The World Health Organisation defines diabetes as a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both".2 Symptoms of diabetes type 2 include: unexplained weight loss (although appetite tends to increase); polyphagia (frequently hungry); polyuria (frequently urinating); polydipsia (frequently thirsty); blurred vision; severe fatigue; poor wound healing; dry or itchy skin and onset of recurrent infections such as vaginal yeast infection, groin rash, or external ear infections.3
Diabetes mellitus affects over 150 million people worldwide and of these , type 2 diabetes mellitus (T2DM) counts for the majority of cases. The WHO predicts the prevalence of diabetes will reach >350 million globally by 2030. In the UK alone there are approximately 1.4 million people diagnosed with type 2 diabetes, with a further 1 million having undiagnosed diabetes4.
Insulin is a hormone produced by the pancreas which enables the body to absorb glucose into cells where it is metabolised to produce energy required for numerous processes occurring in the body. The bodyââ‚¬â„¢s inability to absorb glucose into cells results in accumulation of glucose in the blood (hyperglycaemia), which consequently causes various potential medical complications such as microvascular and macrovascular diseases. Microvascular diseases affect primarily the small vessels including retinopathy, nephropathy and neuropathy. Macrovascular diseases affect mainly the large vessels resulting in cardiac, cerebral and peripheral vascular disease.
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There are many forms of diabetes mellitus, of which the most common are type 1 and type 2. Type 1 diabetes mellitus is characterised by an absolute deficiency of insulin secretion due to the autoimmune destruction of the beta cells of the islets of langherhans.
Type 2 diabetes mellitus (T2DM) characterised by insulin resistance(which precedes overt disease) accompanied with an impaired insulin secretion (hepatic) of varying severity. Hyperglycaemia is derived due to inadequate levels of insulin to normalise plasma glucose levels. Type 2 diabetes is more profound in adults and the prevalence increases with age, obesity and lack of physical activity. With the advancement of age, blood glucose level (HbA1C) peak higher than in young adults and in turn take a greater amount of time to return to normal levels. The main reason for this is the increased accumulation of visceral and abdominal fat along with decreased muscle mass with old age.
Treatment of type 2 diabetes also known as non-insulin-dependent diabetes involves various classes of oral medications available used in conjunction with a dietary and exercise regime. First-line treatment involves lifestyle interventions including diet (low in fat, high in fibre and with plenty of starchy foods, fruit and vegetables) and physical activity (e.g. brisk walking). The diabetes prevention program5 showed that lifestyle changes (150 minutes physical activity such as brisk walking per week) and treatment with metformin both reduced the incidence of diabetes in high risk persons (i.e. individuals with elevated fasting and post-load plasma glucose concentrations)5.
Figure National Institute for Health and Clinical Excellence (NICE) guidelines for drug treatment for diabetes mellitus type 21.
Metformin resides from the biguanides class of drugs and is used mainly as first-line oral therapy when the blood glucose level (HbA1C) is >6.5% and lifestyle interventions for a period of 3 months (Fig. 3) in overweight patients. Metformin exerts its effect by decreasing hepatic glucose production (gluconeogenesis) and increasing glucose uptake and utilisation in skeletal muscle, therefore reducing insulin resistance.
It was discovered that metformin activates adenosine monophosphate-activated protein kinase (AMPK), a critical enzyme both in the muscle and hepatically by Zhou and colleagues6. Activation of AMPK leads to the phosphorylation of acetyl-coenzyme A carboxylase (ACC) resulting in inhibition of fatty acid synthesis and subsequent fatty acid oxidation6. Additionally, decreased expression of sterol-regulatory-element-binding-protein 1 (SREBP-1) is also seen, this transcription factor associated with insulin resistance, dyslipidaemia and diabetes7. Decreased expression of SREBP-1 leads to decreased gene expression of lipogenic enzymes resulting in decreased triglyceride synthesis and hepatic stenosis. AMPK activation also causes GLUT4 translocation in the skeletal muscle, where insulin-independent glucose uptake occurs. There is still limited research regarding the mechanism of action of the biguanides regarding the route taken to increase the activity of AMPK.
Two Cochrane reviews8,9 considering the effectiveness of metformin monotherapy compared with placebo or any other antidiabetic agent(s) combined suggested that greater improvement was seen in control of patients glycaemic levels (i.e. HbA1C and fasting plasma glucose) in comparison with placebo or any other active combination (i.e. alpha-glucosidase inhibitors, thiazolidinediones, meglitinides and insulin). Additionally metformin appears to have a beneficial effect(s) other than glycaemic control such as weight loss, or at least no variation on the patients weight. Improved lipid control is also noticed as reduced plasma levels of fatty acids, triglycerides and VLDLs levels are seen. The UK prospective Diabetes Study (UKPDS) showed the metformin group had reduced hypoglycaemia and little or no weight gain than the groups with intensive sulphonylurea or insulin therapy treatment10. Furthermore, a 36% relative risk reduction in all-cause mortality (p-0.01) was observed in the metformin group as well as 39% relative risk reduction in myocardial infarction (p=0.01) in comparison with the conventional group10.
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Sulphonylureas act by augmenting insulin secretion and is the ideal choice for 1st line antidiabetic oral therapy in patients who are not overweight, or in whom metformin is not tolerated or contra-indicated. There are several sulphonylureas available in long-acting form (i.e. chlorpropamide and glibenclamide) and short-acting form (i.e. gliclazide or tolbutamide). Their mechanism of action involves binding to an ATP-dependant K+ (KATP) channel of pancreatic beta cell surface membranes. This blockade leads to depolarisation, Ca2+ entry and insulin secretion, thus increased insulin secretion.
The efficacy of sulphonylurea monotherapy in comparison with placebo saw an average reduction in glycated haemoglobin HbA1C concentrations of about 1.0%-1.5%11. The UKPDS illustrated significant reductions in macrovascular complications linked with improved glycaemic control after intensive glycaemic control with either sulphonylureas or insulin11. The favourable effects of sulphonylureas are observed when other antidiabetic agents are used in combination. In many type 2 diabetics, lower doses of sulphonylureas are associated with better glycaemic control with fewer adverse effects. The UKPDS showed early combination of metformin and sulphonylureas is associated with a significant reduction in both fasting plasma glucose and HbA1C (7.5% vs. 8.1%, P = 0.006) compared with sulphonylurea monotherapy11 which is consistent with the NICE guidelines1. The incidence of the adverse effect, hypoglycaemia is observed in several large clinical trials at 1-2% per year7. Reversal of glycaemic levels is normally easily achieved by consumption of glucose rich beverages and tablets. . A 2.2kg gain was also seen in concordance with sulphonylurea therapy according the UKPDS12.
Insulin replacement therapy is required in type 2 diabetics when other methods to control their hyperglycaemia has failed. Insulin is needed by all patients with ketoacidosis and needed by most patients with: rapid onset of symptoms; substantial loss of weight; weakness; ketonuria and a first-degree relative who has type 1 diabetes according to the British National Formulary (BNF)13. Insulin treatment and its mode of action is identical to endogenous insulin produced by the islets of langherhans as discussed earlier. Intensive insulin therapy using strict research protocols one can expect decreases in HbA1C levels by about 2%. Conversely the UKPDS has failed to show any significant advantage of insulin therapy over oral antidiabetics or vica versa12. A common adverse effect of insulin therapy is hypoglycaemia and weight gain believed to be due to increased truncal fat11. Insulin-treated obese patients with T2DM observed weight gain of 4kg more than patients on lifestyle intervention therapy after 10 years the UKPDS showed12.
Figure Major target organs and actions of orally antihyperglycaemic agents in T2DM7. TZD = thiazolidinedione; FFA = free fatty acid; AGI = alpha-glucosidase inhibitor
Other antidiabetic drugs are available according to NICE guidelines (Fig. 3) and the BNF such as: acarboses, repaglinide, the thiazolidinediones, the dipeptidylpeptidase-4 (DPP-4) inhibitors and exenatide. A meta-analysis of rosiglitazone (thiazolidinedione) vs placebo/comparator an odds ratio for myocardial infarction was 1.43 with significance of 0.03, the odds ratio of cardiovascular death was 1.64 with borderline significance of 0.0614. The statistically significant increase of myocardial infarction and borderline significance in cardiovascular death should encourage clinicians to take into account the potential adverse effects of rosiglitazone and their patients health status when prescribing oral antidiabetics and should be avoided if possible.
Over the past five decades there has been multiple interventions with the aim of improving hyperglycaemic control and hopefully slowing disease progression in type 2 diabetics. Pharmacological therapies have only achieved this to an extent in initial improvements in glycaemic control. However sustained control is not achieved due to the progressive nature of the disease along with associated adverse effects, such as hypoglycaemia, weight gain, gastrointestinal symptoms and peripheral oedema as well as variable effects on beta-cell function and decline15. Other therapies are in development with the potential to address some of the disadvantages of current treatments.
Sodium-glucose transporter-2 (SGLT-2) inhibitors block glucose reabsorption in the renal proximal tubule, thus promoting glycosuria. Decreased serum glucose is seen with increased urinary glucose loss, but the SGLT-2 inhibitors only appear to have this effect in hyperglycaemic states16. To date, hypoglycaemia has not been reported in animal models or human trials. Another beneficial effect seen due to glycosuria is weight loss16 which is very beneficial in type 2 diabetics. Sergliflozin (GlaxoSmithKline) and dapgliflozin (Bristol-Myers Squibb and AstraZeneca) are currently under development from this class.
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Sergliflozin is based on the structure of a GLUT-1 inhibitor, phlorizin which is highly specific for SGLT-2 in its glycated form16. The main effect of sergliflozin was on post-prandial glucose (PPG) with little effect on fasting plasma glucose (FPG), suggesting the use of this agent is linked with a low risk of hypoglycaemia16.
Dapgliflozin has a half-life of approximately 17 hours and almost maximal SGLT-2 inhibition for at least 24 hours with doses of 25-50 mg17, thus suitable for once-daily regimen. It cause dose-dependent glycosuria in healthy subjects with T2DM17. Adverse effects were associated with more genital infections compared to placebo consistent with many trials15.
Glucokinase activators target glucokinase, a glucose-sensing enzyme found in the liver and pancreas. Impaired functioning of this enzyme can cause disease in humans, such as maturity-onset diabetes of the young type 2, providing a possible pharmacological target18.
Figure The role of Glucokinase in glucose homestasis18
Activation of this enzyme promotes hepatic glucose uptake and pancreatic insulin secretion (Fig 3), thus an ideal target for diabetic therapy. Selective activation of liver glucokinase should produce only glucose-dependent effects and reduce potential hypoglycaemia status. In animal trials, the glucokinase activator PSN GK1 improved glucose tolerance and no there was no significant change in body weight or lipids over nine days19. Human trials have shown the glucokinase activator MK-0599 lowers blood glucose in non-diabetic, healthy subjects when given orally20 suggesting potential use as to decrease hyperglycaemia.
Sirtuins are enzymes that are implicated in many diseases associated with advancing age, such as atherosclerosis, and T2DM15. Sirtuin expression is thought to have an association with release of insulin from pancreatic beta cells. Suppression of SIRT1 (an NAD+ dependent deactylase) has shown a possible regulatory effect of SIRT1 on the insulin signalling pathway via deacetylation of the insulin receptor substrate-2 (IRS-2). As suppression of SIRT1 resulted in inhibited insulin-induced tyrosine phosphorylation of IRS-221. Resveratrol (a naturally occurring sirtuin activator) improves the survival of obese mice on a high calorie diet compared with that of normal mice. Improved insulin sensitivity is also seen in diabetic rats.
Glucagon receptor antagonists target the glucagon receptor. Glucagon is released by pancreatic alpha cells, which acts to increase hepatic glucose output, causing an increase in PPG levels. Patients with T2DM exhibit high levels of glucagon. A number of substances have been identified that block the glucagon receptor and a reduced release in glucose is seen with exogenous administration in healthy and diabetic animals as well as healthy humans15. There is a possibility these drugs will provide a further group of medications targeting PPG.
The number of antidiabetic agents is increasing as we develop on our understanding in the underlying pathophysiology of type 2 diabetes. The increasing range of antidiabetic agents/options available, the clinicians now have a duty to the best of their expertise and experience ensuring a patient's T2DM therapy is of optimum effect and reducing the risk of diabetic complications by critically analysing the features of various antidiabetic agents in concordance with NICE guidelines and self belief. In the current climate where we are experiencing diabetics epidemics and it is essential therapeutic target values are reached along with greater awareness of preventative measures. It is important to note that lifestyle interventions remain the emphasis on preventative measures of both T2DM and all other associated possible macrovascular and microvascular complications5.