Diabetes Mellitus And Its Complications Flashcards
What is diabetes mellitus
Diabetes mellitus (DM) is a syndrome of chronic hypergly-caemia due to relative insulin deficiency, resistance or both.
It affects more than 220 million people worldwide, and it is estimated that it will affect 440 million by the year 2030.
Diabetes is usually irreversible and, although patients can lead a reasonably normal lifestyle, its late complications result in reduced life expectancy and major health costs.
These include macrovascular disease, leading to an increased prevalence of coronary artery disease, peripheral vascular disease and stroke, and microvascular damage causing diabetic retinopathy and nephropathy. Neuropathy is another major complication.
What is the structure of insulin and its secretory process
Insulin is the key hormone involved in the storage and controlled release within the body of the chemical energy available from food. It is coded for on chromosome 11 and synthesized in the beta cells of the pancreatic islets (Fig.
20.1). The synthesis, intracellular processing and secretion of insulin by the beta cell is typical of the way that the body produces and manipulates many peptide hormones. Figure 20.2 illustrates the cellular events triggering the release of insulin-containing granules. After secretion, insulin enters the portal circulation and is carried to the liver, its prime target organ. About 50% of secreted insulin is extracted and degraded in the liver; the residue is broken down by the kidneys. C-peptide is only partially extracted by the liver (and hence provides a useful index of the rate of insulin secretion) but is mainly degraded by the kidneys.
Give an outline on glucose metabolism (production, utilization, hormonal regulation, transport)
Blood glucose levels are closely regulated in health and rarely stray outside the range of 3.5-8.0 mmol/L (63-144 mg/dL), despite the varying demands of food, fasting and exercise.
The principal organ of glucose homeostasis is the liver, which absorbs and stores glucose (as glycogen) in the post-absorptive state and releases it into the circulation between meals to match the rate of glucose utilization by peripheral tissues. The liver also combines 3-carbon molecules derived from breakdown of fat (glycerol), muscle glycogen (lactate) and protein (e.g. alanine) into the 6-carbon glucose molecule by the process of gluconeogenesis.
Glucose production
About 200 g of glucose is produced and utilized each day. More than 90% is derived from liver glycogen and hepatic gluconeogenesis, and the remainder from renal gluconeogenesis.
Glucose utilization
The brain is the major consumer of glucose, and its function depends upon an uninterrupted supply of this substrate. Its requirement is 1 mg/kg bodyweight per minute, or 100 g daily in a 70 kg man. Glucose uptake by the brain is obligatory and is not dependent on insulin, and the glucose used is oxidized to carbon dioxide and water. Other tissues, such as muscle and fat, are facultative glucose consumers.
The effect of insulin peaks associated with meals is to lower the threshold for glucose entry into cells; at other times, energy requirements are largely met by fatty-acid oxidation.
Glucose taken up by muscle is stored as glycogen or metabolized to lactate or carbon dioxide and water. Fat uses glucose as a source of energy and as a substrate for triglyceride synthesis; lipolysis releases fatty acids from triglyceride together with glycerol, a substrate for hepatic gluconeogenesis.
Hormonal regulation
Insulin is a major regulator of intermediary metabolism, although its actions are modified in many respects by other hormones. Its actions in the fasting and postprandial states differ (Fig. 20.3). In the fasting state, its main action is to regulate glucose release by the liver, and in the postprandial state, it additionally promotes glucose uptake by fat and muscle. The effect of counter-regulatory hormones (gluca-gon, epinephrine (adrenaline), cortisol and growth hormone) is to cause greater production of glucose from the liver and less utilization of glucose in fat and muscle for a given level of insulin.
Glucose transport
Cell membranes are not inherently permeable to glucose. A family of specialized glucose-transporter (GLUT) proteins carry glucose through the membrane into cells.
• GLUT-1 - enables basal non-insulin-stimulated glucose uptake into many cells (see Fig. 6.29).
• GLUT-2 - transports glucose into the beta cell, a prerequisite for glucose sensing, and is also present in the renal tubules and hepatocytes.
• GLUT-3 - enables non-insulin-mediated glucose uptake into brain neurones and placenta.
• GLUT-4 - enables much of the peripheral action of insulin. It is the channel through which glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor
Describe the insulin receptor
This is a glycoprotein (400 kDa), coded for on the short arm of chromosome 19, which straddles the cell membrane of many cells (Fig. 20.4). It consists of a dimer with two a-subunits, which include the binding sites for insulin, and two B-subunits, which traverse the cell membrane. When insulin binds to the a-subunits it induces a conformational change in the B-subunits, resulting in activation of tyrosine kinase and initiation of a cascade response involving a host of other intracellular substrates. One consequence of this is migration of the GLUT-4 glucose transporter to the cell surface and increased transport of glucose into the cell. The insulin-receptor complex is then internalized by the cell, insulin is degraded, and the receptor is recycled to the cell surface.
What are the classification of diabetes
Diabetes may be primary (idiopathic) or secondary (Table
20.1). Primary diabetes is classified into:
• Type 1 diabetes, which has an immune pathogenesis and is characterized by severe insulin deficiency
• Type 2 diabetes, which results from a combination of insulin resistance and less severe insulin deficiency.
The key clinical features of the two main forms of diabetes are listed in Table 20.2. Type 1 and type 2 diabetes represent two distinct diseases from the epidemiological point of view, but clinical distinction can sometimes be difficult. The two diseases should from a clinical point of view be seen as a spectrum, distinct at the two ends but overlapping to some extent in the middle. Hybrid forms are increasingly recog-nized, and patients with immune-mediated diabetes (type 1) may, for example, also be overweight and insulin resistant.
This is sometimes referred to as ‘double diabetes’. It is more relevant to give the patient the right treatment on clinical grounds than to worry about how to label their diabetes.
The classification of primary diabetes continues to evolve.
Monogenic forms have been identified (see p. 1007), in some cases with significant therapeutic implications. Although secondary diabetes accounts for barely 1-2% of all new cases at presentation, it should not be missed because the cause can sometimes be treated. All forms of diabetes derive from inadequate insulin secretion relative to the needs of the body, and progressive insulin secretory failure is characteristic of both common forms of diabetes. Thus, some patients with immune-mediated diabetes type 1 may not at first require insulin, whereas many with type 2 diabetes will eventually do so.
What are some causes of type 1 diabetes
Type 1 diabetes belongs to a family of HLA-associated immune-mediated organ-specific diseases. Genetic susceptibility is polygenic, with the greatest contribution from the HLA region. Autoantibodies directed against pancreatic islet constituents appear in the circulation within the first few years of life, and often predate clinical onset by many years. Autoantibodies are also found in older patients with LADA and carry an increased risk of progression to insulin therapy.
Genetic susceptibility and inheritance
Increased susceptibility to type 1 diabetes is inherited, but the disease is not genetically predetermined. The identical twin of a patient with type 1 diabetes has a 30-50% chance of developing the disease, which implies that non-genetic factors must also be involved. The risk of developing diabetes by age 20, curiously, is greater with a diabetic father
(3-7%) than with a diabetic mother (2-3%). If one child in a family has type 1 diabetes, each sibling has a ~6% risk of developing diabetes by age 20. This risk rises to about 20% in HLA-identical siblings who have the same HLA type as the proband. Since type 1 diabetes can present at any age, the lifetime risk for a sibling or child is at least double the risk by age 20.
HLA system
The HLA genes on chromosome 6 are highly polymorphic and modulate the immune defence system of the body. More than 90% of patients with type 1 diabetes carry HLA-DR3-DQ2, HLA-DR4-DQ8 or both, as compared with some 35% of the background population. AlI DQB1 alleles with an aspartic acid at residue 57 confer neutral to protective effects with the strongest effect from DQB1*0602 (DQ6), while DOB1 alleles with an alanine at the same position (i.e.
DQ2 and DQ8) confer strong susceptibility. Genotypic combinations have a major influence upon risk of disease. For example, HLA DR3-DQ2/HLA DR4-DQ8 heterozygotes have a considerably increased risk of disease, and some HLA class I alleles also modify the risk conferred by class II susceptibility genes.
Other genes or gene regions
Genome-wide association studies have greatly broadened our understanding of the genetic background to type 1 diabetes and more than 50 non-HLA genes or gene regions that influence risk have been identified to date. The greatest genetic contribution still comes from the HLA region, but this is modulated by a large number of genes with small effects.
These include the gene encoding insulin (INS) on chromosome 11 and a number of genes involved in immune responses, including the cytotoxic T-lymphocyte-associated protein-4 (CTLA4) gene, the lymphoid-specific protein tyrosine phosphatase (PTPN22) gene and the IL-2R a-subunit of the IL-2 receptor complex locus (IL2RA), all of which are implicated in a variety of HLA-associated autoimmune conditions.
Autoimmunity and type 1 diabetes
Type 1 diabetes is associated with other organ-specific autoimmune diseases including autoimmune thyroid disease, celiac disease, Addison’s disease and pernicious anaemia.
Autopsies of patients who died following diagnosis of type 1 diabetes show infiltration of the pancreatic islets by mononuclear cells. This appearance, known as insulitis, resembles that in other autoimmune diseases such as thyroiditis.
Several islet antigens have been characterized, and these include insulin itself, the enzyme glutamic acid decarboxy-lase (GAD), protein tyrosine phosphatase (IA-2) (Fig. 20.6) and the cation transporter ZnT8. Recent studies have shown that GAD immunotherapy has no benefit. The observation that treatment with immunosuppressive agents such as ciclosporin prolongs beta-cell survival in newly diagnosed patients has confirmed that the disease is immune-mediated.
Environmental factors
The incidence of childhood type 1 diabetes is rising across Europe at the rate of 2-3% each year, suggesting that environmental factor(s) are involved in its pathogenesis. Islet autoantibodies (see above) appear in the first few years of life, indicating prenatal or early postnatal interactions with the environment. Exposures to dietary constituents, entero-viruses such as Coxsackie B4 and relative deficiency of vitamin D are possible candidates, but their role in the causation of the disease has yet to be confirmed. A cleaner environment with less early stimulation of the immune system in childhood may increase susceptibility for type 1 diabetes, as for atopic/allergic conditions (the hygiene hypothesis) (see p. 824), and more rapid weight gain in childhood and adolescence leading to increased insulin resistance might accelerate clinical onset (the accelerator hypothesis).
What is pre-type diabetes and how’s type 1 diabetes prevented
Children who test positive for two or more autoantibodies have a >80% risk of progression to diabetes, and the risk approaches 100% in those who additionally lose their first phase insulin response to intravenous glucose and/or develop glucose intolerance. The ability to predict type 1 diabetes with this degree of precision has opened the way to trials of disease prevention, but intervention before clinical onset of diabetes has so far proved unsuccessful.
What are some conditions associated with type 2 diabetes
Type 2 diabetes is associated with central obesity, hyper-tension, hypertriglyceridaemia, a decreased HDL-cholesterol, disturbed haemostatic variables and modest increases in a number of pro-inflammatory markers. Insulin resistance is strongly associated with many of these variables, as is increased cardiovascular risk. This group of conditions is referred to as the metabolic syndrome
What are some causes of type 2 diabetes
Inheritance
Identical twins of patients with type 2 diabetes have >50% chance of developing diabetes; the risk to non-identical twins or siblings is of the order of 25%, confirming a strong inherited component to the disease. Type 2 diabetes is a polygenic disorder, and, as with type 1 diabetes, genome-wide studies of associations between common DNA variants and disease have allowed identification of numerous susceptibility loci.
Several of these loci subserve beta-cell development or function, and there is no overlap with the immune function genes identified for type 1 diabetes. There is no major gene susceptibility, involving the HLA region. However, transcription factor-7-like (TCF7-L2) is the most common variant observed in type 2 diabetes in Europeans, and KCNQ1 (a potassium voltage-gated channel) in Asians. TCF7-L2 carries an increased risk of around 35%, while other common variants account for no more than 10-20%. TCF7-L2 has now been shown to modulate pancreatic islet cell function. Para-doxically, the genes for type 2 diabetes account for a relatively small fraction of its observed heritability. They do not allow subtypes of the condition to be identified with any confidence, or provide useful disease prediction.
Environmental factors: early and late
An association has been noted between low weight at birth and at 12 months of age and glucose intolerance later in life, particularly in those who gain excess weight as adults. The concept is that poor nutrition early in life impairs beta-cell development and function, predisposing to diabetes in later life. Low birthweight has also been shown to predispose to heart disease and hypertension.
Inflammation
Subclinical inflammatory changes are characteristic of both type 2 diabetes and obesity, and in diabetes, high-sensitivity C-reactive protein (CRP) levels are modestly elevated in association with raised fibrinogen and increased plasminogen activator inhibitor-1 (PAI-1), and contribute to cardiovascular risk. Circulating levels of the pro-inflammatory cytokines TNF-a and IL-6 are elevated in both diabetes and obesity.
Abnormalities of insulin secretion and action
The relative role of secretory failure versus insulin resistance
in the pathogenesis of type 2 diabetes has been much debated, but even massively obese individuals with a fully
functioning beta-cell mass do not necessarily develop diabe-
tes, which implies that some degree of beta-cell dysfunction is necessary. Insulin binds normally to its receptor on the
surface of cells in type 2 diabetes, and the mechanisms of
‘insulin resistance’ are still poorly understood. Insulin resist-
ance is, however, associated with central obesity and accu-
mulation of intracellular triglyceride in muscle and liver in type 2 diabetes, and a high proportion of patients have non-
alcoholic fatty liver disease (NAFLD), see page 303. It has
long been stated that patients with type 2 diabetes retain up to 50% of their beta-cell mass at the time of diagnosis, as
compared with healthy controls, but the shortfall is greater than this when they are matched with healthy individuals who are equally obese. In addition, patients with type 2 diabetes
almost all show islet amyloid deposition at autopsy, derived
from a peptide known as amylin or islet amyloid polypeptide
(APP), which is co-secreted with insulin. It is not known if this is a cause or consequence of beta-cell secretory failure.
Abnormalities of insulin secretion manifest early in the course of type 2 diabetes. An early sign is loss of the
first phase of the normal biphasic response to intravenous insulin. Established diabetes is associated with hypersecretion of insulin by a depleted beta-cell mass. Circulating insulin levels are therefore higher than in healthy controls, although still inadequate to restore glucose homeostasis.
Relative insulin lack is associated with increased glucose production from the liver (owing to inadequate suppression of gluconeogenesis) and reduced glucose uptake by peripheral tissues. Hyperglycaemia and lipid excess are toxic to beta cells, at least in vitro, a phenomenon known as glucotoxicity, and this is thought to result in further beta-cell loss
and further deterioration of glucose homeostasis. Circulating
insulin levels are typically higher than in non-diabetics following diagnosis and tend to rise further, only to decline again after months or years due to secretory failure, an observation sometimes referred to as the ‘Starling curve’ of the pancreas. Type 2 diabetes is thus a condition in which insulin deficiency relative to increased demand leads to hypersecre-tion of insulin by a depleted beta-cell mass and progression towards absolute insulin deficiency requiring insulin therapy.
Its time course varies widely between individuals.
How is type 2 diabetes prevented
Genetic predisposition determines whether an individual is susceptible to type 2 diabetes; if and when diabetes develops largely depends upon lifestyle. A dramatic reduction in the incidence of new cases of adult-onset diabetes was documented in the Second World War when food was scarce, and clinical trials in individuals with impaired glucose tolerance have shown that diet, exercise or agents such as metformin have a marked effect in deferring the onset of type 2 diabetes. Established diabetes can be reversed, even if temporarily, by successful diet and weight loss or by bariatric surgery. Diabetes is therefore largely preventable, although the most effective measures would be directed at the whole population and implemented early in life. Prevention is well worth while, for diabetes diagnosed in a man between the ages of 40 and 59 reduces life expectancy by 5-10 years. By contrast, type 2 diabetes diagnosed after the age of 70 has limited effect on life expectancy in men.
What is monogenic diabetes mellitus
Considerable progress has been made in understanding these rare variants of diabetes. Genetic defects of beta-cell function (previously called ‘maturity-onset diabetes of the young’, MODY) are dominantly inherited, and several variants have been described, each associated with different clinical phenotypes (Table 20.4).
These should be considered in people presenting with early-onset diabetes in association with an affected parent and early-onset diabetes in ~50% of relatives. They can often be treated with a sulfonylurea.
Infants who develop diabetes before 6 months of age are likely to have a monogenic defect and not true type 1 diabetes. Transient neonatal diabetes mellitus (TNDM) occurs soon after birth, resolves at a median of 12 weeks, and 50% of cases ultimately relapse later in life. Most have an abnormality of imprinting of the ZAC and HYMAI genes on chromosome 6q. The commonest cause of permanent neonatal diabetes mellitus (PNDM) is mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium-ATP channel.
Neurological features are seen in 20% of patients. Diabetes is due to defective insulin release rather than beta-cell destruction, and patients can be treated successfully with sulfonylureas, even after many years of insulin therapy.
What are some clinical presentation of diabetes
Presentation may be acute, subacute or asymptomatic.
Acute presentation
Young people often present with a 2-6-week history and report the classic triad of symptoms:
• Polyuria - due to the osmotic diuresis that results when blood glucose levels exceed the renal threshold
• Thirst - due to the resulting loss of fluid and electrolytes
Weight loss - due to fluid depletion and the accelerated breakdown of fat and muscle secondary to insulin deficiency.
Ketonuria is often present in young people and may progress to ketoacidosis if these early symptoms are not recognized and treated.
Subacute presentation
The clinical onset may be over several months or years, particularly in older patients. Thirst, polyuria and weight loss are typically present but patients may complain of such symptoms as lack of energy, visual blurring (owing to glucose-induced changes in retraction) or pruritus vulvae or balanitis that is due to Candida infection.
Complications as the presenting feature
These include:
• Staphylococcal skin infections
Retinopathy noted during a visit to the optician
• A polyneuropathy causing tingling and numbness in the feet
• Erectile dvsfunction
• Arterial disease, resulting in myocardial infarction or peripheral gangrene.
Asymptomatic diabetes
Glycosuria or a raised blood glucose may be detected on routine examination (e.g. for insurance purposes) in individuals who have no symptoms of ill-health. Glycosuria is not diagnostic of diabetes but indicates the need for further investigations. About 1% of the population have renal glyco-suria. This is an inherited low renal threshold for glucose, transmitted either as a Mendelian dominant or recessive trait.
What are some physical signs or symptoms that could help diagnose diabetes
Evidence of weight loss and dehydration may be present, and the breath may smell of ketones. Older patients may present with established complications, and the presence of the characteristic retinopathy is diagnostic of diabetes. In occasional patients, there will be physical signs of an illness causing secondary diabetes (see Table 20.1). Patients with severe insulin resistance may have acanthosis nigricans, which is characterized by blackish pigmentation at the nape of the neck and in the axillae
What are some investigations to make if diabetes mellitus is suspected
Diabetes is easy to diagnose when overt symptoms are present, and a glucose tolerance test is hardly ever necessary for clinical purposes. The oral glucose tolerance test has, however, allowed more detailed epidemiological characterization based on the existence of separate glucose thresholds for macrovascular and microvascular disease.
These correspond with the levels for the diagnosis of impaired glucose tolerance (IGT) and diabetes as specified by the
WHO criteria set out in Box 20.1. Epidemiological studies show that for every person with known diabetes, there is another undiagnosed in the population. A much larger proportion fall into the intermediate category of impaired glucose tolerance.
Impaired glucose tolerance (IGT)
This is not a clinical entity but a risk factor for future diabetes and cardiovascular disease. The diagnosis can only be made with a glucose tolerance test, and is complicated by poor reproducibility of the key 2-hour value in this test. The group is heterogeneous; some patients are obese, some have liver disease and others are on medication that impairs glucose tolerance. Individuals with IT have the same risk of cardiovascular disease as those with frank diabetes, but do not develop the specific microvascular complications.
Impaired fasting glucose (IFG)
This diagnostic category (fasting plasma glucose between 6.1 and 6.9 mmol/L) has the practical advantage that it avoids the need for a glucose tolerance test. It is not a clinical entity, but indicates future risk of frank diabetes and cardiovascular disease. IF only overlaps with IGT to a limited extent, and the associated risks of cardiovascular disease and future diabetes are not directly comparable. A lower cut-off of 5.6 mmol/L (rather than 6.1 mol/L) has been recommended by the American Diabetes Association (ADA) and would, if implemented, greatly increase the number of those in this category.
Haemoglobin Arc (HbAic)
HbAt is an integrated measure of an individual’s prevailing blood glucose concentration over several weeks (see below).
Standardization of this measure has enabled it to be proposed as an alternative diagnostic test for diabetes by the American Diabetes Association. As currently proposed, an HbAic >6.5% (48 mmol/mol) would be considered diagnostic of diabetes, whereas a level of 5.7-6.4% (39-46 mmol/mol) would denote increased risk of diabetes. A WHO Consultation recently also concluded that HbAic ‘can be used as a diagnostic test for diabetes’. Unfortunately, there is relatively little concordance between IT, IF and HbAi. as markers of ‘prediabetes’. Furthermore, there will be many people in a mixed population who are ‘diabetic’ using the HbAic criteria but ‘normal’ on glucose tolerance testing. Many are uncomfortable with this concept.
Other investigations
No further tests are needed to diagnose diabetes. Other routine investigations include urine testing for protein, a full blood count, urea and electrolytes, liver biochemistry and random lipids. The latter test is useful to exclude an associated hyperlipidaemia and, if elevated, should be repeated fasting after diabetes has been brought under control. Diabetes may be secondary to other conditions (see Table
20.1), may be precipitated by underlying illness and be associated with autoimmune disease or hyperlipidaemia.
Hypertension is present in 50% of patients with type 2 diabetes and a higher proportion of African and Caribbean patients.
How is diabetes treated
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 glycemic 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 the best time to educate the patient is soon after diagnosis.
Organized education programmes involve all healthcare workers, including nurse specialists, dieticians and podia-trists, and should include ongoing support and updates wherever possible.
Diet
The diet for people with diabetes is no different from that considered healthy for everyone. Table 20.5 lists recommendations on the ideal composition of this diet. To achieve this, food for people with diabetes should be:
low in sugar (though not sugar free)
• high in starchy carbohydrate (especially foods with a low glycaemic index), i.e. slower absorption
• high in fibre
• low in fat (especially saturated fat).
The overweight or obese should be encouraged to lose weight by a combination of changes in food intake and physical activity.
Carbohydrates
The glucose peak seen in the blood after eating pasta is much flatter than that seen after eating the same amount of carbohydrate as white potato. Pasta has a lower ‘glycaemic index’. Foods with a low glycemic index prevent rapid swings in circulating glucose, and are thus preferred to those with a higher glycaemic index.
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 person’s lifestyle. Advice from dieticians is more likely to affect medium-term outcome than advice from doctors.
People taking insulin or oral agents have traditionally been advised to eat roughly the same amount of food (particularly carbohydrate) at roughly the same time each day, so that treatment can be balanced against food intake and exercise.
Knowledgeable and motivated patients with type 1 diabetes, who get feedback from regular blood glucose monitoring, can vary the amount of carbohydrate consumed, or meal times, by learning to adjust their exercise pattern and treat-ment. This is the basis of the DAFNE (Dose Adjustment For Normal Eating) regimen.
Exercise
Diet treatment is incomplete without exercise. Any increase in activity levels is to be encouraged, but participation in more formal exercise programmes is best. Where facilities for this exist, exercise should be prescribed for everyone with diabetes. Several trials have shown that regular exercise reduces the risk of progression to type 2 diabetes by 30-60%, and the lowest long-term morbidity and mortality is seen in those with established disease who have the highest levels of cardiorespiratory fitness. Both aerobic and resistance training improve insulin sensitivity and metabolic control in type 1 and type 2 diabetes, although reported effects on metabolic control are inconsistent. Patients on insulin or sulfonylureas should be warned that there is an increased risk of hypoglycaemia for up to 6-12 h following heavy exertion.
Tablet treatment for type 2 diabetes
Diet and lifestyle changes are the key to successful treatment of type 2 diabetes, and no amount of medication will succeed where these have failed. The concept is that controlling diabetes is not just a matter of swallowing tablets, and these should in general never be prescribed until lifestyle changes have been implemented. Tablets will however be needed if satisfactory metabolic control (see ‘Measuring control’ below) is not established within 4-6 weeks. A consensus treatment pathway is shown in Figure 20.9 (p. 1013).
The three main options are metformin, a sulfonylurea or a thiazolidinedione.
Biguanide (metformin)
Metformin is the only biguanide currently in use, and remains the best validated primary treatment for type 2 diabetes.
It activates the enzyme AMP-kinase, which is involved in regulation of cellular energy metabolism, but its precise mechanism of action remains unclear. Its effect is to reduce the rate of gluconeogenesis, and hence hepatic glucose output, and to increase insulin sensitivity. It does not affect insulin secretion, does not induce hypoglycaemia and does not predispose to weight gain. It is thus particularly helpful in the overweight, although normal weight individuals also benefit, and may be given in combination with sulfonylureas, thiazolidinediones, dipeptidy| peptidase-4 (DPP4) inhibitors or insulin. Metformin was as effective as sulfonylurea or insulin in glucose control and reduction of microvascular risk in the UK Prospective Diabetic Study (UKPDS), but proved unexpectedly beneficial in reducing cardiovascular risk, an effect that could not be fully explained by its glucose-lowering actions. Adverse effects include anorexia, epigastric discomfort and diarrhea, and these prohibit its use in 5-10% of patients. Diarrhea should never be investigated in a diabetic patient without testing the effect of stopping met-formin or changing to a slow release preparation. Lactic acidosis has occurred in patients with severe hepatic or renal disease, and metformin is contraindicated when these are present. A Cochrane review showed little risk of lactic acidosis with standard clinical use, but most clinicians withdraw the drug when serum creatinine exceeds 150 mol/L.
Sulfonylureas (Table 20.6)
These act upon the beta cell to promote insulin secretion in response to glucose and other secretagogues. They are ineffective in patients without a functional beta-cell mass, and they are usually avoided in pregnancy. Their action is to bind to the sulfonylurea receptor on the cell membrane, which closes ATP-sensitive potassium channels and blocks potassium efflux. The resulting depolarization promotes influx of calcium, a signal for insulin release (Fig. 20.2). Sul-fonylureas are cheap and more effective than the other agents in achieving short-term (1-3 years) glucose control, but their effect wears off as the beta-cell mass declines.
There are theoretical concerns that they might hasten beta-cell apoptosis and they promote weight gain, and are best avoided in the overweight. They can also cause hypoglycaemia and although the episodes are generally mild, fatal hypoglycaemia may occur. Severe cases should always be admitted to hospital, monitored carefully, and treated with a continuous glucose infusion since some sulfonlvureas have long half-lives. Sulfonylureas should be used with care in patients with liver disease. Patients with renal impairment should only be given those primarily excreted by the liver.
Tolbutamide is the safest drug in the very elderly because of its short duration of action.
Meglitinides
Meglitinides, e.g. repaglinide and nateglinide, are insulin secretagogues. Meglitinides are the non-sulfonylurea moiety of glibenclamide. As with the sulfonylureas, they act via closure of the K+-ATP channel in the beta cells (see Fig. 20.2).
They are short-acting agents that promote insulin secretion in response to meals. Their effects are similar to that of the short-acting sulfonylurea tolbutamide, but they are much more costly.
Thiazolidinediones
The thiazolidinediones (more conveniently known as the ‘gli-tazones’) reduce insulin resistance by interaction with peroxi-some proliferator-activated receptor-gamma (PPAR-1), a nuclear receptor which regulates large numbers of genes including those involved in lipid metabolism and insulin action. The paradox that glucose metabolism should respond to a drug that binds to nuclear receptors mainly found in fat cells is still not fully understood. One suggestion is that they act indirectly via the glucose-fatty acid cycle, lowering free fatty acid levels and thus promoting glucose consumption by muscle. They reduce hepatic glucose production, an effect that is synergistic with that of metformin, and also enhance peripheral glucose uptake. Like metformin, the glitazones potentiate the effect of endogenous or injected insulin. The glitazones have yet to demonstrate unique advantages in the treatment of diabetes, and their place in routine diabetes care remains uncertain. Troglitazone and rosiglitazone have been withdrawn for safety concerns liver failure and increased cardiovascular risk, respectively), and pioglitazone is the only remaining agent in this class. Unwanted effects of piogli-tazone include weight gain of 5-6 kg, together with fluid retention and heart failure. Mild anemia and osteoporosis resulting in peripheral bone fractures have also been reported, and there is a possible increase in the risk of bladder cancer.
Dipeptidyl peptidase-4 (DPP4) inhibitors
These enhance the incretin effect (Box 20.2). The enzyme dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1 as this is released into the circulation. Inhibition of this enzyme thus potentiates the effect of endogenous GLP-1 secretion.
Four agents are currently available (linagliptin, saxagliptin, sitagliptin and vildagliptin) with more likely to be available in the future. They have a moderate effect in lowering blood glucose and are weight neutral. They are most effective in the early stages of type 2 diabetes when insulin secretion is relatively preserved, and are currently recommended for second-line use in combination with metformin or a sulfony-lurea. Adverse events are uncommon: the main side-effect is nausea, and there have been occasional reports of acute pancreatitis. Their place in the management of type 2 diabetes has yet to be fully established. Although the short-term safety record is good, DPP4 is widely distributed in the body, and the long-term consequences of inhibition of this enzyme in other tissues are unknown.
Injection therapies for type 2 diabetes
GLP-1 agonists
Exenatide and liraglutide are injectable long-acting analogues of GLP-1, which enhance the incretin effect (Box 20.2). They promote insulin release, inhibit glucagon release, reduce appetite and delay gastric emptying, thus blunting the post-prandial rise in plasma glucose and promoting weight loss.
Their main clinical disadvantage is the need for subcutaneous injection (twice daily for exenatide and once daily for liraglutide), and their major advantage is improving glucose control whilst inducing useful weight reduction. They work well in 70% but have limited benefit in 30% of those treated.
Side-effects include nausea, acute pancreatitis and acute kidney injury. At present they are used as an alternative to insulin, particularly in the overweight. A once weekly version of exenatide has been developed.
GLP-1 promotes beta-cell replication in immature rodents, but there is no evidence to suggest that it can do so in adult humans. GLP-1 receptors are also present in the exocrine pancreas, and the long-term clinical implications of this observation remain unclear.
Other therapies
• Intestinal enzyme inhibitors include acarbose, a sham sugar that competitively inhibits a-glucosidase enzymes situated in the brush border of the intestine, reducing absorption of dietary carbohydrate. Undigested starch may then enter the large intestine where it will be broken down by fermentation. Abdominal discomfort, flatulence and diarrhea can result, and dosage needs careful adjustment to avoid these side-effects.
• Orlistat is a lipase inhibitor which reduces the absorption of fat from the diet. It benefits diabetes indirectly by promoting weight loss in patients under careful dietary supervision on a low fat diet. This is necessary to avoid unpleasant steatorrhoea.
• Gastric banding and gastric bypass surgery have been used in those with marked obesity unresponsive to 6 months’ intensive attempts at dieting and graded exercise. NICE recommends consideration of surgery in those with a BMI >40, or in those with BMI >35 and co-morbidities such as diabetes or hypertension which will be alleviated by weight loss. In the USA, the FDA-recommended BMI thresholds are lower. The risks of surgery are not insignificant, and long-term specialist care and follow-up are needed, including psychological support and nutritional supplements for those with bowel resection, but these concerns should be balanced against the risk of patients staying as they are. About one-third of patients become non-diabetic after gastric bypass, but the condition may recur.
Insulin treatment
Insulin is found in every vertebrate, and the key parts of the molecule show few species differences. Small differences in the amino acid sequence may alter the antigenicity of the molecule. The glucose and insulin profiles in normal subiects are shown.
Short-acting insulins
Insulins derived from beef or pig pancreas have been replaced in most countries by biosynthetic human insulin.
This is produced by adding a DNA sequence coding for insulin or proinsulin into cultured yeast or bacterial cells.
Short-acting insulins are used for pre-meal injection in multiple dose regimens, for continuous intravenous infusion in labour or during medical emergencies, and in patients using insulin pumps. Human insulin is absorbed slowly, reaching a peak 60-90 min after subcutaneous injection, and its action tends to persist after meals, predisposing to hypoglycaemia.
Absorption is delayed because soluble insulin is in the form of stable hexamers (six insulin molecules around a zinc core) and needs to dissociate to monomers or dimers before it can enter the circulation. Short-acting insulin analogues have been engineered to dissociate more rapidly following injection without altering the biological effect. Insulin analogues (Fig. 20.8) such as the rapid-acting insulins (insulin lispro, insulin aspart and insulin glulisine) enter the circulation more rapidly than human soluble insulin, and also disappear more rapidly. Although widely used, the short-acting analogues have little effect upon overall glucose control in most patients, mainly because improved postprandial glucose is balanced by higher levels before the next meal. A Cochrane review has concluded that there is little evidence as to their benefit in type 2 diabetes.
Intermediate and longer-acting insulins
The action of human insulin can be prolonged by the addition of zinc or protamine derived from fish sperm. The most widely used form is PH (isophane insulin), which has the advantage that it can be premixed with soluble insulin to form stable mixtures (biphasic insulins), of which the combination of 30% soluble with 70% NPH is most widely used. Long-acting analogues have their structure modified to delay absorption or to prolong their duration of action. Insulin glargine is soluble in the vial as a slightly acidic (pH 4) solu-tion, but precipitates at subcutaneous pH, thus prolonging its duration of action. Insulin detemir has a fatty acid ‘tail’ which allows it to bind to serum albumin, and its slow dissociation from the bound state prolongs its duration of action. Although popular and widely used, these insulins have little demonstrated advantage over NPH in many clinical situations, although useful in those on intensified therapy or with troublesome hypoglycaemia.
Inhaled insulin
The first inhaled insulin was withdrawn from the market in 2007 on the grounds of limited clinical demand, although lung cancer was also observed.
