The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry,Diabetologia

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The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry
Diabetologia ( IF 8.4 ) Pub Date : 2021-08-21 , DOI: 10.1007/s00125-021-05552-x
Hannah J Burden _{1,

2} , Shannon Adams ₃ , Braydon Kulatea ₃ , Morag Wright-McNaughton ₄ , Danielle Sword ₄ , Jennifer J Ormsbee ₅ , Conor Watene-O'Sullivan _{2,

6,

7} , Tony R Merriman _{2,

8,

9} , Jennifer L Knopp ₅ , J Geoffrey Chase ₅ , Jeremy D Krebs _{2,

4} , Rosemary M Hall _{2,

4} , Lindsay D Plank ₁₀ , Rinki Murphy _{2,

11} , Peter R Shepherd _{1,

2} , Troy L Merry _{2,

3}

Affiliation

Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Department of Medicine, University of Otago Wellington, Wellington, New Zealand.
Centre for Bioengineering, Department of Mechanical Bioengineering, University of Canterbury, Christchurch, New Zealand.
Moko Foundation, Kaitaia, New Zealand.
Waharoa Ki Te Toi Research Centre, Kaitaia, New Zealand.
Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Surgery, School of Medicine, The University of Auckland, Auckland, New Zealand.
Department of Medicine, School of Medicine, The University of Auckland, Auckland, New Zealand.

Aims/hypothesis

The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes.

Methods

A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic–euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation.

Results

The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic–euglycaemic clamp.

Conclusions/interpretation

rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.

Graphical abstract

中文翻译：

CREBRF 糖尿病保护 rs373863828-A 等位基因与毛利和太平洋血统男性早期胰岛素释放增强有关

目标/假设

rs373863828 ( CREBRF p.Arg457Gln)的次要 A 等位基因与 BMI 增加有关，但在波利尼西亚人（太平洋人和新西兰毛利人）人群中降低了 2 型和妊娠糖尿病的风险。本研究调查了 A 等位基因对无糖尿病的超重/肥胖男性胰岛素释放和敏感性的影响。

方法

172 名毛利人或太平洋血统的男性（56 名具有 A 等位基因）完成了一项混合膳食耐受性测试，其中 44 名（24 名具有 A 等位基因）进行了频繁采样的 IVGTT 和高胰岛素-正常血糖钳夹。使用具有协变量年龄、血统和 BMI 的混合线性模型来分析 rs373863828 的 A 等位基因与胰岛素释放和血糖调节标志物之间的关联。

结果

rs373863828 的 A 等位基因与餐后 30 分钟血浆胰岛素的更大增加相关，而不会影响血浆葡萄糖或肠促胰岛素胰高血糖素样多肽-1 或胃抑制多肽的升高。与这一点一致，静脉输注葡萄糖丸后，具有 A 等位基因的参与者具有较高的早期（p < 0.05，在 2 和 4 分钟）血浆胰岛素和 C 肽浓度，血糖升高与纯合子的相似。主要（G）等位基因。尽管血浆胰岛素增加，但 rs373863828 基因型与高胰岛素 - 血糖正常钳夹期间胰岛素敏感性指数或葡萄糖处理的显着差异 ( p > 0.05) 无关。