The type 2 syndrome
Type 2 diabetes is a complex disorder which involves the interaction of multiple genes, multiple environmental factors, and a variety of pathophysiological processes. It has multiple clinical manifestations. For all these reasons it may be considered as a syndrome which manifests in differing ways against different genetic landscapes or environmental pressures. The syndrome has assumed epidemic proportions over a century during which the human environment has changed almost beyond recognition and the phenotype of the human species (affluent variety) has also changed. The syndrome has also evolved over time in parallel with our changing techniques of investigation, diagnostic criteria and understanding of disease. Type 2 diabetes, in short, is much more than a disturbance of glucose metabolism; it is a complex maladaptive response to an environment never previously encountered by our species. This article describes our evolving understanding of an evolving disease.
A syndrome (literally, a concurrence or "running together") is a constellation of associated signs and symptoms. A syndrome may have a single cause with many different manifestations, as in Down's syndrome. Type 2 diabetes, in contrast, is a syndrome in which multiple associated pathophysiological processes and clinical features are linked in a variety of ways to the occurrence of hyperglycaemia.
The focus on glucose metabolism as the key to the nature and management of diabetes has hindered understanding of the type 2 syndrome; it has led to the concept that diabetes can be viewed simply as a malfunction within a machine which can be “fixed” by the appropriate genetic or pharmaceutical intervention. This article proposes a more complex view of the syndrome, a view which takes account of change. To understand this change, we need to take account of the following:
- Developments in our ability to measure and evaluate the pathophysiological changes associated with diabetes.
- Changing definitions of diabetes in the light of these developments.
- External changes in the human environment.
- Time and age-dependent internal changes in homeostasis in response to an altered external environment.
- Social changes affecting the way in which we define, view and respond to a disease.
Diabetes was originally defined by the classic symptoms of thirst, polyuria and weight loss in association with the appearance of glucose in the urine. In the mid-19th century the diagnosis was made by tasting the urine (a task usually delegated to the most junior physician on the ward round), and this was succeeded by chemical tests for glycosuria and subsequently for blood glucose. By the end of the 20th century the diagnosis could be made from a single drop of blood, or by measurement of glycated haemoglobin. Increasing sophistication in measurement of glucose exposure identified a vast section of the population with subclinical “abnormalities” of glucose homeostasis, which led on to debate as to the level of glycaemia that is associated with harmful consequences, and might consequently justify therapeutic intervention[^1]. Repeated (and usually controversial) attempts have been made to define such thresholds.
The management of diabetes, meanwhile, evolved from the quest to relieve symptoms to the quest to prevent long-term complications. The attempt to relate glycaemic exposure to outcome resulted in the development of increasingly sophisticated epidemiological methods. Elliot Joslin (1870-1962) was the first to apply the term “epidemic” to diabetes in 1921, and was among the first to use life insurance statistics to measure its impact. Epidemiological measurement thus became the correlate of physiological measurement[^2].
Measuring the syndrome
The emergence of biochemistry and (later) of molecular biology soon led to an appreciation that diabetes involves changes affecting almost every conceivable aspect of energy metabolism. Furthermore, exposure to high levels of glucose is associated with structural and functional changes in many tissues. Some of these changes affect small blood vessels and are specific to hyperglycaemia, whereas other changes involve the lining of large blood vessels and are influenced by co-factors such as hypertension and hyperlipidaemia. Our increasing ability to image and quantify changes in tissue structure and function at levels ranging from the microscopic to the whole body has, for example, led to increasing ability to examine the distribution of fat both within the body and within specific organs within the body, and to redefine the diabetes syndrome accordingly.
The Changing Environment
The twentieth century was the first period in the history of the human species during which the majority of people within some geographical populations could be described as affluent, as against a small minority. Some commentators see globalization as a process whereby wealthy countries have exported their poverty to underpaid workers and producers in other parts of the world. In all events, sufficient surplus wealth has been generated within affluent countries to enable workers and producers to become consumers themselves, thus driving the economy into a spiral of growth. The practical consequence has been that the food bill has become a relatively minor item of expenditure for many, accompanied by a greatly reduced requirement for physical activity. A further consequence of improved living standards has been greatly increased longevity. Ample and often excessive calorie intake relative to expenditure in people surviving into later life is the likely underlying cause of the changes in the human phenotype which we consider next.
The rise of the affluent phenotype
Although there are earlier anecdotal accounts, it is curious to note that the association between diabetes and obesity was not generally recognised until the work of Joslin in the 1920s. Kelly West explains this by saying that when obesity is rare, most people with diabetes will not be obese. Other investigators of the period commented on the association between hypertension and diabetes, and Himsworth distinguished between insulin-sensitive and insulin-resistant diabetes in the 1930s[^3]; in the 1940s he was among the first to emphasise that diabetes is a syndrome rather than a disease[^4]. Around that time Lister and colleagues first proposed the terms type 1 and type 2 diabetes[^5], describing the latter as follows:
“There are two broad groups of diabetics – the young thin, non-arteriosclerotic group with normal blood pressure and usually an acute onset to the disease, and the older, obese, arteriosclerotic group with hypertension and usually an insidious onset … these types we have provisionally designated type I and type II, respectively”
The association between diabetes, (central) obesity, hypertension and arterial disease was thus well established 60 years ago; lipid abnormalities were later added to the description to create the modern metabolic syndrome: for practical purposes the term metabolic syndrome is used to describe the diabetes syndrome without the diabetes.
The rise of obesity-related diabetes, sometimes referred to as diabesity, paralleled the rise of obesity and the metabolic syndrome in an ageing and affluent population. This cluster of clinical and metabolic features is useful shorthand for a more extensive range of inter-related changes in homeostasis, which might be referred to as the affluent phenotype[^6]. This phenotype reflects not only major changes in the height, weight and body proportions of well-nourished affluent populations; it also reflects the phenomenon of allostasis.
The constancy of the internal environment, or homeostasis, is one of the central principles of physiology. Many homeostatic mechanisms operate on the principle of the set point and feed-back loop. Deviations in ( for example) body temperature or sodium concentration are identified, balancing mechanisms are activated, and the system returns to its former equilibrium.
Homeostasis is - at least in these aspects - a static phenomenon, but the body responds to changes in the external environment in ways that are forward-feeding and adaptive. This is allostasis. The immune system is permanently changed by exposure to some infective organisms, marathon runners and weight lifters in training undergo allostastic changes in metabolic pathways and body composition, and allostatic mechanisms are necessary to survival during chronic undernutrition.
Chronic overnutrition also induces allostatic changes. The populations of affluent countries gain, on average, almost one gram of fat per day between the ages of 25-55. Blood pressure rises with increasing age, glucose tolerance deteriorates, arteries stiffen. New set-points are established, and are then defended by homeostatic mechanisms, which helps to explain why weight loss is difficult for many people.
Glucose homeostasis is maintained over time by adjusting insulin responses to glucose in order to maintain normal glucose uptake. Over time, more insulin is needed to achieve the same response, and it has been proposed that this may have pathological consequences predisposing to type 2 diabetes[^7].
Allostasis calls our current definitions of disease into question. The majority of elderly people in our population are, by the criteria applied to 25 year-olds, overweight, hypertensive and glucose intolerant. Will they therefore benefit from therapies designed to return them to their former state?
What is a disease?
Health and disease have never been satisfactorily defined. The medical historian Robert Hudson has said that “diseases are not immutable entities but dynamic social constructions which have biographies of their own”[^8]. The disease we call (type 2) diabetes is in constant flux, whether in regard to how we describe it, define it, measure it, treat it, or assess its consequences. A mechanistic approach to its causation and treatment, based upon the attempted correction of perceived deviations from “normality” may be foredoomed to failure. Diabetes is just one of a number of complex networked allostatic changes by which our genome responds to an environment never previously encountered. We can learn to live with it, but we cannot defeat it unless we learn to live in a different way.