이진수 이성준 2018-08 27759 https://aurora.ajou.ac.kr/handle/2018.oak/19259 학위논문(박사)--아주대학교 일반대학원 :의학과,2018. 8 급성 뇌경색에서 고혈당과 당뇨는 흔한 합병증이며, 조기 신경학적 악화, 뇌경색의 확대, 출혈 변성 및 사망률의 증가와 관련있다. 부분 연구 1 에서 저자들은 당뇨에 병발된 급성 뇌경색에서 혈전 형성 단백인 fibrinogen과 조기 신경학적 악화의 연관성을 분석하였다. 부분연구 2 에서 저자들은 급성 뇌경색에서 혈관내 재개통 시술에 의한 재관류 이후 환자의 예후와 뇌경색의 확대, 출혈 변성과 초기 혈당 수치의 관련성을 분석하였다. 부분 연구 3 에서 저자들은 당뇨 모델 백서에서 DPP-4 억제제인 evogliptin과 metformin 을 독립적으로, 또는 동시에 투여하였을 때 뇌경색의 부피감소에 미치는 영향을 평가하였다. 부분연구 1: 조기 신경학적 악화와 fibrinogen 3814 명의 급성 뇌경색 발생 72시간 이내의 환자를 대상으로 연구를 진행하였다. 조기 신경학적 악화는 입원 7일 이내 National Institutes of Health Stroke Scale (NIHSS) 2점 이상 증가로 정의하였으며, 조기 신경학적 악화의 발생 여부를 propensity score matching을 통하여 당뇨군(조기 신경학적 악화군, n=261; 대조군, n=522) 과 비당뇨군(조기 신경학적 악화군, n=399; 대조군, n=798) 에서 각각 보정하여 분석하였다. Fibrinogen 수치는 전반적으로 조기 신경학적 악화군에서 높았다. 당뇨군에서 fibrinogen 수치는 조기 신경학적 악화의 예측 인자였으나, 비당뇨군에서는 유의한 영향을 보이지 않았다(혈중 fibrinogen 수치 300–599 mg/dL, odds ratio: 1.618 [95% confidence interval: 1.037 – 2.525], p=0.034, 혈중 fibrinogen 수치 ≥600 mg/dL, 2.575 [1.018 – 6.514], p=0.046; 비당뇨군, p=0.393). 본 결과에 따라 당뇨 환자에서 병발한 급성 뇌경색의 경우 혈중 fibrinogen 수치가 조기 신경학적 악화와 연관됨을 보였다. 부분연구 2: 동맥내 재관류 치료 의 예후와 고혈당 다기관 레지스트리를 통해, 2011 년 1월 ~ 2016 년 5월 사이 전순환 대혈관의 급성 폐색으로 동맥내 재관류 치료를 받은 환자들 중 시술 전후 뇌경색 부피를 뇌 자기 공명 확산 가중 영상(diffusion weighted image, DWI)을 통해 평가한 사람을 분석하였다. 내원시 혈당은 정상 혈당(glucose level ≤110 mg/dL), 중도 고혈당(>110 & ≤170 mg/dL), 명백 고혈당(>170 mg/dL)으로 나누어, 열악한 예후(3개월 modified Rankin Scale score 3–6), 뇌경색의 확대, 및 출혈 변성과의 관련성을 분석하였다. 720명의 레지스트리 군 중 341명이 대상이 되었다. 당화 혈색소 수치는 명백 고혈당 군에서 정상 혈당군과 중도 고혈당에 비하여 높았다(p<0.001). 중도 고혈당(2.37 [1.26–4.45], p=0.007)과 명백 고혈당(2.84 [1.19–6.81], p=0.019) 이 열악한 예후와 관련성을 보였다. 시술 후 뇌경색 부피는 전체 고혈당 군에서 유의하게 높았다(padjusted = 0.003). 혈당과 열악한 예후 및 뇌경색 확대는 재관류가 이주어지지 않은 군에서 특히 유의하였다. 명백 고혈당 만이 2 형 실질 혈종와 연관있었으며(9.28 [1.66–51.88], p = 0.011), 재관류 군에서 특히 유의하였다. 부분연구 3: 당뇨 약제의 신경 보호 가능성 6~8주령 백서에서 복강내 streptozotocin 주사로 1형 당뇨를 유발하였다. 백서들에게 30일 동안 대조군, evogliptin, metformin, 또는 evogliptin +metformin 복합요법을 투약하였다. 이후 중뇌동맥 폐색을 일시적으로 유발하여, 발생한 뇌경색의 부피를 T2 뇌 자기공명 영상으로 평가하였다. 그 결과 복합 투여군이 대조군에 비해 유의하게 낮은 뇌경색 부피를 보였다. 혈당 수치는 대조군에 비해 metformin군과 복합 투여군에서 유의하게 낮은 결과를 보인 반면 당화혈색소 수치는 복합 투여군 에서만 대조군에 비해 유의하게 낮았다. 혈장 insulin 수치는 복합 투여군에서 유의하게 높은 결과를 보였다. 본 실험은 1형 당뇨 모델 백서에서 metformin과 insulin 복합 투여가 적절한 혈당 조절 효과와 베타 세포 기능 촉진을 가져올 수 있으며, 이를 통해 허혈 뇌경색의 부피를 감소시킬 수 있음을 보였다. PART I. Early Neurological Deterioration Fibrinogen Level as a Marker for Early Neurological Deterioration in Patients with Acute Ischemic Stroke and Diabetes I. INTRODUCTION···························································2 II. METHODS···································································3 A. Study population····························································3 B. Data acquisition·····························································4 C. Propensity score matching and statistical analysis·····················5 III. RESULTS·····································································7 A. Analysis of total population···············································7 B. Analysis of diabetic population and propensity score matching······11 C. Analysis of non-DM population and propensity score matching·····16 IV. DISCUSSION·······························································21 PART II. Reperfusion Varying Levels of Hyperglycemia Adversely Affect Clinicoradiographic Outcomes After Endovascular Reperfusion Treatment I. INTRODUCTION··························································26 II. METHODS··································································28 A. Patient enrollment··························································28 B. Evaluation···································································29 C. Procedures·································································· 30 D. Grouping of presenting hyperglycemia and definition of DM········31 E. Statistical analysis························································· 32 III. RESULTS····································································33 A. Baseline characteristics stratified according to glucose status at hospitalization······························································33 B. Reperfusion treatment and outcomes····································36 C. Infarct growth······························································ 40 D. Hemorrhagic complications·············································· 43 IV. DISCUSSION·······························································46 PART III. Potential Neuroprotection Co-administration of Metformin and The DPP-4 Inhibitor Evogliptin Reduces Cerebral Infarct Volume in Diabetic Rat Brain I. INTRODUCTION·························································52 II. METHODS································································· 54 A. Animals and experimental groups·······································54 B. Drug treatment·····························································55 C. Transient middle cerebral artery occlusion·····························57 D. Magnetic resonance imaging············································58 E. Sacrifice and analysis of plasma and tissue··························· 59 F. Immunohistochemistry···················································60 G. Statistical analysis·························································61 III. RESULTS···································································62 A. Effect on body weight, food intake, and serial blood glucose levels after STZ induced diabetes and antidiabetic therapy··················62 B. Effects of antidiabetic medication on final infarct volume···········64 C. Final glucose levels, HbA1c levels, plasma insulin levels and GLP-1 levels after antidiabetic therapy··········································66 D. GLP-1 immunohistochemistry in ischemic rat brain tissue··········69 IV. DISCUSSION······························································74 REFERENCES······································································77 국문요약·············································································89 eng The Graduate School, Ajou University 아주대학교 논문은 저작권에 의해 보호받습니다. 급성 뇌경색에서 고혈당과 당뇨의 위해성과 이에 대항한 신경 보호 기전 Potential Neuroprotection Against Detrimental Effects of Diabetes and Hyperglycemia in Ischemic Stroke Thesis 아주대학교 일반대학원 Seong-Joon Lee 일반대학원 의학과 2018. 8 Master I804:41038-000000027759 http://dcoll.ajou.ac.kr:9080/dcollection/common/orgView/000000027759 Hyperglycemia Diabetes mellitus fibrinogen endovascular therapy evogliptin Hyperglycemia and Diabetes mellitus (DM) is a common comorbidity of ischemic stroke, and it is associated with adverse events such as early neurological deterioration (END), infarct growth, hemorrhagic transformation, and increased mortality. In PART I, we evaluated the association between fibrinogen, a prothrombotic protein, and END of diabetic patients with ischemic stroke. In PART II, we evaluated potential effects of admission hyperglycemia on outcomes, infarct growth, and hemorrhagic transformation after endovascular treatment (EVT). In part III, in diabetic rats, we evaluated the ant-ischemic effects of pretreatment with evogliptin, a dipeptidyl peptidase (DPP-4) inhibitor, and metformin, respectively, and combined. PART I: Early Neurological deterioration and fibrinogen We included 3814 ischemic stroke patients within 72 hours of onset. To evaluate the association between fibrinogen and END (National Institutes of Health Stroke Scale [NIHSS] ≥ 2 increase within 1 week of admission), analysis based on propensity score matching between END and non-END population in DM (END, n=261; non-END, n=522) and non-DM populations (END, n=399; non-END, n=798) was performed. Fibrinogen levels were overall higher in the END subgroup compared to non-END subgroup. Only in the DM population were fibrinogen levels an independent predictor for END (fibrinogen levels 300–599 mg/dL, odds ratio: 1.618, 95% confidence interval: 1.037 – 2.525, p=0.034, fibrinogen levels ≥600 mg/dL, 2.575, 1.018 – 6.514, p=0.046; non-DM population, p=0.393). In diabetic patients with acute ischemic stroke, elevated fibrinogen is associated with END dose-dependently. PART II: Adverse effects of hyperglycemia after reperfusion therapy Between January 2011 and May 2016, patients that underwent EVT with pre-procedural and post-procedural diffusion-weighted imaging were identified from a multicenter registry. Normoglycemia was defined as a glucose level ≤110 mg/dL, moderate hyperglycemia as >110 and ≤170 mg/dL, and overt hyperglycemia as >170 mg/dL. Its effects on poor outcomes (3-month modified Rankin Scale score 3–6), infarct growth, and parenchymal hematoma type 2 were analyzed. Of 720 patients encountered, 341 patients were eligible. Glycated hemoglobin levels were higher in overt hyperglycemia group compared to normoglycemia/moderate hyperglycemia group (p<0.001). Moderate hyperglycemia (odds ratio 2.37 [95% confidence interval 1.26–4.45], p=0.007) and overt hyperglycemia (2.84 [1.19–6.81], p=0.019) were associated with poor outcomes. Post-procedural infarct volumes were significantly greater in hyperglycemic patients (padjusted = 0.003). Both findings were confirmed in the total population, and the non-reperfusion subgroup. Only overt hyperglycemia (9.28 [1.66–51.88], p = 0.011) was associated with parenchymal hematoma type 2. This association was confirmed in the total population, and reperfusion subgroup. PART III: Potential neuroprotection of antidiabetic drugs Type 1 diabetes was induced by intraperitoneal injection of streptozotocin in rats aged 6~8 weeks. The rats were treated with vehicle, evogliptin, metformin, or evogliptin/metformin co-administration for 30 days. Stroke was induced by transient middle cerebral artery occlusion afterwards. Ischemic damage was measured by determining infarct volume through T2 weighted magnetic resonance imaging. The results showed pronounced reduction of infarct volume in the co-administration group. Blood glucose lowering effects were significant in the metformin group and co-administration group, while glycated hemoglobin levels were significantly lower in the co-administration group. Plasma insulin levels were significantly higher in the co-administration group. These results show that combined treatment of metformin and evogliptin provide further glycemic control, improve beta cell function and offer neuroprotective effects against ischemic stroke.