Obesity and Type 2 Diabetes: is the association as causal as we think?

Assigning a 'linear' relationship (i.e. the presence of a risk factor leads to disease development) to chronic diseases tend to lack a complex causal explanation. For instance, implying that diet is the sole cause of cardiovascular disease is simplistic. 

A good example of this is Type 2 diabetes (T2D). The statistic that approximately 70-80 per cent of T2D patients are overweight or obese has fast resulted in the conclusion that there is a causal relationship between obesity and T2D.

However, while obesity is associated with insulin resistance (IR) and IR is a predisposing factor for T2D, the molecular link between obesity and IR remains unclear.

In the meantime, whether obesity is a direct risk factor for T2D is increasingly being questioned. Is obesity a cause, or rather an indicator of T2D development, signalling a red flag for the health conditions that may consequently arise?

While the facts below are not conclusions in themselves, they imply that being overweight is not the sole cause of T2D:

• Approximately 1 in 3 people with obesity have consistently shown to not have any risk factors for the dysmetabolism needed for T2D.
• Approximately 1 in 4 people with a healthy body weight display all the metabolic risks for T2D, i.e. risks that would be typically expected in individuals with obesity.
• According to the 'obesity paradox', overweight individuals are less susceptible to mortality from T2D and other metabolic ailments than lean individuals.
• A bettered understanding of adipocyte ('fat cell') physiology implies that Triglyceride (Tg) storage in adipocytes is healthy until excessive energy abnormally 'outpours' into the liver, muscles and blood.

Extending upon the final point, in the body, fat storage increases via two processes, the first being hypertrophy, meaning expansion within the adipocyte, and the second being hyperplasia, in which new adipocytes are formed due to established cells being 'full'.

Undetermined genetic factors seem to reduce adipocyte hypertrophy (Pharmaceutical drugs such as Glitazones can synthesize this effect, yet can induce undesirable side effects, including edema and potential heart failure).

However, once this hypertrophy has reached its limit, ectopic fat (for instance, as in fatty liver) occurs due to the 'outpour'. Ectopic fat is toxic and results in oxidative stress and 'metaflammation', a low-grade form of systemic inflammation that correlates with a metabolic cascade resulting in IR.

If body weight alone led to this sequelae of events, it would be reasonable to propose a causality. However a significant amount of research now proposes that inflammatory processes specifically linked to IR, T2D and several other chronic diseases may be due to a range of lifestyle and environmental influences, such as poor diet, lack of physical activity, inadequate sleep and endocrine disrupting environmental chemicals; these factors can sometimes occur with weight gain, but often occur in its absence.

This highlights the potential value in moving away from the linear causality model in chronic disease. Rather, a more lateral 'systems' approach to causality, often applied to acute diseases may be a more viable way to examine T2D development. Inherent in a lateral approach lies interactions and feedback between risk factors for disease development, making causality more difficult to propose.

A combination measure of Tgs and wait circumference as an 'outpour' indication is an interesting correlation. Canadian physiologist Dr J-P Despres recently demonstrated that an invariable IR-predictor is a Tg greater than 2mmol/L, paired with a waist circumference higher than the level recommended for the ethnic group of an individual.

What does this imply for T2D management? There is a likelihood that weight loss is less of a priority than implementing lifestyle changes, such as improving eating habits, exercising and sleeping more and managing stress (through measures such as exercise and meditation).

However it should be emphasised that lifestyle factors are interrelated; For instance, lack of sleep can exacerbate stress, which may worsen eating patterns and decrease the likelihood of exercise. For this reason, all lifestyle factors should be addressed for improvement in individuals at risk for T2D.

Mounting evidence is finding exercise to be one of the most effective individual changes, with recent research demonstrating that high intensity resistance exercise decrease IR-associated visceral fat. Despite this, it is undetermined if changes in exercise habits result in changes to other lifestyle factors, such as stress management. 

The lock and key conclusions regarding the causality of T2D are becoming questionable. Although weight loss might be an added benefit from lifestyle changes for T2D prevention and management, the causality of T2D seems more complex than obesity alone, potentially influenced by a range of lifestyle factors. Due to their interplay, all lifestyle factors may require modification for optimum T2D management.

Current recommended waist circumference thresholds by population type

Prof Garry Egger will be a keynote speaker at the forthcoming AustralAsian Academy of Anti-Ageing Medicine Conference in Melbourne, 24-25 August.

Source: The AustralAsian Academy of Anti-Ageing Medicine (A5M)