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Type 2 diabetes as a disease of ectopic fat?
© Sattar and Gill; licensee BioMed Central Ltd. 2014
Received: 5 June 2014
Accepted: 8 July 2014
Published: 26 August 2014
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.
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.
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.
Although obesity and type 2 diabetes mellitus (T2DM) commonly co-exist, the evidence to show that obesity is a cause of T2DM, and the mechanism by which it does so are only now beginning to be fully appreciated. Here, we discuss the range of evidence to support this view. We also describe the concept of ectopic fat as an important mechanistic link between obesity and T2DM in many individuals.
Genes strengthen causal links between obesity and diabetes
The most important gene for obesity so far discovered, FTO (fat mass and obesity-associated protein), was first reported to be linked to T2DM by Frayling et al. in 2007 . Approximately 16% of Europeans are homozygous for high-risk variants of the FTO gene, and this is associated with an average body weight 3 to 4 kg greater than normal. However, the higher risk for T2DM in Europeans is completely abolished after adjusting for BMI, suggesting that the risk conferred by FTO is mediated via higher body mass in this ethnic group, although other data suggest that in other ethnicities, FTO may influence T2DM risk in part independent of BMI . Multiple other genes are linked to T2DM risk, most being linked to β-cell dysfunction rather than insulin resistance, as reviewed by Loos and Bouchard . In terms of T2DM risk assessment, however, there is no benefit in genotyping individuals for their T2DM genes because such information does not improve upon the risk prediction achievable by using a simpler clinical phenotype and knowledge of family history of T2DM . Nevertheless, continued work on T2DM-related genes should help strengthen causal inferences on new risk pathways.
Evidence for the ectopic fat hypothesis in T2DM
Surprisingly, the pathophysiological basis for T2DM continues to attract debate. What is clear, however, is the emergence of one major hypothesis, namely that of ectopic fat leading to organ-specific insulin resistance via a process termed `lipotoxicity’ . Many individuals prone to T2DM appear to show a greater propensity to accumulate visceral fat for a given weight; interestingly, this characteristic may be a downstream consequence of an `impaired’ subcutaneous fat storage capacity, the mechanisms for which deserve greater attention. As extreme example of this concept is lipodystropy; individuals with this condition have an impaired ability to store subcutaneous fat, and consequently with even modest weight gain, they accumulate fat in visceral and ectopic tissues (for example, the liver), leading in turn to marked insulin resistance . At the other extreme are many individuals, particularly women, who, despite attaining very high BMIs (as high as 50 to 60 kg/m2), remain insulin-sensitive, normoglycaemic and normolipaemic. Imaging studies show these individuals to have low levels of visceral and ectopic fat but a high subcutaneous fat content . A pharmacological example underlying the importance of ectopic fat to dysglycaemia comes from the observation that peroxisome proliferator-activated receptor (PPAR)-γ agonists (thiazolidenediones) lower glucose levels despite increasing the patient’s weight. They appear to do so by redistributing fat away from the liver and towards an expanded subcutaneous pool ,. Finally, transplantation of normal adipose tissue in the subcutaneous region of lipoatrophic mice, which are normally severely insulin-resistant, removes their excess hepatic fat and normalises hepatic insulin sensitivity .
Ethnicity, sex, and the ectopic fat hypothesis
There are substantial ethnic differences in diabetes risk. For example, South Asians develop T2DM at lower BMI levels and around a decade earlier in life than white Europeans . Using UK Biobank data, we have recently shown that South Asians with BMI of 22 kg/m2 have equivalent prevalence of T2DM to white Europeans with BMI of 30 kg/m2. The corresponding BMIs for Chinese men and women are 26 and 24 kg/m2, respectively . These remarkable findings help to explain why T2DM rates are rapidly escalating as obesity levels rise in countries such as India and China. A key reason for the greater increase in diabetes risk per unit increase in BMI in South Asians compared with Europeans may be due to a reduced capacity in South Asians to store fat in the primary superficial subcutaneous adipose tissue compartment, leading to earlier `overflow’ into secondary deep subcutaneous and visceral fat compartments, and potentially the liver . Indeed, there is some evidence of differences in morphology of subcutaneous abdominal adipose cells in South Asians compared with Europeans, consistent with reduced capacity to store fat in this depot -, and other evidence suggests that South Asians may have higher levels of liver fat than Europeans ,. Current evidence on ethnicity and ectopic fat is limited by its cross-sectional nature, and further research evaluating ethnic differences in the longitudinal changes in subcutaneous fat storage, adipocyte morphology and function, and ectopic fat deposition with increasing adiposity may yield important insights into the mechanisms underpinning the substantial ethnic differences in diabetes risk.
In terms of sex, we recently showed that men develop diabetes at lower average BMIs compared with women at most adult ages . This finding is consistent with the observation that adult men have greater levels of liver fat and insulin resistance than women of comparable BMI . In general, women carry or have a greater subcutaneous fat storage capacity and, linked to this, carry less visceral fat than do men. Therefore, the average woman has to put on more weight than the average man to reach the point at which she overwhelms her subcutaneous stores and promotes sufficient ectopic fat deposition to develop hyperglycaemia.
As an example showing that differential BMI thresholds depend upon several genetic factors, a 50 year-old South Asian man with a strong family history of T2DM has a near-equivalent 10 year risk (~13% QDdiabetes risk score ) of T2DM at a BMI of 22 kg/m2) as an age-matched white female with no family history of T2DM with a BMI of nearly 40 kg/m2. Thus, sex and ethnicity combine to profoundly influence diabetes risk, and this is likely to reflect, in part, differences in propensity for ectopic fat storage, although of course, other factors also contribute.
The crucial role of ectopic liver fat and related molecular explanations
In terms of chronology, gain of liver fat appears to precede development of T2DM in most individuals, whereas muscle insulin resistance appears to be a longer-standing and earlier abnormality . Considerable recent work has focused on the role of the liver in the development of diabetes, and linked to this, the condition of non-alcoholic fatty liver disease (NAFLD) has been shown to be very common (>50%) in patients with T2DM, and is linked to hepatic insulin resistance .
It is thought that in individual destined to develop diabetes, at a given level of peripheral or hepatic insulin resistance, the ability of the pancreas to hypersecrete insulin is overwhelmed, and so frank diabetes ensues. Pancreatic failure is thought to be largely genetically governed, and as discussed before, multiple genes governing insulin secretion have been identified. However, the possibility that excess fat accumulating in pancreas can impair β-cell function is now also emerging .
Is type diabetes reversible via loss of fat or ectopic fat?
The simple answer to this is `yes’. If we accept that obesity is causally linked to diabetes and that some individuals can lose considerable weight by surgical or dietary means, diabetes must be reversible. In a recent meta-analysis, Buchwald et al. demonstrated that a mean weight loss of around 38.5 kg from a mean pre-surgery BMI of around 48 kg/m2 led to diabetes remission in around 78% of patients . Whether some types of bariatric surgery lead to greater diabetes remission for a weight reduction than others remains debated but, suffice to say, the greater the weight loss in general, the greater the chance of T2DM remission. In a more recent meta-analysis , patients with a shorter duration of T2DM and lower fasting plasma glucose had higher remission rates, though further randomised studies would be helpful to support and extend these findings; in particular, there was sparse data for ethnic groups outside of white Europeans. Perhaps most impressively, many patients previously on insulin also had T2DM remission , suggesting that, at least in some patients, pancreatic function previously thought to be completely lost may be recoverable with substantial weight loss.
In terms of diet, the most recent notable study was led by the Newcastle group of Taylor et al.. This group demonstrated normalisation of blood glucose in 11 patients with diabetes after 1 week of commencing a 600 kcal/day diet. They also demonstrated improvement in liver fat levels, which fell from around 10% to an average within the normal range at 2.9% by week 8, as well as an improvement in β-cell response, the latter potentially linked to the observed reduction in pancreatic fat . These very impressive findings suggest that a rapid resolution of hyperglycaemia can be achieved by substantial caloric reduction. They also suggest the occurrence of rapid and preferential liver fat loss because hepatic triglyceride content decreased by an average of 30% during week 1 of intervention (P < 0.001), whereas total weight reduced by only around 4%. The liver response to insulin also improved by the end of week 1 so that insulin suppression of hepatic glucose output improved from a mean of 43% to 74%, the latter being similar to weight-matched controls without diabetes. These findings all fit with the concept that excess liver fat is intrinsically linked to hepatic insulin resistance and consequently higher fasting glucose levels. Why fat reduction should lead to improved β-cell function is not entirely clear, but is an area in need of greater research.
Of course, these impressive short-term results are merely proof of concept. Cutting energy intake to 600 kcal per day is achievable for most over a short term but, in reality, not sustainable for long periods. The clinical implications of these findings therefore need to further tested in longer-term clinical trials, some of which have now begun. Nevertheless, these observations support the ectopic fat hypothesis for T2DM.
Evidence linking obesity to type 2 diabetes
Type of evidence
BMI is the dominant risk factor for type 2 diabetes. Whereas RRs for CVD with rising BMI tend to be around twofold to threefold once BMI levels reach around 30-35 kg/m2, RRs for diabetes are often around a log scale higher, approaching 50 to 80 times at BMI 35 kg/m2 versus BMI of 21 kg/m2.
Genes linked to higher BMI, in particular the FTO gene, have been clearly shown to predict T2DM.
Ectopic fat in key organs that are relevant to glucose metabolism appears to be crucial for tissue insulin resistance. In the liver, ectopic fat via metabolic intermediates interferes with insulin signalling and thereby contributes to higher fasting glucose levels and hypertriglyceridaemia. Characteristics linked to earlier ectopic fat gain include male sex, family history of diabetes and certain ethnic origins.
BMI or waist size make up around half of the weighting in diabetes risk scores, regardless of ethnicity. Moreover, around half of all patients with diabetes are obese.
Weight loss via dietary or surgical methods can reverse T2DM and even some patients previously on insulin can show remission, suggesting improvements in β-cell function. Rapid reductions in glucose levels appear to relate to changes in liver fat content in the short term whereas diabetes remission appears to relate to the amount of fat loss in the longer term.
Both authors contributed fully to the conception, writing and revision of this article.
Our work in this area has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant n° 115372).
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