1563-P: High Fat and Fructose Feeding Severely Impairs Hepatic Glucose Effectiveness but Not Insulin Action Under Euglycemic Conditions

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-1563-p

DALE S. EDGERTON, GUILLAUME KRAFT, HANNAH L. WATERMAN, BEN FARMER, KALISHA YANKEY, MARTA S. SMITH, JON R. HASTINGS, MELANIE SCOTT, ALAN D. CHERRINGTON

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引用次数: 0

Abstract

Diets high in fat and fructose (HFHF) disrupt glucose metabolism. This study compared the effects of a HFHF diet on liver insulin action vs glucose effectiveness. Dogs were fed either a chow or HFHF diet for 1 month. At the start of each study, 3-3H-glucose was infused and after a basal sampling period, somatostatin and basal glucagon were given. During the experimental period (4h) either insulin was infused into the hepatic portal vein at 4 fold basal, while glucose was delivered to maintain euglycemia (CHOW-INS and HFHF-INS), or glucose was infused to increase its level 2.5 fold, while insulin was maintained at basal (CHOW-GLC and HFHF-GLC) (n=6/grp). Plasma insulin, glucagon, glucose, and hepatic glucose load were matched within the respective groups. In response to selective hyperinsulinemia, net hepatic glucose balance (NHGB) was suppressed from output to uptake (basal period to last h; 1.2±0.1 to -1.0±0.2 vs 1.7±0.2 to 0.0±0.1; deltas of 2.2±0.2 vs 1.6±0.3 mg/kg/min in CHOW-INS vs HFHF-INS, respectively; p=0.2). Selective hyperglycemia, on the other hand, caused changes in NHGB of 1.1±0.2 to -2.5±0.4 vs 1.4±0.1 to 1.7±0.6; deltas of 3.6±0.4 vs -0.3±0.6 mg/kg/min in CHOW-GLC vs HFHF-GLC, respectively (p<0.001). Glucose turnover (Ra) was suppressed (basal period to last h) by 1.7±0.3 vs 1.3±0.1 mg/kg/min (p=0.4) in CHOW-INS vs HFHF-INS, and by 1.9±0.2 vs 0.5±0.1 mg/kg/min (p<0.001) in CHOW-GLC vs HFHF-GLC, respectively. Thus, the HFHF diet had a small, non-significant effect on liver insulin action under euglycemic conditions, whereas it severely impaired the effect of hyperglycemia in the presence of basal insulin (i.e. hepatic glucose effectiveness). These data demonstrate that the “gold standard” hyperinsulinemic euglycemic clamp may overlook substantial diet induced liver dysfunction. Furthermore, Ra accounts for glucose production but not liver uptake, thus has the potential to miss critical and substantial changes in liver glucose metabolism. Disclosure D.S. Edgerton: None. G. Kraft: None. H.L. Waterman: None. B. Farmer: None. K. Yankey: None. M.S. Smith: None. J.R. Hastings: None. M. Scott: None. A.D. Cherrington: Consultant; Abvance Therapeutics. Research Support; Abvance Therapeutics. Advisory Panel; AdipoPharma. Research Support; Cellular Longevity, Inc. dba Loyal. Advisory Panel; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Fractyl Health, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Paratus, Portal Insulin. Advisory Panel; Sekkei Bio, Sensulin Labs, LLC. Consultant; Thetis Pharmaceuticals, LLC. Funding R01DK18243

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1563-P：高脂肪和果糖喂养会严重损害肝脏的葡萄糖功效，但不会在优格血糖条件下损害胰岛素的作用

高脂肪和高果糖饮食（HFHF）会破坏葡萄糖代谢。这项研究比较了高脂肪、高果糖饮食对肝脏胰岛素作用和葡萄糖有效性的影响。给狗喂食饲料或 HFHF 食物，为期 1 个月。在每次研究开始时，输注 3-3H-葡萄糖，并在基础采样期后给予体生长抑素和基础胰高血糖素。在实验期间（4 小时），向肝门静脉输注胰岛素，胰岛素水平为基础水平的 4 倍，同时输注葡萄糖以维持优格血症（CHOW-INS 和 HFHF-INS）；或者输注葡萄糖，葡萄糖水平增加 2.5 倍，胰岛素水平维持在基础水平（CHOW-GLC 和 HFHF-GLC）（n=6/组）。各组的血浆胰岛素、胰高血糖素、血糖和肝糖负荷相匹配。在选择性高胰岛素血症的作用下，肝净葡萄糖平衡（NHGB）从输出到吸收均受到抑制（基础期到最后一小时；1.2±0.1 到 -1.0±0.2 vs 1.7±0.2 到 0.0±0.1；CHOW-INS vs HFHF-INS的deltas分别为2.2±0.2 vs 1.6±0.3 mg/kg/min；P=0.2）。另一方面，选择性高血糖引起的 NHGB 变化为 1.1±0.2 至 -2.5±0.4 vs 1.4±0.1 至 1.7±0.6；CHOW-GLC vs HFHF-GLC 的三角差分别为 3.6±0.4 vs -0.3±0.6 mg/kg/min（p<0.001）。CHOW-INS与HFHF-INS的葡萄糖周转率（Ra）分别为1.7±0.3 vs 1.3±0.1 mg/kg/min（p=0.4），CHOW-GLC与HFHF-GLC的葡萄糖周转率（Ra）分别为1.9±0.2 vs 0.5±0.1 mg/kg/min（p<0.001），CHOW-GLC与HFHF-GLC的葡萄糖周转率（Ra）分别为1.9±0.2 vs 0.5±0.1 mg/kg/min（p<0.001）。因此，HFHF 饮食对优血糖条件下肝脏胰岛素作用的影响很小且不显著，而它严重损害了基础胰岛素存在时高血糖的影响（即肝脏葡萄糖有效性）。这些数据表明，"黄金标准 "高胰岛素血糖钳夹可能会忽略饮食引起的肝脏功能障碍。此外，Ra 只考虑葡萄糖的产生，而不考虑肝脏对葡萄糖的吸收，因此有可能忽略肝脏葡萄糖代谢的关键和实质性变化。披露 D.S. Edgerton：无。G. Kraft：无：无。H.L. Waterman：无。B. Farmer：无：无。K. Yankey：无。M.S. Smith：无。J.R. Hastings：无。M. Scott: None.A.D. Cherrington：顾问；Abvance Therapeutics。研究支持；Abvance Therapeutics.顾问团；AdipoPharma。研究支持；Cellular Longevity, Inc.顾问小组；Fractyl Health, Inc.顾问；Fractyl Health, Inc.研究支持；Fractyl Health, Inc.顾问；诺和诺德公司。研究支持；Novo Nordisk。顾问；Paratus，Portal Insulin。顾问小组；Sekkei Bio、Sensulin Labs, LLC。顾问；Thetis Pharmaceuticals, LLC。资助 R01DK18243

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.