1. INTRODUCTION:
Diabetes mellitus, often simply referred to as diabetes—is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) 1.
Type 2 diabetes mellitus is a long term disease, characterized by a state of fasting hyperglycemia. Type 2 or adult onset diabetes is a chronic metabolic disorder defined by high levels of glucose in blood due to non-secretion of insulin. According to recent estimates, the world diabetic population could rise to 300 milion by the year 2025 due to contemporary lifestyle and obesity.
The hyperglycemia that characterizes type 2 diabetes mellitus and that promotes the development of complications is a consequence of atleast three metabolic abnormalities: resistance of skeletal muscle, adipose tissue and liver to the action of insulin, inadequate insulin secretion such that glucose is taken up from blood stream into tissues efficiently, and excessive hepatic glucose output2.
Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin and insulin action3. Diabetes mellitus is a heterogenous group of diseases, characterized by a state of chronic hyperglycemia, resulting from a diversity of etiologies, environmental and genetic, acting jointly. The underlying causes of diabetes are the controls of carbohydrate, fat and protein metabolism. Characterstically diabetes is a long-term disease with variable clinical manifestations and progression, chronic hyperglycemia from whatever cause, leads to a number of complications including cardiovascular such as hypertension, renal, neurological such as anxiety, stress, ocular and other such inter-current infections4. Desired blood sugar of human body should be between 70 mg/dl -110 mg/dl at fasting state. If blood sugar is less than 70 mg/dl, it is termed as hypoglycemia and if more than 110 mg /dl, it’s hyperglycemia.
Although it has been primarily regarded as a disorder of glucose metabolism and homeostasis, more recently it has been viewed a constellation of metabolic disturbances. Diabetes is a global burden and is rising all over the world due to various reasons.
There are three main types of diabetes:
· Type 1 diabetes: results from the body's failure to produce insulin, and presently requires the person to inject insulin
· Type 2 diabetes: results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency.
· Gestational diabetes: is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy. It may precede development of type 2 DM.
Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.
All forms of diabetes have been treatable since insulin became available in 1921, and Type 2 diabetes may be controlled with medications. Both Type 1 and 2 are chronic conditions that usually cannot be cured. Pancreas transplants have been tried with limited success in type 1 DM; gastric bypass surgery has been successful in many with morbid obesity and type 2 DM. Gestational diabetes usually resolves after delivery. Diabetes without proper treatments can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, retinal damage. Adequate treatment of diabetes is thus important, as well as blood pressure control and lifestyle factors such as smoking cessation and maintaining a healthy body weight.
1.1 Type 1 diabetes:
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, where beta cell loss is a T-cell mediated autoimmune attack.
1.2 Type 2 diabetes:
Type 2 diabetes mellitus is characterized by insulin resistance which may be combined with relatively reduced insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus due to a known defect are classified separately. Type 2 diabetes is the most common type.
In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity. At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.
1.3 Gestational diabetes:
Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life.
Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
2. GLITAZONES:
The thiazolidinediones, also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.
Fig 1. Thiazolidinedione
The thiazolidinediones and glitazones, specifically targeted to combat insulin resistance, offered a new approach to the treatment of type 2 diabetes as ‘insulin sensitizers’. In December 1997, the first drug from this class, trioglitazone was suspended from marketing the UK due to concerns of drug-induced hepatotoxicity. In June 1998, the National Institute of Health terminated a study investigating troglitazones’s potential for preventing type-2 diabetes due to documented causes of fatal hepatotxicity.
In 1999, two new thiazolidinediones, pioglitazone and rosiglitazone, were approved by the US FDA for the treatment of type-2 diabetes. The incidence of hepatotoxicity appears to be minor with both pioglitazone, rosiglitazone. There are, however, other factors that limit the use of these drugs such as weight gain, congestive heart failure etc. There is, therefore, a need for development of newer and safer drugs from this class.
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma). The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.
By activating PPARγ:
· Insulin resistance is decreased
· Adipocyte differentiation is modified
· VEGF-induced angiogenesis is inhibited
· Leptin levels increase (leading to a decreased appetite)
· Levels of certain interleukins (e.g. IL-6) fall
· Adiponectin levels rise
Mechanism of action of TZDs:
It was shown soon after their discovery that TZDs are agonists of the peroxisome proliferator activated receptors-γ (PPAR-γ). Briefly, after the binding of a TZD to PPAR-γ, the macromolecular complex formed by PPAR-γ and the retinoic acid receptor is able to recruit an activator that allows the DNA transcription of peroxisome proliferator response elements (PPRE; Fig. 2). PPAR-γ is essentially expressed in adipose tissue and controls genes that are mostly involved in adipocyte differentiation and lipid metabolism. This cannot entirely explain the glucose-lowering effect of the drug since adipose tissue accounts for less than 5% of glucose utilization. The explanation of this paradox is that TZDs promote the differentiation of adipose tissue into small adipocytes, which are more insulin-sensitive than large adipocytes and, therefore, release into the bloodstream fewer free fatty acids (FFA), more adiponectin, and less TNF-α, resistin, and leptin. This leads to an improvement in peripheral glucose uptake in the skeletal muscle, a decrease in hepatic glucose production, and an increase in fat storage in adipose tissue5.
Fig. 2 Mechanism of action of TZDs.
3. DRUG RECEPTOR INTERACTION:
Glitazones are agonists for the peroxisome proliferator-activated receptor, PPARγ which regulates the transcription of insulin responsive genes involved in control of glucose production, transport, and utilization. PPARγ agonists such as thiazolidinedione drugs are related carboxylic acids such as farglitazar are effective insulin sensitizers in patients with type 2 diabetes mellitus. Oral administration of PPARγ agonists to these patients reverses hyperglycemia and hyperinsulinemia by increasing glucose metabolism in muscle and reducing glucose biosynthesis in liver.
The peroxisome proliferator-activated receptors (PPARS) are members of the nuclear hormone receptors superfamily. The PPAR subtypes (PPARα, PPARβ, and PPARγ) have been the focus of extensive research during the last decade. Glitazones are pharmaceutical agents that activate the PPARγ receptor and are currently marketed for treatment of diabetes type 2. Indeed in human, Glitazones are insulin sensitizers and low glucose level s. In addition, pioglitazone increases HDL levels (5-10%) and rosiglitazone gives a moderate decrease of TG levels (15-20%). However glitazones induce weight gain as a major side effect and in rare cases promote fluid retention6.
4. GOALS AND TREATMENT:
It has recommended a set of glycemic goals for patients with diabetes, which include a preprandial glucose level of 90 to 130 mg/dL and glycosylated hemoglobin (HbA1c) level of 7% or less7. In addition, the American Association of Clinical Endocrinologists has set even stricter glycemic goals, recommending a preprandial glucose level of 110 mg/dL or less, a postprandial glucose level of 140 mg/dL or less, and an HbA1c level of 6.5% or less8. By attaining these goals, patients may reduce their risk for developing long-term complications. To reach these goals, nonpharmacologic, and often pharmacologic, therapy is necessary. Initial therapy for type 2 diabetes includes an appropriate diet and exercise regimen, because both improve insulin resistance and decrease blood glucose levels. However, many patients also need medications to achieve and maintain the target blood glucose levels recommended above. Currently, there are 5 classes of oral antidiabetic agents with unique mechanisms of action. The 5 classes include the TZDs, biguanides, sulfonylureas, nonsulfonylureas secretagogues, and "-glucosidase inhibitors. The TZDs improve insulin sensitivity and stimulate glucose uptake by muscle and adipose tissue. Biguanides primarily decrease glucose output by the liver. Both the sulfonylureas and nonsulfonylurea secretagogues target! Cells to produce more insulin, whereas the "-glucosidase inhibitors reduce glucose absorption by the gut 10, 11. Because all of these classes can effectively reduce blood glucose levels, the optimal treatment regimen must be individualized based on the patient and severity of the disease. A number of studies shows have shown that thiazolidinediones shows long term glycemic control in patients with diabetes
5. PHARMACOLOGICAL EFFECTS:
5.1 Lipids:
Patients with type 2 diabetes invariably manifest the characteristic triad of dyslipidemia that includes a low plasma HDL, an increase in small, dense low density lipoprotein (LDL) particles, and high triglyceride levels 13, 14. The smaller LDL and HDL particles in patients with insulin resistance may be the result of increased hepatic lipase activity. Therefore, the atherogenicity of LDL cholesterol is enhanced, whereas the cardioprotective properties of HDL cholesterol are decreased15. TZD therapy not only improves insulin sensitivity, but also results in a more favorable lipid profile.
5.2 Blood Pressure:
Patients with type 2 diabetes are at considerable risk for cardiovascular disease, and up to 30% have clinically significant hypertension16. Patients with diabetes are twice as likely to have hypertension as those without diabetes17. In microvascular and macrovascular complications when blood pressure was controlled in patients with diabetes18. In addition to lowering blood glucose levels, TZDs have been shown to improve blood pressure.
5.3 Hemostasis and Fibrinolysis:
A direct correlation exists between insulin resistance and increased levels of plasminogen activator inhibitor type-1 (PAI-1). Levels of PAI-1 are elevated in patients with type 2 diabetes. Increases in PAI-1 concentrations and corresponding inhibition of fibrinolysis indicate alterations in coagulation that may be associated with increased arterial thrombosis. TZDs have been shown to decrease levels of PAI-1, which could lead to beneficial effects on cardiac outcomes. These findings suggest that TZDs may play a critical role in reducing endothelial damage by improving fibrinolytic activity and hemostatic function, which could potentially lead to a decreased risk for cardiovascular events.
5.4 Inflammation and Vascular Effects:
Insulin modulates vasodilatory properties of the vasculature. However, the presence of insulin resistance in individuals with type 2 diabetes diminishes this response19. Treatment with TZDs has been shown to reduce certain proinflammatory markers. TZD therapy are still awaited, the improvement in insulin sensitivity and decrease in inflammatory and hemostatic markers suggest that these agents hold the promise of cardiovascular benefit in patients with diabetes.
6. ADVERSE EFFECTS OF TZDS:
TZDs do not induce hypoglycemias in monotherapy, but they do slightly increase the risk in combination with sulfonylureas. With pioglitazone and rosiglitazone, no cases of severe hepatotoxicity, such as those which led to the withdrawal of troglitazone from the market, have been observed20, and in long-term cohort studies, like the PROactive study, TZDs decreased ALT levels by improving liver steatosis. The main adverse effects of TZDs are related to fluid retention21, which can result in pseudo-anemia, edema, and cardiac failure in patients with underlying heart disease. This has resulted in the restricted use of TZDs in Europe. However, TZDs do not induce cardiac hypertrophy or reduce the cardiac ejection fraction. The mechanism underlying the edema is unclear but probably involves both fluid retention and increased vascular permeability. In the majority of cases, edema is not related to cardiac insufficiency. Another frequent, and possibly limiting, adverse effect is weight gain, which is a consequence of the mechanism of action of TZDs. The average increase in body weight is about 2–3 kg, but it can be much more in some subjects. It generally occurs during the first year of treatment with no further increment. It has been shown to be related to the development of subcutaneous fat with no significant modification or even a trend to a decrease in abdominal fat and, as a consequence, no increase in insulin resistance or loss of therapeutic efficacy22.
7. RECENT TRENDS IN TZD:
Bennett WL et al (2011) concluded that the comprehensive information comparing benefits and harms of diabetes medications can facilitate personalized treatment choices for patients. Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.23
G. Derosa and P. Maffioli (2011) concluded that there are different studies about the efficacy and safety and tolerability of thiazolidinediones added to metformin. The reported improved glycemic control with thiazolidinediones use seems to be associated with an increase in weight with an estimated 2–3 kg weight gain suggesting that maybe thiazolidinediones are not safe for the clinical use. Other authors reported that thiazolidinediones give an improvement in the glycemic without giving weight gain. With our review, we want to evaluate the effects of thiazolidinediones plus metformin combination in diabetic patients on the body weight. From the data emerged from our review we can conclude that even if a small increase in mean body weight was observed in patients treated with thiazolidinediones plus metformin therapy, the weight gain was less than previously reported and it was also considerably less than what might have been expected given the large improvements in glycemic control. For these reasons we can safely say that thiazolidinediones in combination with metformin are effective and well tolerated in patients with type 2 diabetes.24
Baker MA et al (2011) concluded that the diabetes increases the risk of failure and death combined, death, and relapse among patients with tuberculosis. This study highlights a need for increased attention to treatment of tuberculosis in people with diabetes, which may include testing for suspected diabetes, improved glucose control, and increased clinical and therapeutic monitoring.25
Dailey G. (2011) concluded that early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM-multifactorial intervention aimed at controlling CVD risk factors.26
Campbell RK. (2011) concluded that 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.27
Ovalle F. (2010) concluded that a wide variety of agents were available to aid glycemic control in patients with type 2 DM. These agents had variable effects on known CV risk factors that might be present in this patient population, including excess body weight, elevated BP, and increased serum lipids. Some of the newer agents improved glycemic control while also having potentially favorable effects on these CV risk factors. The impact of various agents on known CV risk factors should be considered when selecting a therapeutic regimen.28
Steffens JP (2010) concluded that there may be an interaction between periodontal disease and some systemic diseases such as diabetes mellitus. The objective of this review was to verify, by means of a review of clinical trials, if there is a positive association between periodontal disease and the glycemic control of type 2 diabetes mellitus (DM-2) patients. It was concluded that periodontal disease may influence the metabolic control of DM-2. Additional studies with larger sample sizes and longer follow up are necessary for a better clarification of this issue.29
Parminder S. Chaggar et al (2009) concluded that DM is an independent risk factor for the development of HF and its presence confers an adverse prognosis for those already diagnosed with HF. TZDs are potent insulin-sensitisers associated with a number of beneficial cardiovascular effects. However, TZDs increase renal sodium and water reabsorption, leading to fluid retention and overt signs of HF in patients with diabetes. Rosiglitazone has also been associated with an increased risk of myocardial infarction and cardiovascular mortality. However, pioglitazone may have macrovascular benefits. The majority of data on the cardiovascular safety of TZDs are based on non-cardovascular outcome trials and meta-analyses. Concerns regarding the risk of HF and cardiovascular safety of TZDs have led to restrictions on their use in patients with HF. This review addresses the latest evidence for HF with each of the TZD drugs currently available and reflects on the current guidelines regarding their prescription in at-risk patients.30
Mark C. Granberry et al (2007) concluded that TZDs may be used cautiously in patients with type 2 diabetes mellitus who are at risk for heart failure or who have NYHA functional class I or II heart failure. Patients with NYHA functional class III or IV heart failure should not receive TZDs.31
Vivian A. Fonseca MD (2007) concluded that cardiovascular events in patients with type 2 diabetes mellitus are a major problem in clinical practice, and patients with diabetes have derived less benefit from advances in preventive and interventional cardiology. Tighter goals for metabolic management and attention to nontraditional risk factors may be needed in this patient group. Insulin resistance rather than hyperinsulinemia is thought to underlie cardiovascular disease in patients with diabetes. Insulin resistance is associated with cardiovascular events and a wide range of traditional and nontraditional risk factors for cardiovascular disease (e.g., endothelial dysfunction, dyslipidemia, inflammation, vascular wall abnormalities). Therapy with lifestyle modifications, metformin, or thiazolidinediones (TZDs) corrects many of the abnormalities associated with diabetes in addition to lowering blood glucose and correcting diabetic dyslipidemia. TZDs, acting via the peroxisome proliferator-activated receptor–γ, affect a number of mediators involved in the development of the cardiovascular complications of diabetes, including lipid profiles, vascular changes, and inflammatory mediators. TZDs decrease plasminogen activator–1 and C-reactive protein levels. They also reduce the extent of thickening of the carotid artery and reduce hyperplasia after coronary stent implantation. Insulin-sensitizing therapy with TZDs is a promising intervention for patients with diabetes at risk for adverse cardiovascular outcomes.32
Bernard Charbonnel (2007) concluded that cardiovascular outcome study has been completed and published for the thiazolidines-iones in type 2 diabetes, the PROactive study which demonstrates a strong trend in favour of a specific cardioprotective effect of pioglitazone. The other available data, published as meta-analyses, suggest that there is a difference in this regard between pioglitazone and rosiglitazone.33
Granberry Marc C et al (2007) concluded that the thiazolidinediones (TZDs) in the treatment of patients with type 2 diabetes mellitus and heart failure was conducted. TZDs are antihyperglycemic medications that increase insulin sensitivity and improve the underlying defect of insulin resistance and type 2 diabetes mellitus, and they have the potential to slow or decrease the cardiovascular damage that results from these conditions. TZDs are also implicated in weight gain; however, this is accompanied by an improvement in insulin sensitivity and, therefore, its clinical significance is unclear. Edema has been well characterized in patients treated with TZDs. Edema is more common in patients treated with a TZD in combination with insulin and higher doses of TZDs. Because of the potential for fluid retention and worsening edema, clinical studies have excluded patients with New York Heart Association (NYHA) functional class III or IV heart failure. In patients at risk for heart failure or those who have NYHA functional class I or II symptoms, initiation of therapy should be at the lower dose for TZDs with close monitoring of weight gain, edema, and other signs of worsening heart failure. Conclusion. Current data suggest that TZDs may be used cautiously in patients with type 2 diabetes mellitus who are at risk for heart failure or who have NYHA functional class I or II heart failure. Patients with NYHA functional class III or IV heart failure should not receive TZDs.34
C. Le Feuvre (2004) concluded that beneficial metabolic effects of rosiglitazone are now well established and its adverse events, generally minor or mild well known too. Following a brief review of these metabolic effects and main adverse events, we mainly describe fluid retention (and edema) and the heart failure risk, their risk factors, clinical and diagnosis characteristics, possible pathophysiological mechanisms and the main preventive measures are reviewed. Numerous experimental data and/or preliminary studies in type 2 diabetic patients, including effects on cardiovascular risk factors or markers, justify to conduct a large prospective long term clinical program to assess rosiglitazone effects on cardiovascular morbidity and mortality in type 2 diabetic patients at high cardiovascular risk, these studies are briefly described.35
Robert R. Henry MD (2003) concluded that recent evidence indicates that metformin, pioglitazone, and rosiglitazone may improve the dyslipidemic profile, reduce vascular inflammation, and improve endothelial dysfunction, all of which may be particularly important to physicians seeking treatment options to prevent or reduce cardiovascular complications in patients with type 2 diabetes.36
Harold E Lebovitz (2002) concluded that several classes of antihyperglycemic agents are available for the treatment of patients with type 2 diabetes. These agents, including thiazolidinediones, biguanides, insulin secretagogues, α-glucosidase inhibitors, and insulin, offer differing mechanisms of actions and can be used either alone or in combination. The thiazolidinediones are a newer class of oral antidiabetic agents that improve glycemic control and may preserve β-cell function. Clinical trial data suggest that patients with type 2 diabetes experience progressive deterioration of β-cell function. By decreasing insulin resistance, thiazolidinediones may preserve β-cell function, and patients may experience prolonged glycemic control. The thiazolidinediones also exert beneficial effects on dyslipidemia, endothelial function, coagulation, and blood pressure. By improving these components of the metabolic syndrome, thiazolidinediones may reduce the incidence of both microvascular and macrovascular complications. This article provides an overview of the role of thiazolidinediones in the treatment of type 2 diabetes.37
Steven M. Shaw (2002) concluded that glitazones are a new class of anti-diabetic drugs that act by improving sensitivity to insulin and are indicated in the treatment of type 2 diabetes. The glitazones have effects on carbohydrate and lipid metabolism and hold the promise of being able to influence the many components of the insulin resistance syndrome seen in type 2 diabetes. It is possible that the glitazones may be able to prevent or delay the cardiovascular disease which accompanies type 2 diabetes, long-term studies are required to determine if this is the case. In addition to drug treatment patients with type 2 diabetes should be strongly encouraged to make life style changes which will improve glycaemic control such as weight reduction and increase exercise.38
Clifford J Bailey (2001) concluded that thiazolidinediones (TZDs) rosiglitazone and pioglitazone are new oral antidiabetic agents with `insulin sensitising' activity for the treatment of type 2 diabetes. Rosiglitazone and pioglitazone produce a slowly generated antihyperglycaemic effect which is often accompanied by decreases in circulating insulin and free fatty acids. Circulating triglycerides may also decline, while low-density and high-density lipoprotein cholesterol concentrations are either unchanged or slightly increased, with little alteration to their ratio. The blood glucose-lowering efficacy of TZDs is typically additive or possibly more than additive to the effects of other classes of antidiabetic agents. In Europe rosiglitazone and pioglitazone can be used in combination with metformin or a sulphonylurea, whilst in the USA these TZDs can also be prescribed as monotherapy and pioglitazone in combination with insulin. Because TZDs tend to cause fluid retention they are excluded for patients with cardiac insufficiency. TZDs act via the nuclear peroxisome proliferator-activated receptor-gamma (PPARγ), which mediates the transcription of certain genes that are also responsive to insulin, enabling these agents to improve insulin action.39
Bei B Zhang and David E Moller (2000) concluded that type 2 diabetes is a chronic metabolic derangement that results from defects in both insulin action and secretion. New thiazolidinedione insulin sensitizers have been recently launched. New approaches with mechanisms different from current therapies are being explored, including novel ligands of peroxisome proliferator-activated receptor, glucagon receptor antagonists, dipeptidyl peptidase IV inhibitors, and insulin receptor activators.40
8. SUMMARY AND CONCLUSION:
Type 2 diabetes is a growing epidemic in the United States and is a disease associated with significant long-term complications. An important underlying cause of macrovascular complications is insulin resistance, characterized by a Cluster of metabolic abnormalities known as the metabolic syndrome. The TZDs improve insulin sensitivity and measures of β-cell function. Thereby, these agents not only improve glycemic control, but, moreover, have a sustained durable effect over time. In addition, various studies have shown that TZDs improve lipid profiles and vascular function, potentially reducing the risk of cardiovascular events. Other potential cardiovascular benefits associated with TZD therapy include reduction in blood pressure, improvement in hemostatic parameters, and reduction in inflammatory markers. Currently, several ongoing trials are being conducted to address the role of the TZDs in the prevention and management of type 2 diabetes and associated cardiovascular complications. Because the TZDs provide durable glycemic control with favorable effects on measures of β-cell function and consistent benefit on numerous cardiovascular risk factors, these agents should be initiated early in the course of therapy. So it is concluded that the glitazones are used as oral hypoglycemic agents which gives the effective therapy to the patient who is suffering from diabetes because of their targeted site of action and long term effect.
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Received on 22.10.2011 Modified on 12.12.2011
Accepted on 10.01.2012 © AJRC All right reserved
Asian J. Research Chem. 5(2): February 2012; Page 164-170