Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta.
Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta.
Acta Diabetol. 2024 May;61(5):555-564. doi: 10.1007/s00592-023-02230-9. Epub 2024 Jan 27.
Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI.
In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes.
814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored.
A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution.
This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.
2 型糖尿病（T2DM）在遗传上具有异质性，由β细胞功能障碍和胰岛素抵抗驱动。胰岛素抵抗会导致代谢心血管并发症的发生，并且通常与肥胖有关。在 11 个位点上的一组常见变体与胰岛素抵抗以及 2 型糖尿病和冠心病的发病风险相关。这些变体描述了脂肪营养不良的多基因相关性，尽管 BMI 较低，但代谢疾病风险较高。
在这项横断面研究中，我们试图研究由 11 个脂肪营养不良变体组成的多基因风险评分与一个以肥胖和 2 型糖尿病患病率均高为特征的岛屿人群的人体测量、血糖和代谢特征之间的关联。
对 814 名无关成年人（n=477 名对照和 n=337 名 T2DM 病例）进行基因分型，并探讨了与表型的关联。
较高的多基因脂肪营养不良风险评分与较低的肥胖指数（较低的腰围和体重指数测量值）和较高的 HOMA-IR、致动脉粥样硬化血脂异常以及通过内脏脂肪指数评估的内脏脂肪功能障碍相关在 DM 组中。在未经调整和调整协变量的模型中，与风险评分分布的第一四分位数相比，处于多基因风险评分最高四分位数的个体发生 T2DM 的风险更高。
本研究证实了多基因脂肪营养不良风险等位基因与代谢综合征参数和 T2DM 风险之间的关联，尤其是在正常体重个体中。我们的研究结果表明，多基因脂肪营养不良风险等位基因独立于 BMI 增加驱动胰岛素抵抗和糖尿病风险。
