动态示踪酮症倾向2型糖尿病的糖脂代谢流紊乱机制

With the tremendous increase of incidence rate of type 2 diabetes, a new type called ketosis prone type 2 diabetes mellitus (KPDM) increased as well. The clinical manifestations of this disease were inconsistent with typical type 1 and type 2 diabetes and the mechanisms in glucose and lipids disorder of KPDM were still unclear. From our previous studies, we found isotope tracer technology has special superiority in exploring pathophysiology mechanisms in metabolic disease. This study was undertaken to determine the in vivo glucose and lipids flux dynamically in KPDM rats. The study aimed to trace the glucose flux including endogenous glucose production, oral glucose rate of appearance and glucose rate of disappearance and the lipids flux including fatty acids lipolysis, fatty acids storage and the flux of ketone bodies. At the same time, proteins and enzymes relating to lipids synthesis, hormones regulating glucose metabosim were also measured. With combined analysis of the glucose and lipids flux and the lipid parameters, the study was conducted to elucidate metabonomics of glucose and lipids metabolism and the key point for treatment of KPDM. The study serves to optimize the glucose regulation project and has clinical and translational medical significance in preventing the recurrence of ketosis or ketoacidosis.

随着2型糖尿病发病率的迅猛增高，自发酮症倾向2型糖尿病发病也呈上升趋势。该病临床表现与典型1型或2型糖尿病不完全相同，且其糖脂代谢紊乱机制至今尚不明确。我们前期研究表明同位素示踪技术在代谢性疾病的病理生理机制研究中具有独特的方法学优势。本课题拟应用该技术对酮症倾向2型糖尿病大鼠模型体内葡萄糖和脂肪酸流进行示踪。以期阐明体内葡萄糖流（内源性葡萄糖输出率、肠道来源血浆葡萄糖出现率和消失率，以及骨骼肌葡萄糖摄取率）和脂肪酸流（脂肪酸分解率，脂肪组织脂肪酸摄取率，酮体的生成和利用）的全程动态变化。同时测定脂肪酸转移蛋白、脂肪合成酶活性及糖调节激素水平。通过葡萄糖流、脂肪酸流及糖脂代谢相关参数的分析整合，进一步明确酮症倾向2型糖尿病糖脂代谢障碍发生的机理及降糖干预的关键靶点。本研究对于指导酮症倾向2型糖尿病优化降糖方案，预防酮症或酮症酸中毒反复发生具有重要的临床意义和转化医学价值。

酮症倾向2型糖尿病的临床表现与典型1型或2型糖尿病不完全相同，且其糖脂代谢紊乱机制至今尚不明确。本课题应用同位素示踪技术对酮症倾向2型糖尿病大鼠模型体内葡萄糖和脂肪酸流进行示踪。以期阐明体内葡萄糖流和脂肪酸流的全程动态变化,进一步明确酮症倾向2型糖尿病糖脂代谢障碍发生的机理及降糖干预的关键靶点。本课题研究在糖尿病大鼠中，发现空腹血浆葡萄糖浓度在酮症倾向2型糖尿病组较普通糖尿病组明显增高（P = 0.036）。葡萄糖负荷后，血糖浓度峰值（P < 0.0001）和血糖浓度曲线下面积（AUC）（P = 0.0006）在酮症倾向2型糖尿病中均明显升高。糖尿病和酮症倾向2型糖尿病组空腹血浆胰岛素浓度无明显统计学差异（P = 0.49）。然而，葡萄糖负荷后酮症倾向2型糖尿病组血浆胰岛素浓度明显减低(P = 0.023)。且酮症倾向2型糖尿病组血浆胰岛素浓度高峰出现明显延迟(120 vs. 90 min)。酮症倾向2型糖尿病组 (P = 0.028）胰岛素敏感指数（ISI）较非糖尿病组明显减低。酮症倾向2型糖尿病组（P = 0.009）胰岛素原指数（ΔI30/ΔG30）较非糖尿病组明显减低。酮症倾向2型糖尿病组的基础内源性葡萄糖输出率较普通糖尿病组明显增高（P = 0.0034）。基础内源性葡萄糖输出（EGP）与基础血浆葡萄糖浓度呈正相关，R2=0.78。在非糖尿病组中，最低餐后EGP 大约出现在餐后90 min 左右，酮症倾向2型糖尿病组最低餐后EGP 大约出现在餐后150 min 左右。酮症倾向2型糖餐后2小时之内EGP 曲线下面积较正常组明显增高（P = 0.022）。游离脂肪酸出现率（P = 0.03）、血浆β-羟丁酸出现率（P = 0.018）。血浆乙酸出现率（P = 0.022）在酮症倾向2型糖尿病组的出现率明显高于普通2型糖尿病。脂肪组织脂肪酸摄取率（P = 0.009）在酮症倾向2型糖尿病组的出现率明显低于普通2型糖尿病。本研究对于指导酮症倾向2型糖尿病优化降糖方案，预防酮症或酮症酸中毒反复发生具有重要的临床意义和转化医学价值。