Pathogenesis of type 2 diabetes

The pathogenesis of a disease involves a search for its causes, whereas the specific mechanisms involved are considered under pathophysiology. Type 2 diabetes is better considered as a disease spectrum rather than as a distinct disease entity, and has multiple causes. Hyperglycaemia develops as the consequence of failing insulin secretion relative to the body's requirement for insulin, which is typically increased. The condition is rare in traditional environments, but common in societies undergoing rapid economic transition. Predisposing factors in well-fed populations include increasing age, physical inactivity, obesity, socio-economic disadvantage and ethnicity; the relative importance of these factors varies from one environment to the next. Overconsumption of calories is a central causal mechanism, but the relative importance of dietary quality (as against quantity) is still a matter of some dispute. Type 2 diabetes is a polygenic disorder, and the genes associated with its development vary from one ethnic group to another, and may have different functional consequences in different environments. Fetal undernutrition predisposes to diabetes later in life, apparently as the result of irreversible fetal programming.

Nature or Nurture?

Type 2 diabetes appears to have been an uncommon condition at the start of the 20th century, generally diagnosed in more affluent populations. Multiple genes are involved in its causation (see Genetics of type 2 diabetes), but environmental factors are generally necessary for its expression. The US Nurses' Study, for example, found that diabetes was almost 100 times more likely to develop in those nurses who were most overweight at the time of recruitment to the profession.

Developmental Influences

A third dimension is added to the causation of type 2 diabetes by the observation that fetal undernutrition predisposes to the later onset of diabetes. This was, for example, demonstrated in follow up of children in utero at the time of the Dutch Hunger Winter (1944-5). The mechanisms involved are under intensive investigation, but involve fetal programming of metabolic pathways and structural changes in the growing fetus and child. See Early life determinants and T2DM, also Fetal origins of type 2 DM.

Intergenerational Influences

There is growing evidence that maternal overweight and diabetes are associated with an increased risk of diabetes in the offspring. It is at present uncertain to what extent this is due to intrauterine overnutrition or to later environmental influences resulting in obesity.

Lifestyle influences

Physical Inactivity:

Although it seems clear that an active lifestyle reduces the risk of type 2 diabetes, there is some doubt as to the relative role of metabolic factors associated with exercise, as against reduced obesity, in achieving this effect.

Diet

There is no question that overconsumption of calories relative to energy output is the prime cause of weight gain and obesity-related diabetes. No diet will permit its users to gain weight with impunity as to its metabolic consequences. Furthermore, it has been demonstrated that even apparently well-established type 2 diabetes can be reversed by stringent calorie restriction, although the demands upon those concerned are considerable.

This having been said, there is ongoing controversy as to diet quality and its role both in terms of causation and management of diabetes. There are, for example, advocates for both a low and high carbohydrate intake with corresponding modifications in the intake of protein and fat. In general, there seems to be agreement that a traditional high-vegetable and high fibre diet is beneficial, while others argue more specifically for the virtues of a "Mediterranean" diet and similar variants of this theme.

Conversely, it has been argued that specific components of a modern diet are diabetogenic or actively harmful in other ways. For example, the health consequences of consumption of trans fat (liquid cis-unsaturated fats hydrogenated to produce saturated fats with desirable physical properties for food manufacture, and hence an important constituent of fast food) are hotly debated.

Toxins entering the food chain are also considered by some as a potential cause of diabetes.

Socio-economic status

It has been claimed that diabetes is a disease of the poor in wealthy societies, and of the wealthy in poor societies. Historically, it does appear to have affected the wealthier classes in North America and Europe first, and subsequently to have migrated down the social scale. Equally, the wealthier classes of less affluent societies have been the first affected, with similar movement along the social gradient as a consequence of globalization.

In wealthier societies low socio-economic status, although modulated in important ways by ethnicity and culture, is associated both with increased risk of diabetes and of poor outcomes of diabetes. This pattern is probably due to the association between relative poverty, obesity, poor diet and lifestyle factors such as smoking. Equally, the less affluent members of society are typically those with the least access to high-quality health care and advice.

Ethnicity

Although type 2 diabetes is widely perceived as a western disease, people of differing ethnic background living in multicultural societies such as the USA show quite wide variation in their risk of diabetes, and those of European extraction appear relatively less susceptible to those of other ethnicities. It is however difficult to disentangle the relative contribution of genes,culture and socio-economic status to the observed differences in risk.

The greatest susceptibility to type 2 diabetes has been observed in some groups of Pacific islanders, particularly the people of Nauru, and in some American Indian populations, notable the Pima Indians of Arizona.

Environmental factors such as obesity vary between different ethnic groups, with some of the world's highest rates of obesity in Pacific islanders. This makes it difficult reach firm conclusions as to the genetic contribution to diabetes susceptibility, especially as genetic differences between ethnic groups also result in differences in body composition which influence the relationship between weight gain and diabetes. For example, people of South Asian origin typically develop diabetes at lower BMI than people from other ethnic groups.

Summary

Type 2 diabetes is a heterogeneous condition with multiple environmental and genetic influences upon its development. Better ability to discriminate between its phenotypic and mechanistic determinants should improve our ability to target interventions to specific individuals and populations.

Comments

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    Natalie Castillo added a suggestion on 5 January 2016 at 05:39AM
    Wow, interesting facts around Type 2
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