Type 2 diabetes as a disease of ectopic fat?

Abstract

Background: Although obesity and diabetes commonly co-exist, the evidence base to support obesity as the major driver of type 2 diabetes mellitus (T2DM), and the mechanisms by which this occurs, are now better appreciated.

Discussion: This review briefly examines several sources of evidence - epidemiological, genetic, molecular, and clinical trial - to support obesity being a causal risk factor for T2DM. It also summarises the ectopic fat hypothesis for this condition, and lists several pieces of evidence to support this concept, extending from rare conditions and drug effects to sex- and ethnicity-related differences in T2DM prevalence. Ectopic liver fat is the best-studied example of ectopic fat, but more research on pancreatic fat as a potential cause of β-cell dysfunction seems warranted. This ectopic fat concept, in turn, broadly fits with the observation that individuals of similar ages can develop diabetes at markedly different body mass indexes (BMIs). Those with risk factors leading to more rapid ectopic fat gain - for example, men (compared with women), certain ethnicities, and potentially those with a family history of diabetes, as well as others with genes linked to a reduced subcutaneous adiposity - are more likely to develop diabetes at a younger age and/or lower BMI than those without.

Summary: Obesity is the major risk factor for T2DM and appears to drive tissue insulin resistance in part via gain of ectopic fat, with the best-studied organ being the liver. However, ectopic fat in the pancreas may contribute to β-cell dysfunction. In line with this observation, rapid resolution of diabetes linked to a preferential and rapid reduction in liver fat has been noted with significant caloric reduction. Whether these observations can help develop better cost-effective and sustainable lifestyle /medical interventions in patients with T2DM requires further study.

Figure 1

Relationship between body mass index (BMI) and risk for diabetes in US Health Professionals, derived from data extracted from Chan et al. [2].

Figure 2

Simple concept of ectopic fat and development of insulin resistance and frank diabetes. A simple conceptual illustration on the development and location of ectopic fat in individuals once they have ‘overwhelmed’ their ability to store safe subcutaneous fat. Certain factors such as sex (females have greater storage capacity), genetics (with family history of type 2 diabetes mellitus (T2DM) as a broad proxy measure), ethnicity (for example, South Asians) and ageing appear to have relevance to an individual’s ability to store fat subcutaneously. Other factors, such as smoking, may also be relevant but more data are needed to examine this. In temporal terms, it may be that liver fat accumulation occurs closer to the time of development of T2DM whereas muscle insulin resistance is a more proximal development. Perivascular fat may contribute to vascular dysfunction via a process of adverse vasocrine signalling, leading in turn to impaired nutrient blood flow; that is, vascular insulin resistance. Finally, some recent evidence indicates that excess fat may also accumulate in the pancreas to contribute to β-cell dysfunction, and thus development of T2DM. Such excess pancreatic fat appears reversible, and could contribute to diabetes resolution even in some patients with T2DM who are on insulin.

Figure 3

Biochemical findings supporting excess liver fat. This simple figure signals the link between excess calories, leading to excess liver fat and the common biochemical findings of high glucose, altered liver enzymes (alanine aminotransferase (ALT) much greater than aspartate aminotransferase (AST)) and hypertriglyceridaemia. When these three biochemical features are present in overweight or obese individuals who are not excessive alcohol drinkers, the likelihood of non-alcoholic fatty liver disease (NAFLD) is high.