2.1.Diagnosis of type 2 diabetes
Diagnosis of T2D, and its precursor insulin resistance, is made difficult by the lack of symptoms early in the development of the disease, and many cases go undiagnosed. The Australian Diabetes, Obesity and Lifestyle study found that half of all subjects studied who were suffering from T2D had not been previously diagnosed (Dunstan et al., 2002). Predictors of risk for the development of T2D and cardiovascular disease include body mass index (BMI), ethnic origin, blood pressure and cholesterol levels (Gavin et al., 2003). Current clinical guidelines for the diagnosis of diabetes however are based upon blood glucose measures. The World Health Organisation (WHO) standard criteria for diagnosis of T2D involve fasting plasma glucose (FPG) and the response to an oral glucose tolerance test (OGTT). FPG is a measure of plasma glucose after 8 hours of fasting, while the OGTT measures plasma glucose 2 hours following an intake of 75 g glucose. The current guidelines are outlined in Table 1.
|NGT||< 6.1 mmol/L||< 7.8 mmol/L|
|IGT||< 7.0 mmol/L||7.8 – 11.1 mmol/L|
|IFG||6.1 – 6.9 mmol/L||< 7.8 mmol/L|
|Diabetes||≥ 7.0 mmol/L||≥ 11.1 mmol/L|
WHO guidelines for the diagnosis of diabetes and other hyperglycaemic states.
Abbreviations used: NGT – normal glucose tolerance, IGT – impaired glucose tolerance, IFG – impaired fasting glucose (WHO/IDF, 2006).
IGT and IFG are both strong indicators of risk for the development of T2D, with individuals suffering from both conditions placed at even higher risk (Gavin et al., 2003). IGT is characterised by peripheral insulin resistance, while defects in insulin secretion coupled with increased hepatic glucose output characterise IFG (Davies et al., 2000). While the associated health risks, prevalence and distribution vary for IGT and IFG (Unwin et al., 2002), the risk of developing T2D is similar for both, and increases further when both IGT and IFG are present (Gavin et al., 2003).
2.2. Current anti-diabetic treatments
The development of both insulin resistance and impaired glucose tolerance, conditions which precede the onset of T2D, are closely linked with obesity (Sharma, 2006). Excess visceral fat, and the hormones and inflammatory factors it releases, coupled with excess free fatty acid release have been implicated in the development of T2D (Mlinar et al., 2007). For obese patients exhibiting these symptoms, changes to healthier eating patterns and increases in exercise can result in improvements to glucose tolerance. However this approach often fails within the first year of treatment, and therefore the use of various medications is usually required (Nathan et al., 2006). Lifestyle changes immediately following the diagnosis of T2D can often be successful in the early treatment of the disease. Unfortunately, a lack of diagnosis, coupled with difficulties in maintaining lifestyle changes, means that this is not a treatment option which will be effective in the long term for all patients (Nathan et al., 2006).
Metformin is an oral antidiabetic agent, based upon the molecule biguanide. Its mechanism of action involves a reduction in hepatic gluconeogenesis, leading to a reduction in blood glucose levels (Knowler et al., 2002). This can also have the associated benefit of reducing blood insulin levels. Metformin has a number of side effects including gastrointestinal symptoms and has been linked with rare cases of lactic acidosis which can be fatal, although evidence for this has been contradicted in some studies (Salpeter et al., 2006). Metformin is one of only two oral anti-diabetic agents on the WHO list of essential medicines. The second oral anti-diabetic to be listed by WHO is the drug family known as the sulfonylureas, the most commonly used drug of which is glibenclamide. The sulfonylureas mechanism of action involves enhancing insulin secretion (Groop, 1992). For this reason, the sulfonylureas show their best efficacy in the early stages of the disease when β-cell function is still viable. Side effects associated with the sulfonylureas include hypoglycaemia due to their long half life in plasma, and weight gain.
The glinides are a family of drugs with a mechanism of action similar to the sulfonylureas, in that they bind to the same receptor – although at a different binding site – to induce insulin secretion from the β-cells of the pancreas. The glinides have an advantage over the sulfonylureas in that they have a shorter half life in blood plasma. As such, some glinides pose a lower risk of hypoglycaemia then some of the sulfonylureas (Kristensen et al., 2000).
Thiazolidinediones (TZDs or glitazones) are an insulin sensitizing family of compounds. TZDs are ligands for the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ). It is through transcriptional regulation of PPARγ that this family of compounds increase the sensitivity of muscle, liver and adipose tissue to the effects of insulin (Yki-Jarvinen, 2004). However, this family of drugs has been linked to some serious long term side effects. Troglitazone, first approved for use in T2D patients in 1997, was withdrawn from the market in 2000 after it was linked to a number of cases of liver dysfunction and failure (Watkins, 2005). The widely used alternative rosiglitazone has in recent years been linked to increased cardiovascular disease (Nissen and Wolski, 2010). The drug has been withdrawn from sale in the UK and New Zealand. While still available in the US, rosiglitazone is currently branded with additional safety warnings and restrictions on its use, and sales in recent years have fallen significantly (GlaxoSmithKline, 2010).
Exogenous insulin is a very important therapeutic agent for the treatment of diabetes, capable of increasing blood insulin levels when β-cell function has been impaired, and can be given in increasing amounts to overcome insulin resistance. However, insulin is also associated with increases in weight gain, as well as risk of hypoglycaemia if monitoring of blood glucose levels is not rigorously performed.
Glucagon-like peptide 1 agonists (GLP-1 agonists) are mimics of a protein secreted by the L-cells of the small intestine. They act on GLP-1 receptors in pancreatic β-cells, inducing insulin release. GLP-1 agonists have also been shown to stimulate β-cell proliferation (Drucker, 2003, 2005) and suppress glucagon release and gastric motility, while inducing weight loss. Side effects of GLP-1 agonists include a decrease in gastric motility, responsible for the nausea commonly experienced by patients (Kendall et al., 2005).
Amylin is a β-cell hormone co-secreted with insulin. Amylin lowers blood glucose levels by inhibiting glucagon secretion following a meal, and induces satiety by acting upon the area postrema (AP) neurons within the brain stem (Potes and Lutz, 2010). While amylin forms aggregates which make it unsuitable as a therapeutic agent, amylin agonists such as pramlintide can effectively simulate the effects of the physiological amylin. Like GLP-1 agonists, amylin agonists can also induce nausea in patients (Schmitz et al., 2004).
2.3. Problems and adverse effects of current drug therapies
As highlighted above, the currently used range of antidiabetic medicines have a number of adverse side effects, including hypoglycaemia, fluid retention and weight gain, and gastro-intestinal symptoms. As T2D generally progresses over time to a worsening in glycaemic control, the need to utilise multiple therapies together is unfortunately the reality for many patients with T2D (Nathan et al., 2006). Difficulties in managing T2D are exacerbated by the fact that the various drugs available have a wide range of effects in individual patients, in terms of the magnitude of both efficacy and side effects. In addition to these factors, many of the current drugs used to treat T2D lose their efficacy over time (Cohen and Horton, 2007). Therefore, the focus of new treatments has to be on how to personally tailor pharmacotherapy to suit each patient’s characteristics.
We believe that the reason why current therapies are not effective in all patients is that they do not address the heterogeneous nature of T2D. A number of different subtypes of insulin resistance have been described, in a number of different tissues and due to varying insults. If effective treatments for T2D are to be developed, there is a need to gain a better understanding of the different subtypes of insulin resistance. Then, the development of new treatment regimes which specifically target the various subtypes of insulin resistance will be possible – enabling the development of a personalised medicine approach to T2D.