Chapter 36 Diabetes mellitus, insulin, oral antidiabetes agents, obesity
Diabetes mellitus affects at least 2% of many national populations. Its successful management requires close collaboration between the patient and health-care professionals.
Diabetes overview
Diabetes is best regarded as a group of related conditions in which blood glucose levels tend to rise. Diabetes is common and increasing. In large part, this global increase in diabetes may be related to increased levels of obesity. Diabetes can lead to serious medical complications – blindness from retinopathy, renal failure, gangrene and limb amputation, cardiovascular disease and premature death. Aggressive therapy with a combination of pharmacological therapies aimed at lowering blood glucose and blood pressure and optimising lipids can reduce risk of these complications.
History of insulin therapy in diabetes
Diabetes was known to ancient Greek medicine with the description of ‘a melting of the flesh and limbs into urine … the patients never stop making water but the flow is incessant … their mouth becomes parched and their body dry’.1
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 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 Best.2
But at 4 pm I had a terrible shaky feeling and a terrible sweat and hunger pain. That was my first experience of hypoglycaemia. We remembered that 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.3
Diabetes mellitus is classified broadly as:
• Type 1 (formerly, insulin dependent diabetes mellitus, IDDM) which typically occurs in younger people who cannot secrete insulin.
• Type 2 (formerly, non-insulin dependent diabetes mellitus, NIDDM), which usually occurs in older people who are typically (although not always) obese. Type 2 diabetes is best thought of as a group of conditions characterised by a variable combination of reduced insulin secretion and resistance to insulin’s blood glucose lowering action.
• Other causes: including gestational diabetes, disease processes affecting the liver or pancreas such as cystic fibrosis causing a ‘secondary’ diabetes, monogenic forms (maturity onset diabetes of the young, MODY).
Sources of insulin
Insulin is synthesised and stored (bound to zinc) in granules in the β-islet cells of the pancreas. Daily secretion typically 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. In addition, insulin release following oral intake of carbohydrate is facilitated by the action of ‘incretin factors’ such as GLP-1 (see later) released from specialised neuroendocrine cells in the small bowel.
Insulin is a polypeptide with two peptide chains (A chain, 21 amino acids; 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:
• Bovine insulin differs from human insulin by three amino acids.
• Porcine insulin differs from human by only one amino acid.
• Human insulin is made either by enzyme modification of porcine insulin, or by using recombinant DNA to synthesise the pro-insulin precursor molecule for insulin. This is done by artificially introducing the DNA into either Escherichia coli or yeast.4
• Insulin analogues are now widely used and have modifications introduced to the A and/or B chains, which result in more rapid onset and offset of action (rapidly acting analogues), or slower offset (long acting analogues) than naturally occurring insulin.
Insulin receptors
Insulin receptors (comprising 2 α and 2 β subunits) are present on the surface of target cells such as liver, muscle and fat. Insulin binding results in tyrosine autophosphorylation of the β subunit. This then phosphorylates other substrates so that a signalling cascade is initiated and biological responses ensue. Downstream effects of stimulation of the insulin receptor include both immediate/short-term actions (for example translocation of the glucose transporter GLUT4 to the surface of target cell) and longer-term actions (for example increased expression of glucokinase and reduced expression of gluconeogenic and ketogenic enzymes in the liver).
Actions of insulin
• Reduction in blood glucose is due to increased glucose uptake in peripheral tissues (which oxidise glucose or convert into glycogen or fat), and a reduction in hepatic output of glucose (diminished breakdown/increased synthesis of glycogen and diminished gluconeogenesis).
• Other metabolic effects. Although, therapeutically, insulin is thought of as a blood glucose lowering hormone, it has a number of other cellular actions. Insulin is an anabolic hormone, enhancing protein synthesis (which has resulted in cases of misuse by bodybuilders). It also inhibits both breakdown of fats (lipolysis) and ketogenesis. Insulin also has actions on electrolytes, stimulating potassium uptake into cells and renal sodium retention (anti-natriuretic effect). Within brain, insulin may have actions to stimulate memory and act as a nutritional signal to help control appetite/food intake.
Uses
• Diabetes mellitus is the main indication.
• Insulin promotes the passage of potassium into cells by stimulating cell surface Na/K ATPase action, and this effect is utilised to correct hyperkalaemia (see p. 458).
• Insulin-induced hypoglycaemia can also be used as a stress test of anterior pituitary function (growth hormone and corticotropin and thus cortisol are released).
Pharmacokinetics
In health, insulin is 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. Insulin is released continuously and rhythmically from the healthy pancreas with additional increases following carbohydrate ingestion. As described below, modern insulin regimens in diabetes aim to match this pattern as far as possible.
In contrast to the natural pancreatic release, when insulin is injected subcutaneously during the treatment of diabetes, it enters the systemic circulation so that both liver and other peripheral organs receive the same concentration. It is inactivated in the liver and kidney; about 10% appears in the urine. The plasma t½ is only 5 min although clearance of ‘tissue’ insulin levels lags behind this; this is noteworthy when stopping intravenous insulin infusions as it may take 60 min for effects to wear off.
Most commonly, insulin is self-delivered by patients using either a syringe with a fixed needle (after drawing up insulin from a vial) or an insulin pen device (supplied as a preloaded disposable pen or with replaceable cartridges). Within hospital, soluble insulin may be delivered by intravenous infusion. Typically, 50 units soluble insulin is dissolved in 50 mL isotonic saline (i.e. insulin concentration 1 unit/mL).
An alternative and increasingly popular method for delivering insulin, especially in type 1 diabetes, is for patients to use continuous subcutaneous insulin infusion devices (‘insulin pumps’). These small cellphone-size personal devices provide a continuous basal delivery of soluble insulin (usually analogue, see below) with an additional insulin bolus when needed to cover meals or to correct high blood glucose values. Insulin pumps have become more sophisticated over the last decade, with patients able to set multiple pre-programmed basal insulin rates, and/or temporary infusion rates for such things as exercise or illness. Most pumps now have inbuilt software to calculate bolus doses from blood glucose/carbohydrate data. Some of the currently available insulin pumps link to subcutaneous continuous glucose monitors and, excitingly, the expectation is that this hardware will allow the development of an ‘artifical pancreas’ with insulin delivery controlled partially or totally by real-time glucose sensing.
Preparations of insulin (Table 36.1)
Broadly speaking, four different types of insulin with differing time-courses of action are available for treating diabetes (illustrated in Fig. 36.1):
1. Short duration of action (and rapid onset). Soluble insulin (also called neutral or regular insulin). The most recent additions to this class of insulin, lispro, aspart and glulisine, are modified human insulins with changes in the B chain resulting in more rapid absorption after subcutaneous injection and thus a faster onset and shorter duration of action.
2. Intermediate duration of action (and slower onset). Preparations in which the insulin has been modified physically by combination with protamine or zinc to give an amorphous or crystalline suspension; this is given subcutaneously and slowly dissociates to release insulin in its soluble form. Isophane (NPH) insulin, a suspension with protamine, is still widely used. Insulin Zinc Suspensions (amorphous or a mixture of amorphous and crystalline) are now rarely used.
3. Longer duration of action. Newer analogues glargine and detemir (Fig. 36.2) have become widely used, especially in type 1 diabetes. Small changes in the amino acid structure of glargine result in a significant slowing of absorption from subcutaneous depots. In contrast, detemir owes its protracted action to fatty acylation. After absorption, detemir is thus bound to circulating albumin which delays its action.
4. A biphasic mixture of soluble or short acting analogue insulin with isophane insulin.
Fig. 36.1 Approximate pharmacokinetic profiles of human insulin and insulin analogues. The relative duration of action of the various forms of insulin is shown. The duration will vary widely both between and within persons.
(From Hirsch I B 2005 Insulin analogues. New England Journal of Medicine 352:174–183.)
Notes for prescribing insulin
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. Long acting analogue insulins, and protamine insulin suspensions, should not be mixed in a syringe with short acting insulins.
Intravenous insulin
Only soluble (neutral) insulin should be used. Analogue and regular insulin have identical action profiles when given i.v. although the latter tends to be more widely used.
The standard strength
of insulin preparations is 100 units/mL (U100). Solutions of 40 and 80 units/mL remain available in some countries, and health-care providers should be aware of this. Biological standardisation of insulin has been replaced by physicochemical methods (high-performance liquid chromatography, HPLC).
Choice of insulin regimen
There are three common regimens incorporating the insulin types described above for patients requiring insulin:
1. ‘Basal bolus’ therapy: multiple injections of short acting insulin are given during the day to mimic prandial secretion of insulin by the pancreas, combined with once or twice daily intermediate or long acting insulin to provide the background insulin. This approach aims to mimic the non-diabetic pattern of insulin release. The total insulin dose is usually apportioned to be 40–60% background and 40–60% prandial.
When choosing the short acting insulin in a basal bolus regimen, soluble insulin is given 30 min before meals. Short acting analogues may be given immediately before, during or even after the meal, although recent data suggest that even these insulins may be more effective if given 15 min prior to eating. The more rapid waning of action profile also means that the risk of hypoglycaemic reactions before the next meal may be lower with the analogues. For choice of background insulin, long acting analogues may give less risk of nocturnal hypoglycaemia than NPH insulin (see Fig. 36.1) although NPH insulins offer greater flexibility if patients need to change background insulin from day to day (as with some sportsmen or pregnant women, for example).
2. Twice daily therapy involves two injections of biphasic insulin. Although less ‘physiological’ than basal bolus, it is simpler, with fewer insulin injections. The available mixtures are listed in Table 36.1. The most commonly used is 30:70 (soluble: NPH). Typically half to two-thirds of the daily dose may be given in the morning before breakfast and half to one-third before the evening meal. A combination of biphasic insulin with breakfast and fast acting insulin with evening meal and bedtime background insulin may be useful in some children with type 1 diabetes to avoid having to inject insulin at school.
3. Background or prandial insulin alone may be sufficient in type 2 diabetes when patients progress from oral therapy on to insulin. In this situation, oral therapy is usually continued in combination with insulin.
Dose and injection technique
A typical insulin-deficient patient with type 1 diabetes needs 0.5–0.8 units/kg insulin per day with approximately 50% as background. Increasingly, patients with type 1 diabetes are not being prescribed fixed insulin doses. Instead patients are being trained in how to self-adjust insulin doses, to allow for factors which will influence how much insulin is needed: meals with differing carbohydrate contents, digesting and skipping meals, exercise/activity, illness/stress, alcohol, travel, menstrual cycle. These same principles apply to insulin delivered by an insulin pump although many patients require lower total insulin doses by this route.
Initial treatment dose for a patient with type 1 diabetes, without ketoacidosis, is usually 0.3 units/kg daily. This initial management is aimed at introducing patients to regular insulin injections and blood glucose testing and aiming to tighten glycaemic control gradually over the first few weeks/months. Some patients with type 1 diabetes may have a significant residual insulin secretory capacity and may require no insulin for some months after diagnosis, often termed the ‘honeymoon’ period. Others may be started initially on low doses of either background insulin alone or prandial insulin, depending on their clinical status and whether they have any residual endogenous insulin secretion at diagnosis/presentation.
For type 2 diabetes, glycaemic targets have become lower over the last decade so that increasing numbers are treated with insulin. Although dosing calculators have been used, particularly in some clinical trials, in practice patients are often started on low doses of insulin using a simple regimen and then the dose/regimen is built up as indicated by blood glucose response. Most of these patients are insulin resistant and a useful therapeutic strategy is to combine oral insulin-sensitising therapy with metformin or pioglitazone (see below) with injected insulin. Severe insulin resistance merits specialist investigation for a possible underpinning cause.
Injection technique has pharmacokinetic consequences according to whether the insulin is delivered into the subcutaneous tissue or (inadvertently) into muscle and patients should standardise their technique. The introduction of a range of needles of appropriate length 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 intramuscular injection. Clearly, factors such as heat or exercise that alter skin or muscle blood flow can markedly alter the rate of insulin absorption.
Sites of injection should be rotated to minimise local complications (lipodystrophy). Absorption is faster from arm and abdomen than it is from thigh and buttock.
Adverse effects of insulin
Hypoglycaemia
Hypoglycaemia is the main adverse effect of the therapeutic use of insulin. It occurs with excess insulin dosing. Common causes are misjudging or missing meals, activity/exercise and alcohol. Hypoglycaemia is problematic because the brain relies largely, if not exclusively, on circulating glucose as its source of fuel. A significant fall in blood glucose can result in impaired cognition, lethargy, coma, convulsions and perhaps even death (hypoglycaemia was implicated in one series in 4% of deaths aged less than 50 years in patients with type 1 diabetes). Hypoglycaemia is a major factor for insulin-treated patients, with fear of hypoglycaemia being rated as highly as fear of other complications of diabetes such as blindness or limb amputation. Hypoglycaemia is a particular problem for some patients who lose symptomatic awareness of (and associated counterregulatory neurohumoral defences against) hypoglycaemia.
When human insulin first became available, a number of patients reported that they had less symptomatic awareness of hypoglycaemic episodes. Although the bulk of the subsequent scientific studies examining this failed to detect any significant differences in responses to hypoglycaemia between human and animal insulins, the possibility remains that some patients do react differently and a small number of patients still prefer to use porcine insulin. In practice, the debate about human vs animal insulin has become less topical as non-human analogue insulins are being increasingly used in routine clinical practice.
Prevention of hypoglycaemia depends largely upon patient education, but regular mild episodes of hypoglycaemia are an almost unavoidable aspect of intensive glycaemic control, at least with currently available insulin replacement regimens. Patients should be vigilant, particularly if they have reduced symptomatic awareness of hypoglycaemia, carry rapid acting carbohydrates with them and monitor blood glucose regularly, especially with exercise and before driving a motor vehicle.
Treatment of hypoglycaemia is to give 20 g of rapidly acting carbohydrates by mouth (e.g. dextrose tablets, fruit juice or glucose drinks) if the patient is not cognitively obtunded, repeated after 10 min if needed. Where the conscious level is impaired, rescue needs to be non-oral therapy with either i.v. glucose (dextrose) or glucagon. For i.v. glucose, current advice is to avoid using 50% dextrose which is irritant, especially if extravasation occurs. Administration of 50–100 mL of 20% glucose (i.e. 10–20 g), is less thrombogenic. Glucagon (t½
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