有和没有2型糖尿病的肥胖和非肥胖受试者的完整胰岛素原和β细胞功能。

Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes.

作者信息

Røder M E, Dinesen B, Hartling S G, Houssa P, Vestergaard H, Sodoyez-Goffaux F, Binder C

机构信息

Steno Diabetes Center, Gentofte, Denmark.

出版信息

Diabetes Care. 1999 Apr;22(4):609-14. doi: 10.2337/diacare.22.4.609.

DOI:10.2337/diacare.22.4.609

PMID:10189540

Abstract

OBJECTIVE

Type 2 diabetes is a heterogeneous disease in which both beta-cell dysfunction and insulin resistance are pathogenetic factors. Disproportionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnormality in type 2 diabetes whose mechanism is unknown. Increased demand due to obesity and/or insulin resistance may result in secretion of immature beta-cell granules with a higher content of intact proinsulin.

RESEARCH DESIGN AND METHODS

We investigated the impact of obesity on beta-cell secretion in normal subjects and in type 2 diabetic patients by measuring intact proinsulin, total proinsulin immunoreactivity (PIM), intact insulin, and C-peptide (by radioimmunoassay) by specific enzyme-linked immunosorbent assays in the fasting state and during a 120-min glucagon (1 mg i.v.) stimulation test. Lean (BMI 23.5 +/- 0.3 kg/m2) (LD) and obese (30.1 +/- 0.4 kg/m2) (OD) type 2 diabetic patients matched for fasting glucose (10.2 +/- 0.6 vs. 10.3 +/- 0.4 mmol/l) were compared with age- and BMI-matched lean (22.4 +/- 0.6 kg/m2) (LC) and obese (30.8 +/- 0.9 kg/m2) (OC) normal control subjects.

RESULTS

Diabetic patients (LD vs. LC and OD vs. OC) had elevated fasting levels of intact proinsulin 6.6 +/- 1.0 vs. 1.6 +/- 0.3 pmol/l and 7.7 +/- 2.0 vs. 1.2 +/- 0.2 pmol/l; PIM: 19.9 +/- 2.5 vs. 5.4 +/- 1.0 pmol/l and 29.6 +/- 6.1 vs. 6.1 +/- 0.9 pmol/l; and total PIM/intact insulin: 39 +/- 4 vs. 15 +/- 2% and 35 +/- 5 vs. 13 +/- 2%, all P < 0.01. After glucagon stimulation, PIM levels were disproportionately elevated (PIM/intact insulin based on area under the curve analysis) in diabetic patients (LD vs. LC and OD vs. OC): 32.6 +/- 6.7 vs. 9.2 +/- 1.1% and 22.7 +/- 5.2 vs. 9.1 +/- 1.1%, both P < 0.05. Intact insulin and C-peptide net responses were significantly reduced in type 2 diabetic patients, most pronounced in the lean group. The ratio of intact proinsulin to PIM was higher in diabetic patients after stimulation in both LD versus LC: 32 +/- 3 vs. 23 +/- 2%, and OD versus OC: 28 +/- 4 vs. 16 +/- 2%, both P < 0.01. In obese normal subjects, intact proinsulin/PIM was lower both in the fasting state and after glucagon stimulation: OC versus LC: 22 +/- 3 vs. 33 +/- 3% (fasting) and 16 +/- 2 vs. 23 +/- 2% (stimulated), both P < 0.05.

CONCLUSIONS

Increased secretory demand from obesity-associated insulin resistance cannot explain elevated intact proinsulin and disproportionate hyperproinsulinemia in type 2 diabetes. This abnormality may be an integrated part of pancreatic beta-cell dysfunction in this disease.

摘要

目的

2型糖尿病是一种异质性疾病，其中β细胞功能障碍和胰岛素抵抗都是致病因素。不成比例的高胰岛素原血症（胰岛素原/胰岛素升高）是2型糖尿病中的另一种异常情况，其机制尚不清楚。肥胖和/或胰岛素抵抗导致的需求增加可能会导致未成熟的β细胞颗粒分泌，这些颗粒中完整胰岛素原的含量更高。

研究设计与方法

我们通过在空腹状态和120分钟胰高血糖素（静脉注射1毫克）刺激试验期间，采用特定的酶联免疫吸附测定法测量完整胰岛素原、总胰岛素原免疫反应性（PIM）、完整胰岛素和C肽（通过放射免疫测定法），研究肥胖对正常受试者和2型糖尿病患者β细胞分泌的影响。将空腹血糖匹配（10.2±0.6对10.3±0.4毫摩尔/升）的瘦型（BMI 23.5±0.3千克/平方米）（LD）和肥胖型（30.1±0.4千克/平方米）（OD）2型糖尿病患者与年龄和BMI匹配的瘦型（22.4±0.6千克/平方米）（LC）和肥胖型（30.8±0.9千克/平方米）（OC）正常对照受试者进行比较。

结果

糖尿病患者（LD与LC以及OD与OC）空腹时完整胰岛素原水平升高（6.6±1.0对1.6±0.3皮摩尔/升以及7.7±2.0对1.2±0.2皮摩尔/升）；PIM：19.9±2.5对5.4±1.0皮摩尔/升以及29.6±6.1对6.1±0.9皮摩尔/升；总PIM/完整胰岛素：39±4对15±2%以及35±5对13±2%，所有P<0.01。胰高血糖素刺激后，糖尿病患者（LD与LC以及OD与OC）的PIM水平不成比例地升高（基于曲线下面积分析的PIM/完整胰岛素）：32.6±6.7对9.2±1.1%以及22.7±5.2对9.1±1.1%，两者P<0.05。2型糖尿病患者完整胰岛素和C肽的净反应显著降低，在瘦型组中最为明显。刺激后，糖尿病患者中完整胰岛素原与PIM的比率更高，在LD与LC中：32±3对23±2%，在OD与OC中：28±4对16±2%，两者P<0.01。在肥胖正常受试者中，空腹状态和胰高血糖素刺激后完整胰岛素原/PIM均较低：OC与LC相比：空腹时为22±3对33±3%，刺激后为16±2对23±2%，两者P<0.05。