Rational drug design and PPAR Agonists

Insulin resistance is a characteristic biological abnormality associated with type 2 diabetes, and is a key component of the metabolic syndrome, a condition in which an altered glucose control is associated with dyslipidemia, hypertension, and obesity. Thiazolidinediones (TZDs), a new class of oral drugs used for the treatment of type 2 diabetes, reduce insulin resistance via an action on peroxisome proliferator-activated receptors. Although the current use of TZDs is largely limited to the treatment of patients with diabetes, as recommended in the package insert, it is foreseeable that as the metabolic syndrome becomes a better understood clinical condition their use may be extended to the treatment of this cluster of disorders. The aim of the present article is to review the mechanism of action of TZDs, discuss the rationale for their use in the clinical setting, and provide an update on novel pharmacologic agents that, although not yet available for the treatment of diabetes, are likely to further enrich the repertoire of antidiabetic drugs in the very near future.     

The metabolic syndrome and the liver

Together with the worldwide epidemic proportions of obesity the incidence of 'the metabolic syndrome' is rising across countries. The metabolic syndrome is described as a complex condition that is linked to (intra-abdominal) obesity and is characterized by insulin resistance, dyslipidaemia and hypertension. Several definitions for the metabolic syndrome have been suggested, all trying to identify individuals at high risk for both type 2 diabetes and cardiovascular disease. The primary hepatic complication of obesity and insulin resistance is nonalcoholic fatty liver disease (NAFLD). NAFLD is not included as a component of the metabolic syndrome as it is currently defined; however, data suggest an association. Although the data are mainly epidemiological, the pathogenesis of NAFLD and the metabolic syndrome show common components, with the focus on insulin resistance as a key factor. Even so the treatment of patients with the metabolic syndrome and NAFLD shows a certain degree of similarity, and should focus on the management of associated conditions including obesity, glucose and lipid abnormalities. Lifestyle modifications comprising healthy eating habits and regular exercise are the primary interventions recommended to patients with the metabolic syndrome and those with NAFLD. A pharmacological approach like insulin-sensitizing agents, lipid lowering drugs, antihypertensive drugs and antiobesity agents can be successful in the treatment of certain risk factors that are currently clustering with both the metabolic syndrome and NAFLD. In some cases bariatric surgery may be necessary.     

Relationship between antihypertensive drugs and metabolic syndrome

Metabolic syndrome is a cluster of risk factors associated with an increased risk for cardiovascular disease and type 2 diabetes. Based on data from 1988 to 1994, it is estimated that 24% of adults in the United States meet the criteria for diagnosis of metabolic syndrome. The use of certain medications increases the risk for metabolic syndrome by either promoting weight gain or the development of changes in lipid or glucose metabolism. Diuretics and beta-blockers are among the agents recommended for first-line therapy for hypertension, yet these medications increase the risk of metabolic syndrome. Healthcare providers should recognize and understand the risk associated with antihypertensive agents and should appropriately monitor for changes related to metabolic syndrome. Careful attention to drug choices should be given with patients who are overweight or have other risk factors for diabetes or cardiovascular disease.     

Komplexe diätetische und Pharmakotherapie beim metabolischen Syndrom

Metabolic syndrome is characterized by a group of risk factors (obesity, glucose metabolism disorders, dyslipidemia and hypertension) which appear to be caused by obesity related mechanisms of cellular metabolism and the systemic energy balance. A fibre poor diet rich in fat combined with lack of physical activity are important causative factors. A suitable change in diet combined with regular physical exercise and a moderate weight loss of about 5% leads to a massive reduction in the consequential disease diabetes type 2 by 60% in pre-diabetics and reduces the risk factors for metabolic syndrome. Pharmacological therapies using metformin or acarbose were about half as effective in reducing new cases of diabetes, while thiazolidinedione also led to a 60% reduction in new diabetes cases in pre-diabetics in spite of a weight increase. A sensible and realizable change in lifestyle provides a highly efficient therapy of metabolic syndrome, in addition to effective pharmacological options.     

The metabolic syndrome in Africa: Current trends

Metabolic syndrome is a clustering of several cardiovascular risk factors. Contrary to earlier thoughts, metabolic syndrome is no longer rare in Africa. The prevalence is increasing, and it tends to increase with age. This increase in the prevalence of metabolic syndrome in the continent is thought to be due to departure from traditional African to western lifestyles. In Africa, it is not limited to adults but is also becoming common among the young ones. Obesity and dyslipidemia seem to be the most common occurring components. While obesity appears more common in females, hypertension tends to be more predominant in males. Insulin resistance has remained the key underlying pathophysiology. Though pharmacologic agents are available to treat the different components of the syndrome, prevention is still possible by reverting back to the traditional African way of life.     

Ghrelin, obesity and diabetes

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. The search for drugs to treat these metabolic disorders has, therefore, intensified. The stomach-derived peptide ghrelin regulates food intake and body weight. Recent work suggests that ghrelin also controls glucose metabolism. In addition, current evidence suggests that most of the actions of ghrelin could contribute to the metabolic syndrome. The ghrelin signaling system is, therefore, a promising target for the development of new drugs for the treatment of obesity and diabetes. Agents that block the ghrelin signaling system might be especially useful targets. This Review summarizes the potential and the limitations of ghrelin as a tool to better understand, prevent and treat obesity and diabetes.     

Pre-diabetes, metabolic syndrome, and cardiovascular risk

Pre-diabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Pre-diabetes can be identified as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The latter is detected by oral glucose tolerance testing. Both IFG and IGT are risk factors for type 2 diabetes, and risk is even greater when IFG and IGT occur together. Pre-diabetes commonly associates with the metabolic syndrome. Both in turn are closely associated with obesity. The mechanisms whereby obesity predisposes to pre-diabetes and metabolic syndrome are incompletely understood but likely have a common metabolic soil. Insulin resistance is a common factor; systemic inflammation engendered by obesity may be another. Pre-diabetes has only a minor impact on microvascular disease; glucose-lowering drugs can delay conversion to diabetes, but whether in the long run the drug approach will delay development of microvascular disease is in dispute. To date, the drug approach to prevention of microvascular disease starting with pre-diabetes has not been evaluated. Pre-diabetes carries some predictive power for macrovascular disease, but most of this association appears to be mediated through the metabolic syndrome. The preferred clinical approach to cardiovascular prevention is to treat all the metabolic risk factors. For both pre-diabetes and metabolic syndrome, the desirable approach is lifestyle intervention, especially weight reduction and physical activity. When drug therapy is contemplated and when the metabolic syndrome is present, the primary consideration is prevention of cardiovascular disease. The major targets are elevations of cholesterol and blood pressure.     

Prevalence of obesity, glucose homeostasis disorders and metabolic syndrome in psychiatric patients taking typical or atypical antipsychotic drugs: a cross-sectional study

Aims/hypothesis Atypical antipsychotic drugs may be associated with obesity and other components of the metabolic syndrome, but this relationship is controversial. We investigated the hypothesis that atypical antipsychotics are associated with a greater degree of metabolic dysfunction than typical agents.Methods Metabolic parameters were measured in 103 diagnostically heterogeneous psychiatric out-patients. Patients had been taking typical or atypical antipsychotic drugs for a minimum of six months.Results Sixty-nine patients were taking atypical agents, 20 typical agents and 14 a combination. Mean values (±SD) for the whole group were: age 43.8 years (11.4); BMI 29.1 kg/m² (5.1); W:H ratio 0.88 (0.09). Metabolic parameters, including beta cell function and insulin sensitivity, measured by HOMA, did not differ with regard to the prescribed antipsychotic drug. Six patients had undiagnosed diabetes, six patients had impaired fasting glucose, and eight fulfilled criteria for the metabolic syndrome, all of whom were taking atypical agents (p=0.07 vs typical agents). Subgroup analyses of those taking atypical agents revealed differences in BMI (mean, ±SD) between olanzapine (27.3 kg/m²±5.1) and quetiapine (31.9 kg/m²±5.1), p=0.01, and HbA_1c (olanzapine, 5.1%±0.6 vs quetiapine, 5.6%±0.6; p=0.03). Other atypical agents were intermediate with regard to these parameters.Conclusions Obesity, dyslipidaemia and abnormalities of glucose homeostasis are prevalent in this group. Patients taking atypical agents showed a trend towards abnormalities of glucose homeostasis. Prospective studies are needed to explore the precise relationship between antipsychotic drugs, glucose homeostasis, obesity and the metabolic syndrome.These data were presented at the North American Association for the Study of Obesity Annual Scientific Meeting, Las Vegas, November 2004.     

Challenges in developing drugs for the metabolic syndrome

Metabolic syndrome refers to a clustering of established and emerging cardiovascular disease (CVD) risk factors within a single individual. The established risk factors—such as obesity, diabetes, dyslipidemia, hypertension—and other emerging risk factors are closely related to central obesity (especially intra-abdominal adiposity). Insulin resistance is also an important factor in this syndrome’s etiology. However, despite the potential use of having all the CVD risk factors under an umbrella diagnosis of metabolic syndrome, debate continues about the very existence of the metabolic syndrome. Despite the controversies, many existing therapies and new drugs in development are targeting the metabolic syndrome. To date, no drugs are approved specifically for treating the metabolic syndrome. This article discusses some of the challenges in developing therapies for the metabolic syndrome.     

Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders

Type 2 diabetes mellitus and obesity have reached epidemic proportions in many developing and developed nations, leading to talk of the "twin epidemics." The latest projections from the International Diabetes Federation suggest that 190 million people worldwide currently have type 2 diabetes. In addition, > or = 300 million people worldwide have impaired glucose tolerance (IGT). These statistics represent an epidemic of major proportions--possibly the largest epidemic in human history--in terms of glucose intolerance and cardiovascular disease (CVD) risk because individuals with IGT are at substantially higher risk for diabetes and CVD than are members of the general population. Along with IGT, the metabolic syndrome comprises other major CVD risk factors, including insulin resistance, central obesity, and dyslipidemia; insulin resistance has been implicated as the single most common cause of the syndrome. Although the exact prevalence of the metabolic syndrome is unknown, the syndrome is widespread among adults in developed nations, becoming more prevalent with age. Epidemiologic data suggest that in patients with schizophrenia or affective disorders, both diabetes and obesity are 1.5 to 2.0 times more prevalent than in the general population. Furthermore, because adverse effects of certain therapies for human immunodeficiency virus (HIV) infection and psychiatric disorders increase the risk for developing diabetes, obesity, and the metabolic syndrome, such therapies should be carefully chosen, particularly considering CVD risk. Appropriate therapy may be determined via screening of patients for levels of fasting blood glucose and lipids, as well as other CVD risk factors, before initiating use of second-generation antipsychotic agents or highly active antiretroviral therapy.     

Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds.

The metabolic syndrome is a constellation of risk factors of metabolic origin that are accompanied by increased risk for cardiovascular disease and type 2 diabetes. These risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. The two major underlying risk factors for the metabolic syndrome are obesity and insulin resistance; exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. The condition is progressive, beginning with borderline risk factors that eventually progress to categorical risk factors. In many patients, the metabolic syndrome culminates in type 2 diabetes, which further increases risk for cardiovascular disease. Primary treatment of the metabolic syndrome is lifestyle therapy--weight loss, increased physical activity, and anti-atherogenic diet. But as the condition progresses, drug therapies directed toward the individual risk factors might be required. Ultimately, it might be possible to develop drugs that will simultaneously modify all of the risk factors. At present such drugs are in development but so far have not reached the level of clinical practice.     

Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds

The metabolic syndrome is a constellation of risk factors of metabolic origin that are accompanied by increased risk for cardiovascular disease and type 2 diabetes. These risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, a prothrombotic state, and a proinflammatory state. The two major underlying risk factors for the metabolic syndrome are obesity and insulin resistance; exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. The condition is progressive, beginning with borderline risk factors that eventually progress to categorical risk factors. In many patients, the metabolic syndrome culminates in type 2 diabetes, which further increases risk for cardiovascular disease. Primary treatment of the metabolic syndrome is lifestyle therapy--weight loss, increased physical activity, and anti-atherogenic diet. But as the condition progresses, drug therapies directed toward the individual risk factors might be required. Ultimately, it might be possible to develop drugs that will simultaneously modify all of the risk factors. At present such drugs are in development but so far have not reached the level of clinical practice.     

Metabolic syndrome: diabetes and cardiovascular disease

Metabolic syndrome is a complex constellation of risk factors which predispose to diabetes and coronary heart disease. Various components of the metabolic syndrome are: abdominal obesity, impaired glucose regulation, dyslipidemias and hypertension. Insulin resistance and obesity are characteristics of metabolic syndrome. The risk factors predispose to the development of type 2 diabetes and atherosclerosis. Changes in the life style, reduction of obesity and food habits are fundamental in reducing the risk factors. Some patients may, however, require pharmacological intervention for the control of hyperglycemia, obesity, hypertension and dyslipidemias.     

The metabolic syndrome during atypical antipsychotic drug treatment: mechanisms and management

The frequency of obesity, insulin resistance, type 2 diabetes mellitus and other components of metabolic syndrome appear to be significantly elevated in some psychiatric patients. This is a notable example of genetic/environment interaction. Considering the genetic contribution, evidence of insulin resistance in persons with schizophrenia was reported in the pre-pharmacological era. High insulin, glucose, and cortisol levels are observed in first episode psychosis. The frequency of type 2 diabetes mellitus is significantly increased in persons with schizophrenia and bipolar disorder and in their first-degree relatives. Finally, a link exists between schizophrenia and enzymes involved in glycolysis and between antipsychotic drug-induced weight gain and serotonin receptor polymorphism. Important environmental factors are poor dietary habits, smoking, lack of physical exercise, and drug treatment, mostly with antipsychotic drugs (APDs) and perhaps with mood stabilizers. The APDs probably induce metabolic dysfunction by producing sudden appetite increase and weight gain in predisposed subjects. However, direct drug effects on glucose and lipid metabolism independent from body weight change have been proposed. Excessive weight gain is mainly observed with clozapine, olanzapine, chlorpromazine, and thioridazine and is less consistently noted with risperidone or quetiapine. Two recently introduced APDs, ziprasidone and aripiprazole, display a neutral effect on weight and metabolism. Subjects at high risk must be identified early during APD treatment so that provide lifestyle counseling and pharmacological assistance can be provided. The immediate research agenda for the APDs is to improve the animal models of drug-induced metabolic dysfunction; to clarify mechanisms other than weight gain and appetite stimulation; and to test pharmacological agents in randomized, double-blind studies to prevent or reverse metabolic syndrome in selected patients.     

Prevalence of diabetes mellitus, hyperinsulinaemia and metabolic syndrome among 755 adult patients with HIV-1 infection

Metabolic complications of antiretroviral therapy in HIV-infected patients include insulin resistance, diabetes mellitus, dyslipidaemia and lipodystrophy syndrome. Metabolic syndrome is an aggregation of central obesity with glucose and lipid metabolism alterations that confers an increased risk of cardiovascular disease, which reproduces the antiretroviral-associated metabolic and morphological abnormalities. In this study, we report the prevalence of diabetes mellitus, hyperinsulinaemia and metabolic syndrome among 755 adult patients with HIV-1 infection referred to our outpatients unit. The prevalence of diabetes mellitus and metabolic syndrome was 4.5% and 9.1%, respectively. A longer exposure to antiretroviral therapy and a diagnosis of lipodystrophy syndrome were significantly associated with both metabolic disturbances.     

Bone metabolism in metabolic syndrome and its treatment

Metabolic syndrome has recently been identified to be involved in the development of multiple diseases, such as type 2 diabetes (or glucose intolerance), dyslipidemia and hypertension. Its principal features are obesity and insulin resistance. Bone metabolism is a complex process that is regulated by complicated local and systemic factors. Recent investigations demonstrate an involvement of sympathetic nervous system and glucose and lipid metabolism in bone metabolism. Obesity and insulin resistance may favor bone dynamics, whereas diabetes and dyslipidemia may not. More importantly, various drugs for these disorders have been reported to have beneficial effects on bone health. On clinical situation to manage metabolic syndrome, physicians may want to evaluate outcome of their practice for bone metabolism.     

Metabolic syndrome as a predictor of type 2 diabetes,and its clinical interpretations and usefulness

Metabolic syndrome is defined as a cluster of glucose intolerance, hypertension, dyslipidemia and central obesity with insulin resistance as the source of pathogenesis. Although several different combinations of criteria have been used to define metabolic syndrome, a recently published consensus recommends the use of ethnic‐specific criteria, including waist circumference as an indicator of central obesity, triglyceride and high‐density lipoprotein (HDL) cholesterol as indicators of dyslipidemia, and blood pressure greater than 130/85 mmHg. The definition of dysglycemia, and whether central obesity and insulin resistance are essential components remain controversial. Regardless of the definition, the prevalence of metabolic syndrome is increasing in Western and Asian countries, particularly in developing areas undergoing rapid socioenvironmental changes. Numerous clinical trials have shown that metabolic syndrome is an important risk factor for cardiovascular disease (CVD), type 2 diabetes mellitus and all‐cause mortality. Therefore, metabolic syndrome might be useful as a practical tool to predict these two major metabolic disorders. Comprehensive management of risk factors is very important to the improvement of personal and public health. However, recent studies have focused on the role metabolic syndrome plays as a risk factor for CVD; its importance in the prediction of incident diabetes is frequently overlooked. In the present review, we summarize the known evidence supporting metabolic syndrome as a predictor for type 2 diabetes mellitus and CVD. Additionally, we suggest how metabolic syndrome might be useful in clinical practice, especially for the prediction of diabetes.     

Psychotropic drug considerations in depressed patients with metabolic disturbances

Depression, obesity, diabetes mellitus, and the metabolic syndrome are conditions commonly treated in primary care. The prevalence of each condition separately does not explain the frequency of their co-occurrence. Depression may lead to or exacerbate these endocrine and metabolic conditions. Conversely, these medical conditions may lead to or exacerbate depression. Psychotropic drugs that treat depression may increase appetite with resultant weight gain. Rarely, such agents may be associated with weight loss. We review the potential for psychotropic drugs to alter body weight and provide a table as a guide to drug selection. Unless circumstances dictate otherwise, clinicians should select psychotropic drugs least likely to induce weight gain when treating depressed patients with obesity, diabetes mellitus, or the metabolic syndrome. Even drugs generally thought to be “weight neutral” may occasionally be associated with weight gain. Thus, alerting patients to this potential and due diligence form the cornerstone of weight management in the depressed patient.     

Guidelines Updates in the Treatment of Obesity or Metabolic Syndrome and Hypertension

Obesity and overweight are nowadays very prevalent worldwide. They are known to be linked with an increased risk of developing cardiovascular comorbidities and mortality. Abdominal obesity is frequently associated with a collection of metabolic disorders that include elevated blood pressure, characteristic lipid abnormalities (low high-density lipoprotein cholesterol and high triglycerides) and increased fasting glucose, with an underlying situation of insulin resistance, which has been defined as metabolic syndrome, conferring a high cardiovascular risk profile to these subjects. A multidisciplinary approach is required, including lifestyle changes and pharmacological and surgical approaches. Intensive management of all the risk factors of the metabolic syndrome is also needed to reduce body weight and waist circumference, lessen insulin resistance and avoid the development of new-onset diabetes and cardiovascular disease associated with this entity. This article will review the recently published literature and guideline updates on this topic, although it is not yet included in the highlights.     

Pregnancy Complications and the Risk of Metabolic Syndrome for the Offspring

Metabolic syndrome is a growing problem globally, and is a contributor to non-communicable diseases such as type II diabetes and cardiovascular disease. The risk of developing specific components of the metabolic syndrome such as obesity, hyperlipidemia, hypertension, and elevated fasting blood sugar has been largely attributed to environmental stressors including poor nutrition, lack of exercise, and smoking. However, large epidemiologic cohorts and experimental animal models support the “developmental origins of adult disease” hypothesis, which posits that a significant portion of the risk for adult metabolic conditions is determined by exposures occurring in the perinatal period. Maternal obesity and the rate of complications during pregnancy such as preterm birth, preeclampsia, and gestational diabetes continue to rise. As our ability to reduce perinatal morbidity and mortality improves the long-term metabolic consequences remain uncertain, pointing to the need for further research in this area.