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Type 2 diabetes as a disease of ectopic fat?

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BMC Medicine

BioMed Central

Insulin resistance, NAFLD, Pancreas, Adiposity, Sex, Ethnicity, Family history of diabetes

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      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.

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      Most cited references 28

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      A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.

      Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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        Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis.

        The prevalence of obesity-induced type 2 diabetes mellitus is increasing worldwide. The objective of this review and meta-analysis is to determine the impact of bariatric surgery on type 2 diabetes in association with the procedure performed and the weight reduction achieved. The review includes all articles published in English from January 1, 1990, to April 30, 2006. The dataset includes 621 studies with 888 treatment arms and 135,246 patients; 103 treatment arms with 3188 patients reported on resolution of diabetes, that is, the resolution of the clinical and laboratory manifestations of type 2 diabetes. Nineteen studies with 43 treatment arms and 11,175 patients reported both weight loss and diabetes resolution separately for the 4070 diabetic patients in these studies. At baseline, the mean age was 40.2 years, body mass index was 47.9 kg/m2, 80% were female, and 10.5% had previous bariatric procedures. Meta-analysis of weight loss overall was 38.5 kg or 55.9% excess body weight loss. Overall, 78.1% of diabetic patients had complete resolution, and diabetes was improved or resolved in 86.6% of patients. Weight loss and diabetes resolution were greatest for patients undergoing biliopancreatic diversion/duodenal switch, followed by gastric bypass, and least for banding procedures. Insulin levels declined significantly postoperatively, as did hemoglobin A1c and fasting glucose values. Weight and diabetes parameters showed little difference at less than 2 years and at 2 years or more. The clinical and laboratory manifestations of type 2 diabetes are resolved or improved in the greater majority of patients after bariatric surgery; these responses are more pronounced in procedures associated with a greater percentage of excess body weight loss and is maintained for 2 years or more.
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          Nutrient sensing and inflammation in metabolic diseases.

          The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.
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            Author and article information

            Affiliations
            Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA UK
            Contributors
            naveed.sattar@glasgow.ac.uk
            Jason.gill@glasgow.ac.uk
            Journal
            BMC Med
            BMC Med
            BMC Medicine
            BioMed Central (London )
            1741-7015
            26 August 2014
            26 August 2014
            2014
            : 12
            : 1
            4143560 123 10.1186/s12916-014-0123-4
            © Sattar and Gill; licensee BioMed Central Ltd. 2014

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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            Opinion
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            © The Author(s) 2014

            Medicine

            family history of diabetes, ethnicity, sex, adiposity, pancreas, nafld, insulin resistance

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