The past few decades have seen a substantial rise in the prevalence of diabetes from an estimate of 150 million to 220 million in 2010 and 300 million in 2025 which 90% of the cases are Type 2 diabetes. What is Type 2 diabetes? Type 2 diabetes mellitus is a progressive disease, which is characterized by hyperglycaemia (HbA1c 6.5%) resulting from varying degree of insulin resistance and defects in insulin secretion due to loss of ']-cell function. It results from a combination of both environmental factors such as obesity, physical inactivity and genetic factor.
Why is glycaemic control important?
Patients with Type 2 diabetes have almost double the mortality rate compared with those without as chronic hyperglycaemia is associated with microvascular ( eg. retinopathy, neuropathy, nephropathy) and macrovascular (eg heart disease, stroke, amputations) complications. Fortunately, long term studies have demonstrated that strict blood glucose control with intensive therapy reduces the development and progression of microvascular and macrovascular complications. Each 1% reduction in HbA1c was associated with a 43% reduction in peripheral vascular disease, a 37% reduction in microvascular disease, a 14% reduction in myocardial infarction and a 12% reduction in stroke. We can see from the findings that strict glycaemic control is vital for effective type 2 diabetes management.
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How do we manage Type 2 Diabetes?
Management of type 2 diabetes often involves with initial lifestyle interventions. Lifestyle intervention with modest exercise, dietary modification and weight loss are effective in improving glycaemic control. However, lifestyle measures are often difficult for patients to adopt and maintain. Therefore pharmacological treatment is needed if lifestyle measures did not improve patients'' condition (HbA1c is still '' 6.5%).
Current pharmacological treatment
Metformin is a biguanide that acts independently of pancreas. It primarily effectively improves insulin sensitivity to reduce plasma glucose level. This is done mainly via decreasing hepatic glucose production and increasing glucose utilization by skeletal muscle. Metformin acts particularly in the liver by a reduction in SREBP-1 and ACC (enzyme acetyl-coenzyme A carboxylase) activity. This would regulates gene expression of lipogenic enzyme and hence help regulate fat metabolism in liver. The increased hepatic fatty acid oxidation would then decrease the fat accumulation in hepatocytes and thus improve liver insulin sensitivity (Fig 1).
Metformin is also found to protect pancreatic ']-cell from lipotoxicity. The most effective glycaemic control, with the benefits on body weight and lipid- profile, made metformin a first line drug among different diabetic treatments. (including sulphonylurea, '\-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin and diet.) Besides, when comparing metformin to insulin, chlorpropamide, or glibenclamide, it also showed significantly greater effects with respect to any diabetes related end point. However, metformin caused gastrointestinal side effect like diarrhea and has been contraindicated in patients with history of cardiac disease, hepatic dysfunction and/or renal impairment due to increased risk of lactic acidosis in patients with renal dysfunction and advancing age.
On the other hand, sulphonylurea( which is also known as insulin secretagogues) stimulate']-cell insulin secretion by binding to sulphonylurea receptor (SUR). This closes pancreatic potassium channels, leading to membrane depolarization. As the result, voltage dependent calcium channel (VDCC)open and the subsequent influx of calcium ions triggers insulin secretion(Fig 2). This is how sulphonylurea reduced fasting glucose in type 2 diabetic patients.
Similarity and Differences between sulphonylurea generation
The first generations (eg tolbutamide,chlorpropamide) and the second-generations (eg gliclazide, glibenclamide) of sulphonylurea have been associated with a higher risk of hypoglycaemia compared to the newer sulphonylurea agents: meglitinide class (eg nateglinide,repaglinide)
In fact, the three generations have the same action mechanism (which makes all of them associated with weight gain as the side effects). However, the rates of onset are where they differ. Generally, first and second generations sulphonylurea bind and detach from sulphonylurea receptor more slowly, resulting in a prolonged release of insulin (hyperinsulinaemia) and the higher risk of hypoglycaemia compared to meglitinides which produces rapid, short-lived insulin secretion.
First line treatment: compare metformin and sulphonylurea
The judgment on the use of metformin or sulphonylurea as first line therapy is dependent to their efficacy, cost and safety record (as both were used for more than 50 years). Although both drugs act by lowering fasting glucose levels, sulphonylurea is associated with higher risk of weight gain and hypoglycaemia comparing with metformin. More importantly, metformin is found to have a greater effect compared to the other medications and is therefore justified to be the common first line drug for type 2 diabetes. If metformin is contraindicated, the use of meglitinde would be a recommended choice as the risk of hypoglycaemia is reduced compared to older generations of sulphonylurea.
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Thizaolinediones (TZDs), also known as ''glitazones'' are perixosome proliferator activated receptor '^ agonist (PPAR'^ agonist). It activates PPAR'^ which acts by increasing gene expression regulating glucose and lipid uptake to improve insulin resistance. TZDs also act by shifting adipocytes from visceral to subcutaneous space and this reduces ectopic deposition of free fatty acids (FFA) in the liver and skeletal muscle. Besides that, TZDs increase GLUT4 translocation to cellular membrane thus increasing peripheral glucose disposal. In addition, TZD increases insulin-dependent inhibition of hepatic glucose output. This is how TZDs reduce fasting blood glucose.
TZDs have been found to possess the ability to preserve or improve pancreatic ']cell function because TZDs decrease plasma FFA levels and decrease deposition of FFA as triglyceride in '] cells. As a result, ']cells regranulates and increase in endogenous insulin production is observed.
Current TZDs used on the market are pioglitazone and rosiglitazone. Treatment with pioglitazone or rosiglitazone improves glycaemic control but a Cochrane Review established the use of rosiglitazone and pioglitazone increase the occurrence of oedema. Besides that, other side effects include weight gain, and fractures. Therefore TZDs are contraindicated in patients with history of congestive heart failure or in patients with higher risk of fracture. The withdrawal of troglitazone due to liver toxicity causes concern about liver toxicity being a class effect (although studies do not prove this). That''s why regular monitoring of liver enzyme (every 2-3months) is required at the start of TZD therapy and periodically thereafter.
Second line treatment: The combination of metformin and sulphonylurea OR metformin and TZD?
Concomittant use of metformin and TZD represents an integrated approach to managing type 2 diabetes more comprehensively compared to the combination of metformin and sulphonylurea. Metformin action on hepatocytes (reducing hepatic glucose production) complements TZD actions on the adipocytes (improves body''s insulin sensitivity and increase peripheral glucose disposal), at the same time reducing the side effects of both agents increases both agents'' efficacy. The uses of sulphonylureas are also associated with hypoglycaemia which poses a significant risk for patients (eg elderly, living alone, and working at heights). Therefore, the use of TZD in addition to metformin is considered a better option unless contraindicated.
Exenatide is an injectable GLP-1(glucagon like peptide 1) mimetics. GLP-1 is an incretin hormone that suppresses excess glucagon secretion and stimulates insulin secretion in the postprandial state which is helpful in reducing postprandial hyperglycaemia. GLP-1 also slows gastric emptying and reduces food intake (figure 4). GLP-1 has found to protect ']-cells from apoptosis and promote ']-cells proliferation in vitro. For the reasons above, exenatide is included in the third line therapy as part of the stepwise management of type 2 diabetes. However, exenatide is associated with gastrointestinal side effects.
Third line treatment: Insulin or exenatide?
Comparing the use of insulin and exenatide, exenatide is found to be more effective than insulin glargine or biphasic insulin aspart in reducing postprandial hyperglycaemia. Due to the reason above and the reason that exenatide results in weight loss while insulin results in weight gain, exenatide should be preferable compared to insulin from both the patient and clinician point of view. However, the drawback is exenatide is expensive. Therefore there is a need to weigh the balance between exenatide''s cost and effectiveness.
DPP-IV inhibitor (dipeptidyl peptidase -4)
DPP-IV is the enzyme responsible for rapid clearance and inactivation of GLP-1(figure 4). By inhibiting DPP-IV, the half-life of naturally occurring GLP-1 can be prolonged as postprandial plasma levels of GLP-1 are depressed in type 2 diabetes. Available DPP-IV inhibitors on the market include sitagliptin and vildagliptin. Cochrane Review has found that DPP-IV inhibitors lowers postprandial blood glucose without causing severe hypoglycaemia and no weight gain was observed. However, DPP-IV inhibitors are associated with possible effect on immune system which can be monitored by having regular blood test.
Insulin administration is initiated alone or with combination with oral antidiabetic agents when patient exhibit failure in maintaining glycaemic control even with maximal doses of oral antidiabetic agents. The current available insulin regimens are biphasic, basal and prandial regimens. Since there is no study that compared the various insulin regimens as a whole, it is difficult to know which regimen protocol provides the best results overall. Exogenous insulin regimens have been shown to be beneficial to the patient as it may provide some ''']-cell rest''. However, weight gain correlated with insulin, fear of injection, and reduction in quality of life are the reasons of patients'' unwillingness to start insulin therapy. Patients should not be led to believe that insulin treatment is their last resort which probably causes them to abandon dietary and exercise plans.
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Acarbose interfere with enzymatic action in the small bowel, delaying breakdown of complex carbohydrate thereby slowing glucose absorption. Due to indigested carbohydrate fermented by bacteria in the large bowel, patients experience excess flatulence and diarrhea which is intolerable causing poor compliance. As it only lowers only postprandial and not fasting plasma glucose levels, its efficacy is limited. Acarbose is only considered if patient is unable to use other oral glucose-lowering medication. Serum aminotransferase levels shold be measured every 3months during the first year of acarbose therapy.
Pathophysiology of Type 2 Diabetes
According to De Fronzo''s triumvirate, type 2 diabetes is a glycaemic disorder resulting from three main mechanisms:
i) decrease disposal of glucose in peripheral tissues (insulin resistance)
ii) a defect of ']-cell function
iii) overproduction of glucose by liver
Insulin resistance (IR) plays a fundamental component in the pathophysiology of diabetes. IR occurs when target cells fail to respond to ordinary levels of circulating insulin resulting in increase fatty acid and glucose production. Increase FFA causes serine/threonine phosphorylation on insulin receptor substrate-1 (IRS-1) which reduces insulin-mediated tyrosine phosphrorylation of IRS-1 and cause reduction in GLUT4 translocation to cell membrane thus reducing glucose uptake(figure 5).
Increase in glucose levels, reduction in insulin-stimulated glycogen synthesis, poor suppression of endogenous glucose production and increase lipolysis in visceral fat causes loss of glucose and lipid homeostasis leading to hyperinsulinaemia as higher than normal concentrations of insulin are needed in order to maintain normoglycaemia.
Increase in insulin secretion is compensated by increase in'] cells mass thus maintain near-normoglycaemia with mild increase of blood glucose at fasting and after glucose load which is damaging to '] cell over time.'] cell mass gradually decrease over the course of time due to increase in '] cell apoptosis which might be due to genetic susceptibility, glucose toxicity and lipotoxicity.'] cell decompensate and hypoinsulinaemia occurs therefore body is unable to cope with elevated glucose levels resulting in impaired glucose tolerance, also known as a a prediabetic state.'] cell further deteriorates and insulin resistance pave way to hyperglycaemia of type 2 diabetes.
Future Drug Development
Current antidiabetic drugs are often limited by inconvenient dosage, safety and tolerability issues. Therefore there is a need for new and more efficacious agents, targeting prevention of disease and its progression.
Drug name Mechanism of action
R-Acetohexamide Binds to SURs, causes insulin release
Meglitinide and analogs
Meglitinide, BTS67582 Binds to SURs, causes insulin release
K+ channel openers
MCC134, NN414 Open K+ channels
RX871024, BL11282, S2208, KU14R, RX801080 Close KATP channels, which leads to Ca2+ influx, direct activation of exocytotic machinery; bind to putative imidazoline receptors (I3)
Other non-sulphonylurea insulin secretagogs
JTT608 Promotes the closure of KATP channels without activating SUR
Succinic acid esters Inhibit glucagon secretion, bypass defects in glucose transport, stimulate insulin release
KRP297, MCC555, NC2100, LG100754 Bind nuclear receptor in adipose and other tissues, decrease peripheral insulin resistance
GW501516 Activator of PPAR'_
NN2211, CJC-1131 Stimulate insulin release, inhibit glucagon secretion, slow gastric emptying, stimulate ']-cell proliferation and ductal cell differentiation
Inhibitors of GLP-1 analogs
NVPDPP728 Anti-apoptotic properties
Table 2: Novel treatments for type 2 diabetes.
Novel treatments that are in development for type 2 diabetes are included table 2.
R-acetohexamide, a novel sulphonylurea has been developed as it exhibits a faster onset of action therefore causing a reduced event of hypoglycaemia. Meglitinides analog-BTS67582, have shorter duration of action compared to sulphonylurea, lesser risk of hypoglycaemia and do not cause weight gain. Potassium channel openers (KCO) are also in development as opening of K+ channels reduces insulin secretion which providing ']-cell rest. NN414 was also found to prevent glucose-induced apoptosis in ']-cell in vitro. Imidazolines like RX871024 are being developed as they have been found to be novel insulinotrophic agent that increases insulin secretion in rat pancreatic islets (Table 2) After failure of muraglitazar and tesaglitazar due to increase in death, development of dual agonist PPAR'^/'\ with the hope of combining the effect of PPAR'\ (fatty acid oxidation) and PPAR'^ (glucose lowering) have been proceeded with great caution. Another possible alternative is to create a PPAR'_ agonist, GW 501516 as PPAR'_ activation changes skeletal muscle fuel preference from glucose to fatty acids.
Liraglutide (NN2211) which is a GLP-1 analog with similar mode of action to exenatide is now being appraised by NICE to be used as an adjunct in type 2 diabetes.
Islet cell transplants, use of surrogate ']-cells or gene therapy may be used to increase ']-cells differentiation.
Pancreatic ']-cells dysfunction can be improved by increasing ']-cells apoptosis by drug that reduce oxidative stress induced on ']-cells by lipotoxicity and glucotoxicity.
Combination of GLP-1 mimetics with DPP-IV inhibitor to possibly increase the duration of action with allow decrease in dose for both (reduce side effects for both)
Inhibit protein tyrosine phosphatase 1B (PTP-1B) as PTP-1B is responsible for dephosporylating tyrosine residues on insulin receptor.
Serine/Threonine phosphorylation can be reduced/inhibited or increase tyrosine phosphorylation of IRS-1.
If patients are only treated after type 2 diabetes is diagnosed, there would be the loss of glycaemic control over time even with intensive oral antidiabetic agent due to continuous ']-cell dysfunction and patients often have to resort to insulin regimens.
Through identification and treatment in the prediabetic state, ']-cells function could be restored and hence progression to type 2 diabetes could possibly be prevented. Besides, newer therapeutic agents should focus on the preservation and improvement in ']-cell function in order to slow the progression of type 2 diabetes.
With better knowledge of the underlying molecular defects in the future, possible genetic assessment of patient hopefully would allow personalized treatment of type 2 diabetes.