Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes

IF 14.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Care Pub Date : 2025-05-20 DOI:10.2337/dc25-0151

Venkatesh L. Murthy, Paolo Piaggi, Phillip Lin, Shilin Zhao, Lindsey K. Stolze, Andrew S. Perry, Robert L. Hanson, John Jeffrey Carr, James G. Terry, Leslie J. Baier, Clifton Bogardus, Clary Clish, Eric R. Gamazon, Jonathan Krakoff, Ravi V. Shah

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Abstract

OBJECTIVE To identify metabolic signatures of insulin action/secretion in Indigenous Americans (IAs) and their association with diabetes. RESEARCH DESIGN AND METHODS We defined circulating metabolomic signatures of insulin action/secretion in 446 IAs, including glucose disposal rate during low-dose insulin clamp (Mlow) and endogenous glucose production (EGP) during insulin infusion (suppression of hepatic glucose production). We then determined associations of these metabolic scores with glucose tolerance (in a separate set of ∼700 IAs) and diabetes/metabolic risk in ∼2,000 individuals (from Coronary Artery Risk Development in Young Adults [CARDIA] study). We used tissue-specific gene–metabolite mapping to pinpoint genetic pathways of type 2 diabetes (T2D) implicated by metabolomic signatures. RESULTS In young IAs (mean age 29 years; mean BMI 34.9 kg/m2) without diabetes, phenotype–metabolome associations across multiple insulin action phenotypes were linked to mechanisms of fatty acid and amino acid metabolism and inflammation (among others). Metabolite-based scores of insulin action were strongly related to incident diabetes in our discovery IA population (Mlow; 49 metabolites; standardized hazard ratio [HR] 0.49; 95% CI 0.35–0.69; P < 0.0001) and also associated with measures of insulin resistance in a distinct IA population (|ρ| ∼0.3–0.5 correlation) and in the CARDIA group (median age 33 years). At ∼20 years of follow-up in CARDIA, we observed a strong BMI- and glucose-independent association of the metabolite profile of Mlow (HR 0.65; 95% CI 0.56–0.74; P < 0.0001) and EGP suppression (HR 0.66; 95% CI 0.57–0.76; P < 0.0001) with incident diabetes, directionally opposed to BMI and glucose. Genes implicated by the metabolomic signatures were strongly linked to T2D. CONCLUSIONS Metabolic signatures of clamp-determined insulin action are strongly associated with incident diabetes, suggesting causal–functional pathways of T2D.

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印第安人对胰岛素的生理反应确定了与糖尿病相关的代谢易感性谱

目的了解美洲原住民（IAs）胰岛素作用/分泌的代谢特征及其与糖尿病的关系。研究设计和方法我们定义了446例IAs中胰岛素作用/分泌的循环代谢组学特征，包括低剂量胰岛素钳夹（Mlow）期间的葡萄糖处置率和胰岛素输注期间的内源性葡萄糖生成（EGP）（抑制肝脏葡萄糖生成）。然后，我们确定了这些代谢评分与葡萄糖耐量（在一组单独的~ 700 IAs中）和糖尿病/代谢风险（来自年轻人冠状动脉风险发展[CARDIA]研究）之间的关联。我们使用组织特异性基因代谢物定位来查明与代谢组学特征有关的2型糖尿病（T2D）的遗传途径。结果年轻IAs患者(平均年龄29岁；平均BMI 34.9 kg/m2)，没有糖尿病，多种胰岛素作用表型的表型-代谢组学关联与脂肪酸和氨基酸代谢和炎症（等）的机制有关。在我们发现的IA人群中，基于代谢产物的胰岛素作用评分与糖尿病发病率密切相关(Mlow；49个代谢物;标准化风险比[HR] 0.49；95% ci 0.35-0.69；P, lt;0.0001)，也与不同IA人群（|ρ| ~ 0.3-0.5相关）和CARDIA组（中位年龄33岁）的胰岛素抵抗测量值相关。在CARDIA患者随访约20年时，我们观察到Mlow代谢物谱与BMI和葡萄糖有很强的相关性(HR 0.65；95% ci 0.56-0.74；P, lt;0.0001)和EGP抑制(HR 0.66；95% ci 0.57-0.76；P, lt;0.0001)发生糖尿病，与BMI和葡萄糖方向相反。与代谢组学特征相关的基因与T2D密切相关。结论钳形胰岛素作用的代谢特征与糖尿病的发生密切相关，提示T2D的因果功能通路。

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来源期刊

Diabetes Care 医学-内分泌学与代谢

CiteScore

27.80

自引率

4.90%

发文量

449

审稿时长

1 months

期刊介绍： The journal's overarching mission can be captured by the simple word "Care," reflecting its commitment to enhancing patient well-being. Diabetes Care aims to support better patient care by addressing the comprehensive needs of healthcare professionals dedicated to managing diabetes. Diabetes Care serves as a valuable resource for healthcare practitioners, aiming to advance knowledge, foster research, and improve diabetes management. The journal publishes original research across various categories, including Clinical Care, Education, Nutrition, Psychosocial Research, Epidemiology, Health Services Research, Emerging Treatments and Technologies, Pathophysiology, Complications, and Cardiovascular and Metabolic Risk. Additionally, Diabetes Care features ADA statements, consensus reports, review articles, letters to the editor, and health/medical news, appealing to a diverse audience of physicians, researchers, psychologists, educators, and other healthcare professionals.