The pathogenesis of post-renal transplantation diabetes mellitus : β-cell dysfunction rather than insulin resistance is the main factor

Abstract

[한글]

신이식후 당뇨병의 발병 기전 : 인슐린저항성 보다는 메타세포 기능이상이 주요한 발병 인자이다

신이식후 발생하는 당뇨병의 유병률은 정상 인구에서의 당뇨병 유병률 보다 훨씬 높다.

이에 대한 원인적 요소로 면역억제제, 유전적 영향, 스트레스 및 이뇨제의 사용 등이 제시되고 있으나 아직까지 그 기전은 정확히 알려져 있지 않으며 특히 인슐린저항성과 인슐린결핍 중 어느 것이 더 중요한 요인인지에 대해서도 아직 밝혀지고 있지 않다. 본 연구는 신이식후 당뇨병의 병리기전과 가능한 위험요인에 대해 알아보기 위해서 연구를 수행하였다. 본 연구는 114명의 환자(평균 연령 39세, 23-55세 사이)를 대상으로 이식 전 1주일과 이식 후 9개월에서 12개월 사이에, 인슐린(0.1U/kg)을 정맥 투여한 후 혈당감소 속도를 통하여 인슐린저항성을 측정하였으며, 75 g 경구당부하 검사를 통하여 인슐린분비능을 각각 측정하였다. 이식 후에 시행한 경구당부하 검사의 결과를 통하여 WHO 기준에 따라 이식환자들을, 정상(normal glucose tolerance, NGT), 내당능쟁애(impaired glucose tolerance, IGT), 그리고 당뇨병(post-renal transplantation diabetes mellitus, PTDM) 군으로 나누었다. 방사능면역분석법으로 인슐린과 프로인슐린을 측정하였고, 지방과 근육의 변화는 impedence 방법을 통해 측정하였다. 세 군 사이에 스테로이드와 cyclosporin A의 복용량에는 차이가 없었다. 이식 전 나이, 공복 및 경구당부하 2시간혈당, 프로인슐린/인슐린 비 등은 세군 간에 의미있는 차이를 보였다. 인슐린 저항성은 이식 후에 모든 군에서 증가했으나, 이식 후 NGT판에서 가장 현저하게 나타났다. 이식 후 프로인슐린/인슐린 비는 NGT군에 비해 PTDM군에서 의미있게 높았다. 지방 성분(%)은 IGT와 PTDM 군에서 의미있게 높았으며 근육성분은 이식 후 IGT와 PTDM군에서 의미있게 감소하였다(p<0.05).

이러한 결과들은, 베타세포 기능장애를 나타내는 이식 전 공복 및 경구당부하 2시간혈당, 프로인슐린/인슐린 비가 이식 후 당뇨병 발병에 대한 예측인자가 될 수 있을 것으로 사료되며 이러한 분비능에 장애를 가진 환자가 이식 후 면역억제제에 의한 인슐린분비의 감소가 당뇨병의 주요한 발병 원인으로 추측된다. 하지만 체성분 변화에 따른 인슐린 저항성 또한 PTDM 발생에 어느 정도는 기여 할 것으로 사료된다

[영문]

The prevalence of post-renal transplantation diabetes, mellitus(PTDM) is known to be much higher than that of diabetes, mellitus(DM) in a normal population. Immurlosuppressants, genetic influences, stress, and diuretics have been suggested as the etiopathogenic factors. However, the predominant factor and its exact mechanism is still controversial, and whether insulin resistance or insulin deficiency has the main role in the development of PTDM has, not yet been identifiers. To investigate the pathogenesis and possible risk factors for PTDM, we recruited 114 patients(mean age 39 years range 23-55 years) with normal glucose tolerance, and performed 75g oral glucose tolerance tests(OGTT) and insulin tolerance tests 1 week before and 9-12 months after transplantation, respectively.

The subjects were classified into three groups one the basis of OGTT after transplantation by WHO criteria: 1) 36 subjects with normal glucose tolerance(NGT); 2) 51 subjects with impaired glucose tolerance(IGT); and 3) 27 subjects with post-renal transplantation diabetes mellitus(PTDM). Each group was 31.6%, 45.7%, and 23.7%, respectively. Post transplantation patients can further be categorized into a weight-gain group(n=68, 60%) and non-weight-gain group(n=46, 40%).There were more PTDM patients in the weight-gain group than non-weight-gain group(26% vs. 20%). Changes in the fat content(%) and muscle content were determined by the impedance method. Dosages of steroid and cyclosporin-A(CsA) were equivalent among the 3 groups. Before transplantation, the fasting plasma glucose level, 2-h plasma

glucose level, fasting plasma insulin and proinsulin/insulin ratios were significantly higher in the IGT and PTDM groups than in the NGT group. In addition, the area under the curve(AUC)-insulin on OGTT was significantly lower in the PTDM group than in the NGT group before transplantation and particularly decreased in the PTDM group after transplantation. After transplantation, however, the index of insulin resistance, Kitt, was increased in all groups, particularly in the NGT group. Furthermore, the proinsulin/insulin ratios revealed significantly higher values in the PTDM group than in the NGT group after transplantation. The fat content(%) in the IGT and PTDM groups was significantly increased and true muscle content in these two groups was significantly decreased after transplantation(p<0.05). SHBG levels were significantly higher in the IGT and PTDM groups than in the NGT group after transplantation(18.7±2.5, 19.9±3.4 vs.

15.4±1.6 nM/L, p<0.05), and there was also a significant increase in the IGT and PTDM group, in the weight-gain group, not non-weight-gain group (Tab1e 3).

Free testosterone levels were significantly increased after transplantation, but were lower in the IGT and PTDM groups compared to that in the NGT group after transplantation (40.9±6.6, 30.58±8.7 vs,52.4±6.6 nM/L). Free testosterone was

lower in PTDM patients than in NGT patients in both the weight-gain and non-weight-gain groups(24.3±8.7 vs. 47.5±10.1, 39.1.±]0.2 vs. 60.0±4.2 nM/L).

Leptin levels were significantly higher in the IGT and PTDM groups than in the NGT groups after transplantation(9.5±1.6, 8.1±2.9 vs. 5.9±1.6μg/L), and this effect was more pronounced in the IGT and PTDM groups with weight gain.

These results revealed that fasting and 2-h plasma glucose levels, as well as proinsulin/insulin ratio before transplantation, which may all be indicators of β-cell dysfunction, could be the predictors for the development of PTDM and β-cell dysfunction rather than insulin resistance was Proved to be the main factor for the pathogenesis of PTDM. In addition, after transplantation, further deterioration of insulin secretion by immunosuppressants, and the development of insulin resistance caused by the changes of fat content, muscle mass and body weight accompanied by the changes of SHBG, free testosterone and leptin were also shown to be important predisposing factors for PTDM.