E. A. M. Gale

The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation

This article presents the conclusions of a WHO Expert Consultation that evaluated the utility of the ‘metabolic syndrome’ concept in relation to four key areas: pathophysiology, epidemiology, clinical work and public health. The metabolic syndrome is a concept that focuses attention on complex multifactorial health problems. While it may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool. Further efforts to redefine it are inappropriate in the light of current knowledge and understanding, and there is limited utility in epidemiological studies in which different definitions of the metabolic syndrome are compared. Metabolic syndrome is a pre-morbid condition rather than a clinical diagnosis, and should thus exclude individuals with established diabetes or known cardiovascular disease (CVD). Future research should focus on: (1) further elucidation of common metabolic pathways underlying the development of diabetes and CVD, including those clustering within the metabolic syndrome; (2) early-life determinants of metabolic risk; (3) developing and evaluating context-specific strategies for identifying and reducing CVD and diabetes risk, based on available resources; and (4) developing and evaluating population-based prevention strategies.

Does diabetes therapy influence the risk of cancer

Type 2 diabetes is associated with three of the five leading causes of cancer mortality in the USA—carcinoma of the colon, pancreas and breast (postmenopausal) [1]. The excess risk for each cancer is ~30% (colon), ~50% (pancreas) and ~20% (breast) [2–4]. Type 1 diabetes carries an excess cancer risk of ~20%, but involves a different range of tumours [5]. The major cancers linked with type 2 diabetes are also associated with obesity or insulin resistance, suggesting that factors other than glucose play an important role [6]. These observations, although wellattested, have attracted relatively little interest within the world of diabetes. This is partly due to the dominant role of cardiovascular disease, which largely accounts for the twofold increase in mortality associated with type 2 diabetes [7], and partly, perhaps, because cancer has seemed unavoidable. The latter assumption can no longer be considered correct, for several studies have shown metformin to be associated with a lower risk of cancer than insulin or sulfonylureas [8–10]. Bowker and colleagues examined the relationship between diabetes treatment and mortality in a health database from Saskatchewan, and found that cancer mortality was almost doubled among insulin users (HR 1.9, 95% CI 1.5–2.4, p<0.0001) relative to metformin users, and that sulfonylureas were also associated with increased mortality (HR 1.3, 95% CI 1.1–1.6, p=0.012) [9]. A study published in this issue of Diabetologia confirms these observations, while showing that cancer risk in metformintreated patients is similar to that in patients who have not as yet received medication for diabetes. Furthermore, the paper suggests that the effect of metformin may be tumour-specific, in that its use was associated with a reduced risk of cancer of the colon and pancreas, but not of cancer of the breast or prostate [10]. The antitumour effect of metformin seems to be mediated via its ability to increase the AMP-activated protein kinase (AMPK) signalling pathway [11]. AMPK, which is activated by a rise in the AMP:ATP ratio, plays a key role in cellular energy balance. Activation restores levels of ATP by switching on ATP-generating pathways and switching off ATP-consuming pathways, and this enzyme is thought to mediate many of the metabolic actions of metformin [12]. Increased AMPK activity also leads to an inhibition of the downstream mammalian target of rapamycin (mTOR) complex; mTOR kinase integrates U. Smith The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Goteborg, Sweden

Lessons from the glitazones: a story of drug development

Troglitazone, the first in the thiazolidinedione class of oral hypoglycaemic agents, was launched in the USA in March, 1997. It reached Europe later that year, only to be withdrawn within weeks on the grounds of liver toxicity. Meanwhile it went on to generate sales of over

Spring harvest? Reflections on the rise of type 1 diabetes.

2 billion in the USA, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was withdrawn in March, 2000. Rosiglitazone and pioglitazone reached the US market in 1999 as first-line agents to be used alone or in combination with other drugs, but in Europe the same dossiers were used one year later to apply for a limited licence as second-line agents restricted to oral combination therapy. How should we use the glitazones? And how did they achieve blockbuster status without any clear evidence of advantage over existing therapy?

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

Childhood diabetes appears to have been a relatively rare disorder in Europe and North America in the first half of the 20th century, with incidence rates comparable to those seen in some Asian populations today. The incidence began to rise around the middle of the twentieth century, and an increase has been documented since then in many populations around the world [1]. For example, between 1989 and 1998, there was an overall year-on-year rise of 3.2% across Europe, equivalent to a doubling time of 25 years, and the most rapid relative increase was in children under the age of 5 years. Central and Eastern Europe, previously regions with a low incidence, now showed a rapid increase, suggesting a possible catch-up phenomenon [2]. A change of this magnitude in relatively stable populations cannot be explained by the increased transmission of diabetes susceptibility genes from one generation to the next, and strongly suggests some form of environmental influence.

Nice insulins, pity about the evidence.

Aims/hypothesisTo set up a clinical trial to establish whether nicotinamide can prevent or delay clinical onset of Type 1 diabetes.MethodThe European Nicotinamide Diabetes Intervention Trial is a randomised, double-blind, placebo-controlled intervention trial undertaken in 18 European countries, Canada and the USA. Entry criteria were a first-degree family history of Type 1 diabetes, age 3–40 years, confirmed islet cell antibody (ICA) levels greater than or equal to 20 JDF units, and a non-diabetic OGTT; the study group was further characterised by intravenous glucose tolerance testing, measurement of antibodies to GAD, IA-2 and insulin and HLA class II genotyping.ResultsICA screening was carried out in approximately 30,000 first-degree relatives. A total of 1004 individuals fulfilled ICA criteria for eligibility, and 552 (288 male) were randomised to treatment. Of these, 331 were aged less than 20 years (87% siblings and 13% offspring of the proband with diabetes) and 221 were 20 years of age or more (76% parents, 21% siblings and 3% offspring). Oral glucose tolerance was normal in 500 and impaired in 52 (9.4%), and first phase insulin response in the IVGTT was below the 10th centile in 34%. Additional islet autoantibodies were identified in 354 trial entrants. Diabetes-associated HLA class II haplotypes were found in 84% of the younger age group and 80% of the older group. The protective haplotype HLA-DQA1*0102-DQB1*0602 was found in 10% overall.Conclusions/interpretationENDIT has shown that a trial of an intervention designed to halt or delay progression to Type 1 diabetes can be carried out on a multinational collaborative basis, as and when potentially safe and effective forms of intervention become available. Primary screening with biochemically defined autoantibodies will substantially reduce the number of lower risk individuals to be included in future intervention trials

Cancer and diabetes: are we ready for prime time?

In February 2006 the German Institute for Quality and Efficiency in Healthcare (IQWiG), an independent body with a mandate to assess the evidence for medical interventions, released its final report on the use of short-acting insulin analogues in the treatment of type 2 diabetes. The report found no advantage over soluble (regular) human insulin. Given that analogues cost more than soluble insulin, the report concluded that there was no evidence to support their use in patients with type 2 diabetes [1]. A subsequent report concluded that the benefits of shortacting analogues in type 1 diabetes were marginal at best [2], and a report on the long-acting analogues is on its way: many suspect that this will be almost equally negative. Although some have taken issue with the way in which the analysis was performed, for reasons to be discussed later, the conclusions of the initial report were not unexpected. It was not so much the advice that provoked controversy as the fact that it was acted upon: healthcare purchasers decided that they would no longer reimburse the costs of short-acting analogues prescribed for patients with type 2 diabetes. The response from some industry representatives, patient bodies and clinicians was one of predictable outrage. From the point of view of industry, the German pharmaceutical market is worth 37.8 billion euros per year [3], third only in importance to those of the USA and Japan, and analogues have a larger share of insulin sales in Germany than anywhere else in the world. Patients were affected at a more personal level, for many link their safety and well-being to an insulin formulation that suits them, and feel threatened if someone proposes to take this away. Some physicians were equally displeased, for clinicians notoriously dislike challenges to their autonomy and judgement. Add to this volatile mix the fact that some (but by no means all) patient organisations and clinicians are well-funded by industry, and you have a recipe for trouble. Most of the anger was directed towards IQWiG, and the debate that followed was loud and sometimes ugly. Peter Sawicki, Chairman of IQWiG, had his name dragged through the media. A petition to the government protesting at the withdrawal of the analogues was signed by 180,000 patients, and ‘independent’ commentators duly appeared in the media to discredit the report [4]. The outcome was revealing. The insulin manufacturers denied the evidence, but they did not dispute it. Instead, they simply opted to reduce the price of their quick-acting analogues to match that of human insulin, and the concerns of the healthcare providers melted away. Story over? Not quite.

To boldly go--or to go too boldly? The accelerator hypothesis revisited

From time to time workers in apparently unrelated fields look sideways to discover that others are working on the same problem from a different angle. This happened recently when investigators in diabetes and cancer found that they were exploring much the same territory, a discovery triggered in part by publications in this journal last year [1–5]. Controversial though some of the reports have proved, the effect has been an explosion of interest in this previously underexplored area. The result has been an increased appreciation of the intimate connection between metabolism, cell growth and turnover, together with new observations that may come to influence clinical management of diabetes. An association between diabetes and cancer was first reported as an incidental finding in 1932, in a paper stating that ‘it would appear that either diabetics tend to develop cancer or that cancer patients tend to develop symptoms recognised as diabetic’. Cancers of the uterus, pancreas and intestine already featured on the list of associated tumours [6]. Later reports, in contrast, suggested a lower mortality rate from cancer relative to the non-diabetic population because patients with diabetes died earlier from vascular disease [7]. Nonetheless, clinical observation continued to suggest an excess risk of endometrial and pancreatic cancer, but the nature and extent of the association between type 2 diabetes and a range of cancer types only became clear when large-scale cancer registries began to report their findings. The ADA and the American Cancer Society (ACS) responded to the concerns raised in this journal by holding a meeting (in conjunction with the EASD and the European Cancer Organization) in Atlanta in December 2009. The aims were to analyse the current state of knowledge concerning cancer and diabetes, and to identify the most important gaps in understanding [8, 9]. The meeting focused on four key questions, as follows:

GLP-1 based agents and acute pancreatitis

Biological science notoriously leads us into a world of increasing complexity, and concepts that purport to rearrange familiar observations into a new and simpler pattern therefore merit careful consideration. Such is the accelerator hypothesis, proposed by Terry Wilkin [1]. In this issue of Diabetologia, Wilkin provides a brief review of his hypothesis, and explores some of its implications for the classification of diabetes [2]. The accelerator hypothesis proposes that the conditions we call types 1 and 2 diabetes are for practical purposes one and the same. Whilst conceding that the aetiology of beta cell damage may differ, the hypothesis postulates that superimposed insulin resistance then drives both forms of diabetes down the same pathway to end-stage beta cell failure. The difference between the two types of diabetes lies in their rate of progression, which is determined by three accelerators. First comes constitution, for the hypothesis postulates that individuals predisposed to diabetes have an intrinsically high rate of beta cell apoptosis. Even so, diabetes is unlikely to develop unless one or both of the remaining accelerators are encountered. The most important of these is insulin resistance. Fuelled by physical inactivity and visceral weight gain, this accelerates beta cell apoptosis and the onset of diabetes. The other accelerator, operative only in those who also have HLA susceptibility alleles or other predisposing genes, is autoimmunity. According to the hypothesis, beta cells stressed by insulin resistance offer more of a target to the immune system, thus superimposing one cause of beta cell death upon another (Fig. 1), which explains why so-called type 1 diabetes progresses more rapidly. Since the major acquired contributor to insulin resistance is excess weight gain, this not only forms the ‘missing link’ between types 1 and 2 diabetes, but explains why the incidence of both conditions is rising in parallel, and why both are presenting earlier in life [1]. Wilkin’s article in this issue of Diabetologia now proposes that the accelerator hypothesis, arguably strengthened by evidence that has emerged over the past 6 years, could form the basis for a new, simpler and more rational classification [2]. Thus the argument. But is it valid? The hypothesis has met with a mixed reception. Brilliantly named and eloquently advocated, it has entered the common parlance of type 1, but not of type 2 diabetes. The original article has been cited 88 times in the literature, and a number of subsequent studies claim to have tested or confirmed it. There has been particular appeal in the notion that increasing adiposity has driven the parallel rise and apparent overlap of types 1 and 2 diabetes in childhood and adolescence. Further support has come from studies that have identified a role for insulin resistance in the pathogenesis of type 1 diabetes, and the hypothesis underpins a proposed prevention trial with metformin. Notwithstanding, opinion is highly polarised: many have dismissed the arguments out of hand, and two referees advised outright rejection of Wilkin’s recent article. Diabetologia (2007) 50:1571–1575 DOI 10.1007/s00125-007-0726-9

Collateral damage: the conundrum of drug safety

Drug safety falls victim to the three monkey paradigm