All patients with diabetes require diet therapy. Good glycaemic control is unlikely to be achieved with insulin or oral therapy when diet is neglected, especially when the patient is also overweight. Insulin is always indicated in a patient who has been in ketoacidosis, and is usually indicated in patients who present under the age of 40 years. Insulin is also indicated in older patients following primary or secondary failure of oral therapy (see below). Tablets should be avoided in younger patients and are contraindicated in pregnancy. In older patients the approach to therapy is empirical. Diet alone should be tried in the first instance, and dietary knowledge and compliance should always be reassessed with care before proceeding to the next step. This is of particular importance in the obese patient who fails to lose weight.
When diet fails to achieve satisfactory control, thin patients are usually treated with a sulphonylurea drug, and obese patients with a biguanide. Primary failure of treatment occurs when these agents (alone or in combination) never achieve the desired level of control.
Other patients may show a good initial response followed by progressive loss of control over the succeeding months or years; this is referred to as secondary failure of treatment.
Since this approach is largely empirical, it is not surprising that practice differs from one country to another. For example> metformin (the only biguanide in common use) is very widely employed in France, tends to be used less in the UK, and is not licensed in the USA. Criteria of control also vary, so that what is classed as primary failure at one centre may be seen as a success in another. The most widespread error in management is procrastination;
the patient whose control is inadequate on tablets should start insulin without undue delay.
Diet
The diet for a diabetic patient is no different from the diet considered healthy for the population as a whole.
Carbohydrate
This should consist of unrefined carbohydrate rather than simple sugars such as sucrose. Carbohydrate is absorbed relatively slowly from fibre-rich foods, preventing the rapid swings in circulating glucose seen when refined sugars are ingested. For example, the glucose peak seen after eating an apple is much flatter than that seen after drinking the same amount of carbohydrate as apple juice.
Calories Calories should be tailored to the needs of the patient. The total amount of carbohydrate in the diet should provide 50-55% of the total calories with fat 30-35% and protein 15%.
THE OVERWEIGHT DIABETIC PATIENT is started on a reducing diet of approximately 1000-1600 kcal daily (4000-6000 kJ).
THE LEAN PATIENT is put on an isocaloric diet.
PATIENTS WHO ARE UNDERWEIGHT because of untreated diabetes require energy supplementation.
Prescribing a diet
Most people find it extremely difficult to modify their eating habits, and repeated advice and encouragement are needed if this is to be achieved. A diet history is taken, and the diet prescribed should involve the least possible interference with the life-style of the patient. It is important to stress that patients on insulin or oral agents should eat the same amount at the same time each day. Patients on insulin require snacks between meals and at bedtime to buffer the effect of injected insulin. Alcohol is not forbidden, but its energy content should be taken into account. Patients on insulin should be warned to avoid alcoholic binges since these may precipitate severe hypoglycaemia.
The role of patient education and community care The care of diabetes is based on self-management by the patient, who is helped and advised by those with specialized knowledge. The quest for improved glycaemic control has made it clear that whatever the technical expertise applied, the outcome depends on willing cooperation by the patient. This in turn depends on an understanding of the risks of diabetes and the potential benefits of glycaemic control and other measures such as maintaining a lean weight> stopping smoking and taking care of the feet. If accurate information is not supplied, misinformation from friends and other patients will take its place. For this reason, many patients have exaggerated fears of, for example, blindness (about 1 patient in 20 is blind after 30 years of diabetes), death during hypoglycaemia (extremely rare), or the risk of passing diabetes on to their children (2-5% of offspring develop IDDM). Organized training programmes involving all healthcare workers including nurse specialists, dietitians and chiropodists are now a recognized part of good diabetes care.
Tablet treatment
Sulphonylureas
These have two main actions:
1 They increase basal and stimulated insulin secretion.
2 They reduce peripheral resistance to insulin action.
The effects upon insulin secretion are most marked in the early stages of treatment, but the peripheral effects are more important for maintenance therapy. The sulphonylureas should be avoided in young ketotic patients, who require early insulin therapy, and are contraindicated in pregnancy. Insulin should be substituted during major surgery or severe intercurrent illness. These drugs have similar actions and potency. All should be used with care in patients with liver disease, and only those primarily excreted by the liver should be given to patients with renal impairment. Sulphonylureas all encourage weight gain and are not the first choice in obese patients. Tolbutamide is the safest drug in the very elderly because of its short duration of action. Chlorpropamide has the disadvantages of a long duration of action and a wider range of side-effects, and is now less widely used.
DRUG INTERACTIONS. All sulphonylureas bind to circulating albumin and may be displaced by other drugs, such as sulphonamides, that compete for their binding sites. Their clinical effect may be reduced by thiazide diuretics or steroid therapy. SIDE-EFFECTS. Hypoglycaemia is the most common and dangerous side-effect. Because the action of many sulphonylureas persists for more than 24 hours, recurrent or prolonged hypoglycaemia is likely, and hospital admission is usually necessary. Skin rashes and other sensitivity reactions may occur.
Chlorpropamide use is often associated with a facial flush when alcohol is taken. It may also cause a cholestatic jaundice and a syndrome of inappropriate antidiuretic hormone (ADH) secretion in 2-4% of patients.
Biguanides
Metforrnin acts by reducing glucose absorption from the gut and by increasing insulin sensitivity. Unlike the sulphonylureas it does not induce hypoglycaemia in normal volunteers. It is usually reserved for patients in middle or old age, particularly for the overweight since it does not promote weight gain. It may be given in combination with sulphonylureas when a single agent has proved to be ineffective.
Its side-effects include anorexia, epigastric discomfort and diarrhoea. Lactic acidosis has occurred in patients with severe hepatic or renal disease, and metformin is contraindicated when these are present.
Other drugs
Acarbose, an a-glucosidase inhibitor, inhibits intestinal amylase, sucrase and maltase activity, thereby reducing carbohydrate absorption. It is being used in NIDDM patients who are inadequately controlled on diet alone or on diet with oral hypoglycaemic agents. Its long-term value is unproven.
Insulin treatment
Injections
The needles used to inject insulin are very fine and sharp. Even though most injections are virtually painless, patients are understandably apprehensive and treatment begins with a lesson in injection technique. Insulin is either drawn up into special plastic insulin syringes marked in units (100 U in 1 ml), or is administered by a pen injection device. Injections are given at 90° to the skin of the thighs or abdomen, and the needle is usually inserted to its full length. Most patients starting insulin injection prefer pen devices when given a choice.
ADVANTAGES OF PEN INJECTION DEVICES
• Useful in the visually impaired (audible clicks, clear numbering)
• Easy to use
• Convenient to carry around
• Can be used discreetly in public places (e.g. restaurants)
• Some psychological benefit in ‘needle phobias’
• Available free in the UK
DISADVANTAGES OF PEN INJECTION DEVICES
• Zinc insulins cannot be used because they aggregate in the pen cartridges.
• Pen needles are not yet available on prescription.
• Pens produced by one manufacturer cannot be used with insulin from another.
The injection site used should be changed regularly to prevent areas of lipohypertrophy. The rate of insulin absorption depends on local subcutaneous blood flow, and is accelerated by exercise, local massage or a warm environment. Absorption is more rapid from the abdomen than from the arm, and is slowest from the thigh. All these factors can influence the shape of the insulin profile. All patients need careful training for a life with insulin, but routine hospital admission to begin insulin treatment is unnecessary where facilities for community support exist.
Choice of insulin
SPECIES. Insulin is found in every creature with a backbone, and the central part of the molecule shows few species differences. (For example, fish insulin produces hypoglycaemia in humans.) Small differences in the amino acid sequence may alter the antigenicity of the molecule. Beef insulin differs from human insulin by three amino acids and pork from human by one. Both may induce antibody formation, beef more readily than pork.
Human insulin is produced by DNA coding of cultured yeast or bacterial cells to produce proinsulin, with subsequent enzymatic cleavage to insulin. All forms of injected insulin, even human, may result in antibody formation, but insulin antibodies usually have little clinical importance. Human insulin has largely replaced the other varieties, mainly as the result of market forces. Some patients report altered perception of hypoglycaemia on human insulins. This effect has not been reproduced in double blind trials, but such patients should be offered the opportunity to try a different species of insulin.
PURITY. Insulins used in the Western World are now of very high purity, but older products are still widely distributed elsewhere. FORMULATION (Table 17.5). There are two main types
of insulin:
1 Insulin prepared in a clear solution (soluble or crystalline). These insulins are short-acting and are the only insulins to be used in emergencies such as ketoacidosis or for surgical operations.
2 Insulins premixed with retarding agents (either protamine or zinc) that precipitate crystals of varying size according to the conditions employed. These insulins are intermediate or long acting.
Clinical use
In normal subjects a sharp increase in insulin occurs after meals; this is superimposed on a constant background of secretion. Insulin therapy attempts to reproduce this pattern. In order to achieve this, a common strategy is to give intermediate-acting insulin to control the afternoon and night blood sugar level, and shortacting insulins morning and evening to match meal times.
Ideal control is often hard to achieve for four reasons:
In normal people, insulin is secreted directly into the portal circulation and passes directly to the liver in high concentration. The insulin injected by diabetics passes into the systemic circulation before passage to the liver.
2 Subcutaneous soluble insulin takes 60-90 min to achieve peak plasma levels-the onset and offset of action are too slow.
3 The absorption of subcutaneous insulin into the circulation is variable; the longer acting the preparation, the more erratic the absorption.
4 Basal insulin levels are constant in the normal state, but injected insulin invariably peaks and declines, with resulting swings in metabolic control.
Individuals vary and therapy must be tailored accordingly. One approach to therapy is outlined here.
YOUNG PATIENTS are started on two injections daily of an intermediate insulin at a dose of 8-10 U twice daily. Some recovery of endogenous insulin secretion may occur over the first few months (the ‘honeymoon period’) and the insulin dose may need to be reduced. Requirements rise thereafter and a multiple injection regimen is then appropriate for most younger patients. This is flexible and usually highly acceptable.
PATIENTS WITH NIDDM. Twice-daily injections of premixed soluble and isophane insulins, e.g. Mixtard, are effective in the majority of patients with NIDDM. OLDER PATIENTS may sometimes manage adequately on a single daily injection.
If glycaemic control is inadequate with the standard approach, the alternatives are multiple insulin injections or continuous subcutaneous insulin infusion (CSII). Both methods require a planned approach to life, with special attention to diet and exercise and frequent bloodglucose testing.
shown as blue lines and intermediate- or long-acting insulin as
purple lines. The arrows indicate when the injections aregiven. (a) Twice daily soluble and intermediate. (b) Splitting the evening injection. (c) Three times daily soluble with
additional intermediate or long-acting insulin given before bedtime. B, breakfast; L, lunch; S, supper; Sn, snack (bedtime).
MULTIPLE INJECTIONS. The introduction of ‘pen injection’ devices has made this approach much more acceptable to patients. Two variants are shown diagrammatically. Multiple injection regimens and infusion devices have the advantage of flexibility concerning meal times, which is of great value to patients with busy jobs, shift workers and those who travel regularly. The amount eaten at each meal can be chosen at meal time and an appropriate dose of insulin given. With twice daily regimens, the size and timing of meals is fixed more rigidly.
INFUSION DEVICES. CSII is delivered by a small pump strapped around the waist that infuses a constant trickle of insulin via a needle in the subcutaneous tissues. Mealtime doses are delivered when the patient touches a button on the side of the pump.
This approach is particularly useful in the overnight period. Disadvantages include the nuisance of being attached to a gadget, skin infections, and the risk of ketoacidosis if the flow of insulin is broken (since these patients have no protective reservoir of depot insulin). Infusion pumps should only be used by specialized centres able to offer a round-the-clock service to their patients.
