Summaries of selected highlights of the 1 st International Congress on ‘Prediabetes’ and the Metabolic Syndrome, Berlin, Germany, April 13-16, 2005

Thursday April 14

08.30-10.30 Plenary session: Setting the scene: glucose intolerance – what’s in a name?
Alberti G, Zimmet P and Ryden L

‘Prediabetes’: a historical context (Summary of an oral presentation by Professor Alberti)

Professor Alberti opened today’s meeting by providing a historical viewpoint on the definition of ‘prediabetes’. Although the exact origin of the term is unclear, the earliest known mention was by Maranon in the early 1940’s, with the first mention in humans from Camerini-Davalos in 1951 in relation to pregnancy. In the 1960’s, ‘prediabetes’ was more familiarly used to describe patients with no glycosuria and a usually normal fasting blood sugar level, but having a diabetic abnormality in standard glucose tolerance tests. In contrast and around the same time, the British Diabetic Association recommended that ‘prediabetes’ should only be used retrospectively to describe the life of a diabetic before their diagnosis was confirmed.

The World Health Organization (WHO) replaced the term ‘prediabetes’ in the 1980’s with statistical risk classes. However, these terms never received wide acceptance and tended to cause patients difficulties both psychologically and with insurance companies. The term impaired glucose tolerance (IGT) was developed in 1979-1980 (NDDG, WHO), and it was only later in 1997 and 1999 (ADA, WHO) that the term impaired fasting glucose (IFG) was developed.

‘Prediabetes’, as it is currently known, owes its re-birth to Tommy G Thompson, the US Secretary of State for Health, who on 27 th March 2002 in the USA used it to describe people with either IGT or IFG, in an attempt to warn Americans of their high future risk of developing diabetes. Professor Alberti confirmed that in 2005 the term was firmly embedded in every day use. However, for the purpose of the Congress, it was in inverted commas since it did not in his opinion yet deserve full official recognition as it is still a slightly peculiar way of describing observed events. This modern use of ‘prediabetes’ solely relates to people with IGT and IFG, and is equivalent to potential diabetes rather than the original use of the term that described a retrospective diagnosis of diabetes.

Professor Alberti concluded by suggesting that whilst conveying a clear message, ‘prediabetes’ could be misleading. This is because it does not include some people at high risk of developing diabetes, for example those with a first-degree family history or in a normoglycaemic risk group, and only half of those with prediabetes will actually develop diabetes.

A global snapshot of ‘prediabetes’ (Summary of an oral presentation by Professor Zimmet)

Professor Zimmet continued the session by providing a global overview of ‘prediabetes’ in terms of isolated impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), or a combination of the two, and highlighted the necessity to conduct an oral glucose test before diagnosing IGT. Prevalence data from a number of countries has generally found that IGT is more prevalent than IFG.

On a global level, the type 2 diabetes epidemic in 2005 comprises of 97 million known cases, and an equivalent number of unknown cases, with around 314 million people having IGT. By 2025, it is estimated this will rise to approximately 500 million people raising concerns about a potential cardiovascular epidemic. From global projections, the major changes will occur in Eastern European states, the Middle East and India.

Professor Zimmet followed this by presenting data from Australia, and highlighted the increasing prevalence of IGT from 1980 to 2000 as recognised by the Australian Diabetes, Obesity and Lifestyle Study. However, additional data from Drs Söderberg and Ramachandran from Sweden and India, respectively, suggest that the ‘prediabetes’ epidemic of IGT/IFG may be reaching a plateau in certain countries.

Professor Zimmet reminded the audience that the mechanisms of IGT and IFG are likely to be different; IFG is thought to be associated with a defect in insulin secretion whilst IGT is thought to be associated with hyperinsulinaemia or insulin resistance. Thus ‘prediabetes’ may encompass two different mechanisms of disease, necessitating the need for further research into both the mechanism and outcome of these two states. In addition, gender differences are evident between IGT and IFG with women generally having a higher prevalence rate of IGT whilst men have a higher prevalence of IFG.

People with IGT or IFG have almost similar cardiovascular disease (CVD) risk levels as people with diabetes. New data from Australia show that both IGT and IFG are associated with a 60-90% increase in mortality compared with normal glucose tolerance (NGT). In addition, some regional variations still exist in terms of rural and urban areas. Both IGT and IFG have similar progression to diabetes, although this risk is increased if a patient has both IGT/IFG. An additional risk for diabetes is associated with increasing waist circumference. The economic cost of diabetes provides compelling evidence for countries to take action to reduce the incidence of ‘prediabetes’. Professor Zimmet illustrated this by describing the increase in renal dialysis due to type 2 diabetes.

Professor Zimmet concluded his presentation by suggesting that globally ‘prediabetes’ is a huge epidemic, is likely to drive a new wave of CVD, and presents a number of research challenges including gender differences, development of strategies to prevent ‘prediabetes’ in different communities, and finding ways of making this cost-effective for developing countries.

A fatal association exists between cardiovascular disease and diabetes (Summary of an oral presentation by Dr Ryden)

In the last presentation of this session, Dr Ryden discussed the fatal association that exists between cardiovascular disease (CVD) and diabetes as seen through the eyes of a cardiologist. People with diabetes generally have a higher risk of mortality than those without diabetes in all age groups. This is predominantly due to CVD, rather than diabetes itself. It has also been noted that there is increased mortality with increased levels of glycated haemoglobin due to CVD and in particular ischaemic heart disease, which has not been observed with other non-cardiovascular causes of disease. Dr Ryden highlighted the importance of early recognition of both diabetes and CVD, and that aggressive treatment to reduce blood lipids, blood pressure and blood glucose in diabetic patients translated into an improved outcome, and the potential to reduce the mortality of diabetic patients to that observed with non-diabetic patients.

From the EURO Heart Survey, which recruited patients with coronary artery disease, 1920 patients were unaware of a diabetic state and following testing by oral glucose tolerance tests, only 42% had normal glucose tolerance (NGT). Around 1 in 5 patients in the coronary care unit were diabetic and had double the mortality of non-diabetic patients. In addition, diabetic patients were very prone to mortality from myocardial infarction (MI), and this was true across all age ranges, although females, especially those of a young age, had a particularly high risk. This leads to the question, why does gender make a difference?

The last part of Dr Ryden’s presentation discussed glucose as a risk factor. From a number of studies, blood glucose at admission to the hospital may potentially predict morbidity and mortality in patients with an MI. In addition, patients with abnormal glucose tolerance after MI have a poorer prognosis than those with NGT confirming that early detection is critical. In a study carried out in Reykjavik between 1967-1991, heart failure was found to start much earlier when diabetes mellitus was diagnosed. Dr Ryden stressed the need to redefine diabetes since patients with ‘prediabetes’ are at similar risk to those with diabetes, potentially due to defects in their β-cells. The diabetic heart has diastolic impairment and a lack of response to injury potentially related to metabolic or vascular factors, and dysglycaemia can be linked to CVD through oxidative stress.

In conclusion, diabetes and CVD are more common than is realised, and the negative impact of dysglycaemia is present before the onset of diabetes. These factors result in poor prognosis, and there is a need for increased attention to these patients. Therapeutic success will depend on collaboration across a number of different therapeutic areas.

11.00-12.30 Plenary session: Are we ready to treat the metabolic syndrome? Alberti G and Grundy S

Definition of the metabolic syndrome (Summary of an oral presentation by Professor Alberti)

Professor Alberti began the session by outlining the history of the definition of the metabolic syndrome. Kylin first described the metabolic syndrome over 82 years ago in a paper highlighting the association between hypertension, hyperglycaemia and hyperuricemia. In the 1940s and 1950s, Vague described the disposition of body fat and its relationship to glucose and other cardiovascular risk factors. In 1967, an abstract presented at the EASD by Avogaro and Crepaldi described the association of several of these risk factors with diabetes. In 1988, Reaven outlined ‘Syndrome X’ and the association between glucose intolerance, hypertension and dyslipidaemia, with insulin resistance suggested as the underlying cause. Since Syndrome X was already in use by cardiologists, the ‘metabolic syndrome’ has emerged as the most durable and popular term for the syndrome. After many studies, several key components of the metabolic syndrome were identified: glucose intolerance, central obesity, hypertriglyceridemia, hypertension, increased Apo B, decreased fibrinolysis, decreased high-density lipoprotein cholesterol ( HDL-C) and increased small dense low-density lipoproteins. The exact aetiology of the metabolic syndrome is not understood but it is a cluster of risk factors for cardiovascular disease and diabetes. Until recently, an exact definition remains elusive since the World Health Organisation (WHO), National Cholesterol Education Program (NCEP), and European Study Group for Insulin Resistance (EGIR) have each published their own definitions, different from each other.

Professor Alberti continued his presentation by discussing the consensus meeting held by the International Diabetes Federation (IDF) in 2004 to update the 1999 WHO definition. It was agreed that central obesity was a prerequisite for the metabolic syndrome, particularly when associated with elevated plasma triglycerides. Low levels of HDL-C, hypertension and high fasting glucose or previously diagnosed diabetes, but not insulin resistance (due to the difficulty of obtaining simple and reproducible measurements), were also agreed as important components of the syndrome.

Professor Alberti then presented the final conclusions of the consensus meeting in relation to specific cut-off points. The cut-off point for waist circumference as a measure of central adiposity was chosen as 94cm (males) and 80 cm (females) for Europeans. However, the importance of ethnic-specific cut-off points for waist circumference as a measure of central adiposity was recognised. Therefore, cut-off points for people from South Asia or China were 90 cm (males) and 80 cm (females) and for Japanese, 85 cm (male) and 90 cm (female). The definition of the metabolic syndrome was agreed as follows:
Central obesity plus any two of the following factors:

• Increased triglycerides >1.7 mM (150 mg/dl)
• Low HDL-C <0.9 mM (40 mg/dl) [males], 1.1 mM (50 mg/dl) [females]
• Raised blood pressure ≥130 mm systolic; ≥85 mm diastolic
• Raised fasting plasma glucose ≥5.6 mM (100 mg/dl) or pre-existing diabetes mellitus or pre-existing abnormal glucose value.

Professor Alberti finished his presentation by describing the next steps that include prospective studies looking at cardiovascular and diabetes outcomes, validation of the cut-off points and detailed studies of components which are candidates to become part of the definition of the metabolic syndrome.

Should the metabolic syndrome cluster be expanded? (Summary of an oral presentation by Dr Grundy)

Dr Grundy expanded upon Professor Alberti’s presentation to discuss other factors closely related to the metabolic syndrome including issues related to pathogenesis. There are multiple metabolic risk factors that are related to metabolic syndrome including atherogenic dyslipidaemia, elevated blood pressure, elevated plasma glucose, the pro-thrombotic state and the proinflammatory state.

In addition to the metabolic risk factors, which are believed to be directly atherogenic, there are underlying risk factors of the metabolic syndrome including obesity, insulin resistance, genetic factors and other factors such as aging, physical inactivity and hormonal factors. It is not known how these underlying risk factors interrelate. However, if pathogenesis and the underlying risk factors are considered, abdominal obesity and insulin resistance are closely related. In the presence of abdominal obesity, there is greater insulin resistance, and insulin resistance stimulates the obese state.

Several studies in people from South Asia were presented to support the hypothesis that primary insulin resistance recapitulates obesity and that they both have the same metabolic effects. Several candidate genes have been proposed as the cause of primary insulin resistance, including one polymorphism associated with insulin resistance and early onset type 2 diabetes.

Dr Grundy concluded his presentation by outlining the different components, which could be measured in future epidemiologic, metabolic and genetic studies including body fat, insulin resistance and other metabolic risk factors, which would help to better define metabolic syndrome.

14.00-15.30 Parallel session: ‘Polylogue’ – the metabolic syndrome
Barter P, Bilheimer D, Greene D, Slama G and Porath A

Fibrates in the treatment of the metabolic syndrome (Summary of an oral presentation by Dr Barter)

The session opened with Dr Barter’s summary of the evidence base for management of the metabolic syndrome. Dr Barter explained that each feature defining the syndrome contributes to an increased risk of cardiovascular disease, and that management of the metabolic syndrome requires a multifactorial approach. This approach includes lifestyle measures to promote weight reduction, anti-hypertensive therapy, and use of statins, fibrates and niacin to treat dyslipidaemia.

There is also compelling circumstantial evidence that fibrates (PPAR-α agonists) reduce the cardiovascular risk associated with metabolic syndrome by actions beyond their effects on plasma lipids. Trial evidence to support this action of PPAR-α agonists such as fibrates is not yet available but in the fibrate endpoint trials, the cardioprotective effect is large in individuals with features of the metabolic syndrome and small in those without. Dr Barter indicated that more definitive information about PPAR-α agonists should become available from the extensive results of the FIELD trial, when announced at AHA Scientific Sessions in November 2005. Dr Barter remarked that these trials provide further circumstantial evidence that the syndrome is a greater entity than the sum of the individual parts used currently to define it, and supports the view that fibrates should be considered along with other medications in patients with the metabolic syndrome.

Pharmaceutical industry view (Summary of an oral presentation by Dr Bilheimer)

Dr Bilheimer discussed the issues facing pharmaceutical companies when developing drugs for the treatment of the metabolic syndrome. He described how the risk of the metabolic syndrome and diabetes can be considered as a series of contributing risk factors which initiate insulin resistance with normal glucose tolerance but after some time this develops into the metabolic syndrome, which then develops into undiagnosed type 2 diabetes and eventually diagnosed diabetes. Cardiovascular risk starts as early as the first step of insulin resistance and continues throughout the course of the progression to diabetes. Therefore there are many challenges for the development of drug therapies, which can be used at different stages of the disease progression.

The rationale for diagnosing and treating the metabolic syndrome is to prevent or delay the onset of coronary heart disease. Furthermore, the early diagnosis and treatment of the metabolic syndrome may also prevent or delay the emergence of type 2 diabetes. There are two options for pursuing indications for drugs to treat the metabolic syndrome; identify drugs which have impact on categorical clinical indications or drugs which have a broad impact on the metabolic syndrome, attacking a common feature that would influence all the major criteria of the metabolic syndrome. This would probably require evidence of a treatment effect for each component of the metabolic syndrome.

If the development of a new drug is successful, there would be several challenges for the pharmaceutical company. The trial design would be difficult since the use of placebo may not be allowed for ethical reasons and the new agent would need to be compared against established therapies. Another challenge for the registration of new drug classes for the metabolic syndrome is that regulating agencies might limit the use of the drug to populations with obvious disease until safety and efficacy have been defined by clinical endpoint trials, while limiting its use in lower risk patients destined to get the disease and its complications later. Such an action would delay studies needed to determine the true preventative aspects of a new therapy in those with early manifestations of the metabolic syndrome.

Dr Bilheimer finished his presentation by summarising the many issues, which are facing pharmaceutical companies during the development of new therapies, particularly for the metabolic syndrome.

Challenges of the metabolic syndrome (Summary of an oral presentation by Dr Greene)

Dr Greene opened his presentation by posing the question: does the endocannabinoid system constitute a potential pharmacologic approach to define and target the metabolic syndrome from a mechanistic and clinical prospective? The endocannabinoid system appears to modulate eating behaviour, is upregulated in chronic obesity and promotes weight gain, lipogenesis, insulin resistance, dyslipidemia and glucose intolerance. Therefore, it may help to refine the definition and potentially the underlying mechanism and treatment of the metabolic syndrome. The key elements of the endocannabinoid system include two endogenous molecules that interact with CB1 and CB2 receptors.

Dr Greene described studies in knockout mice which showed that the endocannabinoid system is the mechanism that permits over-eating. This has also been studied in a number of clinical trials, which also indicate the clinical relevance of these data. In the clinical studies, administration of a receptor antagonist called Rimonabant (which binds selectively to the CB1 receptor) produced consistent weight reduction in 12-month studies, improved high-density lipoprotein cholesterol and triglyceride, increased insulin sensitivity and reduced the prevalence of metabolic syndrome. When the patient population was subdivided into those with, and those without metabolic syndrome, weight loss was the same in both populations but there was better improvement in the peripheral metabolic effects in those patients with metabolic syndrome.

Dr Greene concluded his presentation by reiterating the properties of the endocannabinoid system and suggested that it represents an example of where a drug can help to define and refine the therapy of this disease.

Use of the ‘polypill’ in the metabolic syndrome (Summary of an oral presentation by Dr Slama)

Dr Slama provided a clinician’s viewpoint on the discussion. In diagnosing the metabolic syndrome, physicians must first choose between the numerous definitions proposed by such organizations as the WHO, IDF, EGIR and NCEP-ATP III. Although each is valid, all of the definitions carry the same drawback in that they rely on a series of more or less arbitrary threshold values. When all components of the syndrome are above recognised thresholds, the ‘polypill’ is clearly warranted. However, when all parameters are only slightly disturbed the choice is less clear and three different attitudes may prevail. The ‘regulation-ruled attitude’ is to choose lifestyle modifications alone, as legally the metabolic syndrome does not exist. The ‘academic attitude’ is to await the results of long-term trials designed specifically to compare the relative merits of each definition and to compare the effects of different interventional strategies, before making a decision. Alternatively, clinicians may adopt a ‘proactive attitude’, utilising the polypill before the evidence for its applicability in ‘borderline’ metabolic syndrome is proven.

In spite of the economic burden of his decisions, Dr Slama feels strongly driven towards the ‘proactive attitude’, owing to pressure from the pharmaceutical industry and the bulk of evidence that more and more people are facing increased risk of morbidity and mortality.

Health economic aspects of the metabolic syndrome (Summary of an oral presentation by Dr Porath)

Dr Porath concluded the session by presenting the payers’ and insurers’ viewpoint. He explained that these groups are beginning to recognise the importance of the metabolic syndrome as a risk factor for cardiovascular disease (CVD), but due to limited resources, modern health systems need to incorporate medical management of metabolic conditions into the framework of their global cardiovascular (CV) management priorities.

Only recently, payers have expanded their management programmes to include primary prevention of CVD in high-risk patients, in addition to secondary prevention strategies. Dr Porath warned that even if insurers were willing to include patients with lower levels of CV risk, decisions regarding candidate treatment groups would need to be made. These would be based on the strength of evidence of the potential risks, prevalence or incidence of the metabolic condition, and the potential effectiveness of preventive measures.

Caution is needed to avoid diversion of scarce resources away from other groups, such as those with diabetes, thus compromising their care. Moreover, evidence that population-based intervention is able to reduce CV events and other adverse outcomes over the long term is inconclusive.

14.00-15.30 Parallel session: ‘Prediabetes’ and the metabolic syndrome: characteristics and risks Unwin N and Hanefeld M

IFG and IGT – state of the art (Summary of an oral presentation by Dr Unwin))

Dr Unwin opened this session by explaining that in 1979-1980 the term impaired glucose tolerance (IGT) replaced borderline diabetes, and in 1985 the WHO considered IGT to be a clinical class of glucose intolerance. In 1997 and 1999, the term impaired fasting glucose (IFG) was introduced and both IGT and IFG are used to describe an intermediate stage between normal glucose homeostasis and diabetic hyperglycaemia. In this presentation current WHO definitions were used to describe the epidemiology and metabolic characteristics of IGT and IFG as risk factors for cardiovascular disease (CVD).

From epidemiology studies including DECODE, DECODA and a number of African studies, insulin resistance and IGT both increase with age whilst IFG reaches a plateau with increasing age. In addition, IGT and IFG are highly prevalent but IGT is more common in women whilst IFG is more common in men, and there is poor concordance between them. Dr Unwin commented that it was especially important to note that variations in these trends can exist among different populations, and the analyses may be country specific.

Dr Unwin continued his presentation by discussing the pathophysiology of IGT and IFG in relation to control of fasting glucose, response to glucose load, and the fact that IGT is associated with a greater insulin resistant state than IFG, which is associated with a defect in insulin secretion (debated in the following presentation by Dr Hanefeld). However, the audience should be aware that there are conflicting results that may be due either to true population differences or methodological differences. In terms of IGT and IFG as risk factors for CVD, data has shown that there is little difference in lipid levels or blood pressure between individuals with either isolated IGT or isolated IFG although IGT is associated with a greater risk of CVD typical of the insulin resistant state.

A number of studies have looked at the risk of developing diabetes by investigating glucose tolerance over a 5-6 year period. The risk was similar for isolated IGT and IFG, but higher than for patients with normal glucose tolerance (NGT). If these studies are viewed from the aspect of baseline glucose tolerance, around 40% of patients who developed diabetes showed NGT at baseline. In studies with high analytical power, both fasting and 2-hour glucose levels are associated with CVD and total mortality.

In 2003, the American Diabetes Association Expert Committee proposed lowering the IFG threshold to 5.6 mmol/l. However, this remains controversial and its utility is currently unclear.

Dr Unwin concluded his presentation by summarising the following points: there is a high prevalence of IFG/IGT; limited concordance exists between them; they have potentially different pathophysiology; both are risk factors for diabetes and CVD although IGT may be more sensitive and intervention in patients with IGT has been shown to prevent diabetes but remains unknown for IFG.

IFG and IGT as CV risk factors (Summary of an oral presentation by Dr Hanefeld)

Dr Hanefeld continued this session by discussing the same data as Dr Urwin but with a different interpretation. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are not clinical classifications but are rather risk factors. Each bears a similar risk for conversion to type 2 diabetes but have differences in their demographic epidemiology. IFG is more related to insulin resistance whereas there is a deficit of early phase insulin secretion in IGT (in contradiction to Dr Unwin’s presentation). The NCEP-ATP III definition considers fasting hyperglycaemia and not post-challenge hyperglycaemia as a single trait for the metabolic syndrome.

The Risk Factors in IGT for Atherosclerosis and Diabetes (RIAD) study showed that the level of cardiovascular (CV) risk and prevalence of metabolic syndrome traits is similar for IGT and IFG but evidence from other prospective studies suggests that postprandial or 2-hour post-challenge plasma glucose is a CV risk factor, whereas fasting plasma glucose in IFG is not. Intima media thickening of the common carotid arteries was associated with IGT rather then IFG in the RIAD study, and multivariate analysis identified 2-hour post-challenge plasma glucose as an independent predictor of intima media thickening within a broad spectrum of coronary risk factors. More recent data suggest that oxidative stress and low-grade inflammation may link postprandial glucose excursion with endothelial dysfunction and plaque development.

In summary, Dr Hanefeld presented evidence that IFG and IGT are similar as diabetic risk factors. IGT is more closely related to CV risk therefore it should be considered as part of the ‘glucose trait’ of the metabolic syndrome in its own right. However, it is still unclear what importance IFG has as a risk factor for cardiovascular disease.

16.00-17.30 Parallel session: ‘ Prediabetes’ and the metabolic syndrome in the young Kaufman F and Caprio S

Prevention of childhood diabetes (Summary of an oral presentation by Professor Kaufman)

Professor Kaufman opened the session by remarking that in an ecological model to try to prevent the emerging global epidemic of type 2 childhood diabetes, schools, communities and governments all have a role to play. In the US and other countries, overweight children tend to eat less fruit and vegetables, eat more high fat snacks and fast food, consume greater volumes of sweetened beverages, and participate in lower levels of activity including greater time spent watching television.

In terms of community-based approaches, these could involve environmental change such as the provision of sidewalks and bicycle paths, increasing neighbourhood safety and better urban planning. From a health and medical approach, this involves greater support for patient self-management including the promotion of breast-feeding, healthy eating and physical activity, as well as monitoring changes in risk factors associated with obesity such as blood pressure, lipids and impaired glucose tolerance.

School-based programmes in the US, UK, Japan and Singapore have shown positive effects on adiposity, fitness and metabolic measures when lack of physical activity, consumption of sweetened beverages, and poor nutritional education were targeted. In the UK informing children of the adverse effects of sweetened sodas improved their food choices and led to weight loss, prompting several countries and local governments to regulate the sale of junk food and drink, as well as increasing physical activity programmes and improving health education.

Professor Kaufman continued the discussion with policy issues including those advocated on a federal and local level by the Department of Health Services in the US, and the Los Angeles Unified Schools District program, which she is heavily involved in. Professor Kauffman concluded by suggesting that the global strategy on diet, physical activity and health reported by the WHO in 2004 should be followed to improve youth access to healthy lifestyle choices and prevent type 2 diabetes.

 

Development of childhood diabetes (Summary of an oral presentation by Dr Caprio)

Dr Caprio’s presentation aimed to describe the increased prevalence of childhood obesity and the emergence of type 2 diabetes in children, the prevalence of impaired glucose tolerance (IGT) and the metabolic syndrome in the obese youth, and the mechanism of insulin resistance in obese adolescents. From worldwide epidemiology studies, Hispanic and African adolescents have greater obesity compared with Caucasians. In addition there has been a 10-fold increase in the number of adolescents with type 2 diabetes over the last 20 years and this is associated with significant health problems.

Dr Caprio explained that most, if not all, adults who go on to develop type 2 diabetes have IGT, which is highly predictive of diabetes and cardiovascular disease. However, little is known about the progression of IGT to diabetes in children. Dr Caprio presented data showing that IGT was detected in 20% of a multi-ethnic clinic-based population of children and adolescents with obesity. Studies in obese adolescents also revealed profound insulin resistance, which was the most important risk factor linked to IGT in childhood obesity. Progression of IGT to type 2 diabetes was found to occur very quickly in young people. Factors associated with transition between categories of glucose tolerance included marked weight gain, profound insulin resistance at baseline, and reduced first-phase insulin secretion at baseline.

From a prospective longtitudinal study of IGT in childhood obesity, there was excessive accumulation of intramyocellular fat in the soleus muscle of adolescents with obesity and IGT, compared with age- and adiposity-matched individuals with normal glucose tolerance (NGT). Furthermore, subjects with IGT tended to have more visceral fat and less subcutaneous fat than subjects with NGT. Dr Caprio ended the session by concluding that obesity in youth involves altered partitioning of fat in both skeletal and adipose tissues that is closely linked with changes in glucose homeostasis such as insulin resistance.

16.00-17.30 Parallel session: Epidemiology of ‘prediabetes’ and the metabolic syndrome Shaw J, Chan J, Ramachandran A and Mbanya J

The global view (Summary of an oral presentation by Dr Shaw)

Dr Shaw opened the session by providing a global view of the scale of the problem. Declining levels of physical activity, increasing caloric intake and subsequent rises in the rate of obesity are taking their toll in people of most ethnic and cultural backgrounds.

The country with the highest prevalence of impaired glucose tolerance (IGT), as estimated in 2003, is Nauru and other countries in the Middle East and Gulf States also have fairly high prevalence. When number of cases of IGT are considered, India has the highest number of cases. Dr Shaw described the gender differences in impaired fasting glucose (IFG) and IGT, with IFG being more common in men than women, and IGT is usually more common in women than men. This is probably as a result of glucose values since the mean fasting plasma glucose is higher in men than in women. By contrast, the mean two-hour plasma glucose is higher in women than in men.

‘Prediabetes’ is more common and more uniformly distributed than diabetes, but the epidemiology of the metabolic syndrome has been severely hampered by lack of agreement on its definition. In addition, ethnic differences between the cut-off points for some criteria for the metabolic syndrome have not yet been addressed. For example, different local methods have been used to obtain the cut-off points for central obesity. Dr Shaw explained that this seriously underestimates the problem in Asian populations, who suffer from greater metabolic disturbances for any given level of obesity. However, Dr Shaw commented that despite difficulties in estimating the global prevalence of the metabolic syndrome, its serious implications in terms of the risks of developing diabetes and cardiovascular disease have been acknowledged in most populations.

‘Prediabetes’ and the metabolic syndrome in Asia (Summary of an oral presentation by Dr Chan)

Dr Chan opened her presentation by stating that nearly 50-60% of people with diabetes will come from Asia, in particular from India and China. She then described how the human gene pool may have been unable to cope with changes in both lifestyle and socio-economic status from a hunter-gatherer to a more sedentary way of life. As an example, Dr Chan described Hong Kong, which in less than 100 years has changed from a fishing village to a cosmopolitan city, and during this time has seen a marked increase in diabetes, the metabolic syndrome and obesity.

In China, it is estimated that 60 million patients aged between 35 and 74 have either diabetes or impaired fasting glucose, with men having a higher risk profile. In developed countries, the major increase in diabetes is in the young or middle-aged, and almost 50% are at risk of developing diabetes. Dr Chan continued her presentation by stating that at a BMI of 22–23, 20–30% of people already had one or more risk factors for the metabolic syndrome.

Community based data suggests that current Asian guidelines may be too high since body composition varies compared with Caucasians. Individuals with low socio-economic status and educational levels have a 2–3 times greater risk of developing the metabolic syndrome and diabetes, and conversely people that are well-educated tend to be less likely to smoke, be obese or have a sedentary lifestyle. The presence of a genetic component is evident from the findings that siblings are 3–4 times more likely to have diabetes, obesity, hypertension or central obesity. It has also been found that a dose relationship exists between the number of cigarettes smoked per day and the prevalence of diabetes. A correlation exists between overweight children (aged 9–13 years) and endothelial dysfunction, acting as a warning sign for future problems. In Hong Kong, 2–5% of 12–18 year olds have the metabolic syndrome, with males having a higher prevalence except during puberty.

Dr Chan concluded her presentation by re-capping the points raised above and stressing that the high prevalence of both cardiovascular disease factors and the metabolic syndrome among young and middle aged groups may potentially result in an epidemic of heart and kidney disease. The challenge will be to identify and manage the components of the metabolic syndrome.

‘Prediabetes’ and the metabolic syndrome in India (Summary of an oral presentation by Dr Ramachandran)

Dr Ramachandran presented the Indian viewpoint of the prevalence of prediabetes and metabolic syndrome. He told the audience that both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were highly prevalent in India (8.7% and 8.1%, respectively), with 33% overlap between populations. IGT was common in all areas and at all ages, whereas diabetes was more prevalent in people over 40 years (24%, diabetes vs 15.7%, IGT) with only 5% of diabetic patients aged less than 40 years.

A study, which compared the prevalence of diabetes in rural populations 14 years apart, demonstrated a 3-fold increase, while the prevalence of IGT remained the same. This has important implications since 70% of the population of India is defined as belonging to rural populations.

Dr Ramachandran also explained that IFG was associated with β-cell defects and higher levels of insulin resistance than IGT. He described three studies comparing the prevalence of metabolic syndrome. The studies used different criteria for defining the metabolic syndrome; one used a modified NCEP-ATP III (with a lower the waist circumference), one used the EGIR and one used NCEP-ATP III criteria. The study using the modified criteria demonstrated that 41.1% of urban Indians had the metabolic syndrome compared with 34.1% in the other studies, with advancing age and female gender predicting increased prevalence of the syndrome. As clustering of cardiovascular risk factors are common in both IGT and IFG, high prevalence of these parameters and the metabolic syndrome predict a major public health burden from diabetes and cardiovascular disease in India in the future.

‘Prediabetes’ and the metabolic syndrome in Africa (Summary of an oral presentation by Dr Mbanya)

Dr Mbanya presented prevalence data from Africa, and began by describing the common misconception that there is a low prevalence of type 2 diabetes. In rural sub-Saharan Africa the prevalence of type 2 diabetes is 1–3.5% whilst in urban sub-Saharan Africa the prevalence is 3–7.7%. However, this is greater in some specific sub-populations such as South Africa.

The prevalence of impaired glucose tolerance and impaired fasting glucose varies across different African regions. There are no published studies of the prevalence of the metabolic syndrome in Africa, although a number of studies have published the prevalence of components of the metabolic syndrome in countries such as Cameroon, Tunisia, Nigeria, Gambia, Tanzania and South Africa. Differences in the components of the metabolic syndrome have been found in relation to place of residence, for example, country and rural or urban dwelling, gender, social class, and level of education.

Dr Mbanya concluded his presentation by highlighting the difficulties encountered when trying to compare such studies. These are particularly due to variation in definitions and cut-off levels. In particular, European cut-off levels can not be extrapolated to African studies, and lipid levels may be lower compared with those observed in the rest of the world leading to an underestimation of the prevalence of the metabolic syndrome.

Disclaimer

This report is provided compliments of MSD on behalf of the organisers of the 1 st International Congress on ‘Prediabetes’ and the Metabolic Syndrome. Before prescribing any of the medicines discussed in these presentations please consult the local manufactures’ prescribing information for full details. These views expressed herein are not necessarily are those of Merck & Co., Inc., or its related affiliates.

Copyright © 2005 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.