Type 2 diabetes as a disease of ectopic fat?

BMC Medicine

Jason MR Gill¹  Naveed Sattar¹ 

[1] Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK

关键词: Family history of diabetes;    Ethnicity;    Sex;    Adiposity;    Pancreas;    NAFLD;    Insulin resistance;   

Others  :  1121512
DOI  :  10.1186/s12916-014-0123-4

 received in 2014-06-05, accepted in 2014-07-08,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Sattar and Gill; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ, Smith SR: Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab 2011, 96:1654-1663.
• [2]Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC: Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994, 17:961-969.
• [3]Sattar N, Wannamethee SG, Forouhi NG: Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities? Diabetologia 2008, 51:926-940.
• [4]Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JRB, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJF, Barroso I, Wareham NJ, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316:889-894.
• [5]Rees SD, Islam M, Hydrie MZ, Chaudhary B, Bellary S, Hashmi S, O'Hare JP, Kumar S, Sanghera DK, Chaturvedi N, Barnett AH, Shera AS, Weedon MN, Basit A, Frayling TM, Kelly MA, Jafar TH: An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabet Med 2011, 28:673-680.
• [6]Loos RJ, Bouchard C: FTO: the first gene contributing to common forms of human obesity. Obes Rev 2008, 3:246-250.
• [7]Bao W, Hu FB, Rong S, Rong Y, Bowers K, Schisterman EF, Liu L, Zhang C: Predicting risk of type 2 diabetes mellitus with genetic risk models on the basis of established genome-wide association markers: a systematic review. Am J Epidemiol 2013, 178:1197-1207.
• [8]Cusi K: The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr Diab Rep 2010, 10:306-315.
• [9]Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB: Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol 2010, 207:245-255.
• [10]Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring HU: Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008, 168:1609-1616.
• [11]Gupta AK, Bray GA, Greenway FL, Martin CK, Johnson WD, Smith SR: Pioglitazone, but not metformin, reduces liver fat in Type-2 diabetes mellitus independent of weight changes. J Diabetes Complications 2010, 5:289-296.
• [12]Smith SR, De Jonge L, Volaufova J, Li Y, Xie H, Bray GA: Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism 2005, 541:24-32.
• [13]Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI: Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000, 275:8456-8460.
• [14]Cleland SJ, Sattar N: Impact of ethnicity on metabolic disturbance, vascular dysfunction and atherothrombotic cardiovascular disease. Diabetes Obes Metab 2005, 5:463-470.
• [15]Ntuk UE, Mackay D, Gill JMR, Sattar N, Pell J: Ethnic specific obesity cut-offs for diabetes risk: Cross-sectional study of 490,288 UK Biobank participants.Diabetes Care ᅟ, ᅟ:ᅟ. In Press.
• [16]Sniderman AD, Bhopal R, Prabhakaran D, Sarrafzadegan N, Tchernof A: Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol 2007, 36:220-225.
• [17]Chandalia M, Lin P, Seenivasan T, Livingston EH, Snell PG, Grundy SM, Abate N: Insulin resistance and body fat distribution in South Asian men compared to Caucasian men. PLoSONE 2007, 2:e812.
• [18]Balakrishnan P, Grundy SM, Islam A, Dunn F, Vega GL: Influence of upper and lower body adipose tissue on insulin sensitivity in South Asian men. J Investig Med 2012, 60:999-1004.
• [19]Anand SS, Tarnopolsky MA, Rashid S, Schulze KM, Desai D, Mente A, Rao S, Yusuf S, Gerstein HC, Sharma AM: Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: the Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE). PLoS One 2011, 6 7:e22112.
• [20]Petersen KF, Dufour S, Feng J, Befroy D, Dziura J, Dalla Man C, Cobelli C, Shulman GI: Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A 2006, 103:18273-18277.
• [21]Logue J, Walker JJ, Colhoun HM, Leese GP, Lindsay RS, McKnight JA, Morris AD, Pearson DW, Petrie JR, Philip S, Wild SH, Sattar N: Scottish Diabetes Research Network Epidemiology Group. Do men develop type 2 diabetes at lower body mass indices than women? Diabetologia 2011, 54:3003-3006.
• [22]Sattar N: Gender aspects in type 2 diabetes mellitus and cardiometabolic risk. Best Pract Res Clin Endocrinol Metab 2013, 27:501-27507.
• [23][http://www.qdscore.org/index.php] webcite ᅟ: QDiabetes risk score. In ᅟ. ; ᅟ. .
• [24]Taylor R: Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia 2008, 51:1781-1789.
• [25]Preiss D, Sattar N: Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond) 2008, 115:141-150.
• [26]Stefan N, Kantartzis K, Häring HU: Causes and metabolic consequences of Fatty liver. Endocr Rev 2008, 29:939-960.
• [27]Hotamisligil GS, Erbay E: Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008, 8:923-934.
• [28]Birkenfeld AL, Shulman GI: Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014, 59:713-723.
• [29]Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R: Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011, 54:2506-2514.
• [30]Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, Bantle JP, Sledge I: Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009, 122:248-256. e5
• [31]Yan YX, Wang GF, Xu N, Wang FL: Correlation between postoperative weight loss and diabetes mellitus remission: a meta-analysis.Obes Surg 2014, ᅟ:ᅟ. Epub ahead of print.
• [32]Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, Borecki IB, Knowles JW, Yerges-Armstrong L, Ohlsson C, Perry JR, Chambers JC, Kooner JS, Franceschini N, Langenberg C, Hivert MF, Dastani Z, Richards JB, Semple RK, Frayling TM: Genetic evidence for a normal-weight “metabolically obese” phenotype linking insulin resistance, hypertension, coronary artery disease and type 2 diabetes.Diabetes 2014, ᅟ:ᅟ [Epub ahead of print].
• [33]Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, et al: Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet 2014, ᅟ:ᅟ. Epub ahead of print.