肥胖对非胰岛素依赖型糖尿病细胞内葡萄糖代谢缺陷的影响

Contribution of obesity to defects of intracellular glucose metabolism in NIDDM.

作者信息

Chung J W, Suh K I, Joyce M, Ditzler T, Henry R R

机构信息

Department of Medicine, University of California, San Diego, La Jolla, USA.

出版信息

Diabetes Care. 1995 May;18(5):666-73. doi: 10.2337/diacare.18.5.666.

DOI:10.2337/diacare.18.5.666

PMID:8586004

Abstract

OBJECTIVE

To examine the contribution of obesity to insulin resistance and abnormalities of intracellular glucose and fat metabolism in NIDDM.

RESEARCH DESIGN AND METHODS

Glucose turnover measurements and indirect calorimetry were performed in 10 obese non-insulin-dependent diabetes mellitus (NIDDM) and 10 lean NIDDM subjects (body mass index 35.3 +/- 1.0 vs. 24.1 +/- 0.5 kg/m2, P < or = 0.001) in the basal state and during hyperinsulinemic (720 pmol.m-2.min-1) euglycemic (5.0-5.5 mmol/l) clamps.

RESULTS

Obese and lean NIDDM subjects demonstrated similar basal rates of glucose uptake (GU) (1.15 +/- 0.08 vs. 1.26 +/- 0.08 mmol/min, NS) as well as oxidative (0.49 +/- 0.07 vs. 0.53 +/- 0.05 mmol/min, NS) and nonoxidative (0.67 +/- 0.10 vs. 0.73 +/- 0.12 mmol/min, NS) glucose metabolism. During hyperinsulinemic glucose clamp studies, rates of GU were lower in obese NIDDM subjects (34.1 +/- 2.3 vs. 55.2 +/- 3.8 mumol.kg fat-free mass [FFM]-1.min-1, P < or = 0.001) as were rates of oxidative (14.1 +/- 1.3 vs. 22.1 +/- 2.1 mumol.kg FFM-1.min-1, P < or = 0.005) and nonoxidative (20.0 +/- 2.3 vs. 33.1 +/- 3.6 mumol.kg FFM-1. min-1, P < or = 0.01) glucose metabolism. Although absolute rates of insulin-stimulated GU were decreased in the obese group, the relative distribution into glucose oxidation (GOX) and nonoxidative glucose metabolism (NOX) was comparable in both groups (GOX 42% in obese and 41% in lean subjects; NOX 58% in obese and 59% in lean subjects). The NIDDM groups had similar basal free fatty acid levels that were suppressed equally during hyperinsulinemic clamps. However, basal fat oxidation (Fox) was greater in the obese NIDDM group (103 +/- 11 vs. 73 +/- 8 mumol/min, P < or = 0.05) and was less suppressed to insulin (74 +/- 13 vs. 16 +/- 3 mumol/min, P < or = 0.001).

CONCLUSIONS

These results indicate that when obesity is present in NIDDM subjects with this degree of hyperglycemia, insulin-stimulated GU is lower by 35-40%. Reduced GU in obese NIDDM subjects leads to decreased intracellular substrate availability and lower rates of oxidative and nonoxidative glucose metabolism. Insulin suppression of Fox is also impaired when obesity is present and may contribute to decreased insulin-mediated GU in NIDDM. We conclude that obesity increases insulin resistance in NIDDM primarily by effects on GU rather than the intracellular pathways of glucose metabolism.

摘要

目的

研究肥胖对非胰岛素依赖型糖尿病（NIDDM）患者胰岛素抵抗以及细胞内葡萄糖和脂肪代谢异常的影响。

研究设计与方法

对10名肥胖非胰岛素依赖型糖尿病患者和10名体重正常的NIDDM患者（体重指数分别为35.3±1.0与24.1±0.5kg/m²，P≤0.001）在基础状态及高胰岛素血症（720pmol·m⁻²·min⁻¹）正常血糖（5.0 - 5.5mmol/l）钳夹试验期间进行葡萄糖代谢率测定和间接热量测定。

结果

肥胖和体重正常的NIDDM患者基础状态下的葡萄糖摄取（GU）率相似（分别为1.15±0.08与1.26±0.08mmol/min，无显著差异），氧化（分别为0.49±0.07与0.53±0.05mmol/min，无显著差异）和非氧化（分别为0.67±0.10与0.73±0.12mmol/min，无显著差异）葡萄糖代谢率也相似。在高胰岛素血症葡萄糖钳夹试验中，肥胖NIDDM患者的GU率较低（分别为34.1±2.3与55.2±3.8μmol·kg去脂体重[FFM]⁻¹·min⁻¹，P≤0.001），氧化（分别为14.1±1.3与22.1±2.1μmol·kg FFM⁻¹·min⁻¹，P≤0.005）和非氧化（分别为20.0±2.3与33.1±3.6μmol·kg FFM⁻¹·min⁻¹，P≤0.01）葡萄糖代谢率也较低。尽管肥胖组胰岛素刺激的GU绝对率降低，但两组葡萄糖氧化（GOX）和非氧化葡萄糖代谢（NOX）的相对分布相当（肥胖组GOX为42%，体重正常组为41%；肥胖组NOX为58%，体重正常组为59%）。NIDDM组基础游离脂肪酸水平相似，在高胰岛素血症钳夹试验期间均受到同等程度的抑制。然而，肥胖NIDDM组基础脂肪氧化（Fox）较高（分别为103±11与73±8μmol/min，P≤0.05），且对胰岛素的抑制作用较小（分别为74±13与16±3μmol/min，P≤0.001）。

结论

这些结果表明，在患有这种程度高血糖的NIDDM患者中，肥胖时胰岛素刺激的GU降低35 - 40%。肥胖NIDDM患者GU降低导致细胞内底物可用性降低，氧化和非氧化葡萄糖代谢率降低。肥胖时胰岛素对Fox的抑制作用也受损，这可能导致NIDDM患者胰岛素介导的GU降低。我们得出结论，肥胖主要通过影响GU而非葡萄糖代谢的细胞内途径增加NIDDM患者的胰岛素抵抗。