PPAR-γ藥物對第2型糖尿病患脂肪細胞激素RBP4及臨床表現的影響

PPAR-γ Effects on Retinal Binding Protein 4 (RBP4) and clinical manifestations in Type 2 Diabetes

林昆德(Kun-Der Lin)

指導教授 ： 辛錫璋

高雄醫學大學/醫學院/醫學研究所/博士(2014年)

https://doi.org/10.6832/KMU.2014.00057

摘要

第2型糖尿病的成因相當多，包括先天的遺傳因素和後天的環境因素等。就糖尿病的疾病生理學而言，肥胖、脂肪組織的增生以及胰島素阻抗性的升高都佔有一個重要的成分。胰島素阻抗性的增加和脂肪細胞肥大、脂肪細胞激素不正常分泌則有密切的關聯。
Retinol-binding protein 4(RBP4)是一個新的脂肪細胞激素，它會造成胰島素阻抗性的增加，在動物的模式中RBP4的注射會使血糖升高，在細胞實驗的研究上RBP4調控CRBP-I/JAK2/STAT5路徑，進一步使細胞凋亡；小型研究中肥胖的人、潛伏性糖尿病人和胖的糖尿病患中RBP4的濃度也是逐漸的增高。所以RBP4會增加胰島素阻抗性、進而影響糖尿病病患的臨床控制。
PPAR-γ的活化會改善脂肪細胞的分化、進一步改善胰島素的阻抗性，也可以減緩內皮細胞對於發炎反應的傷害，減緩糖尿病腎病變的進展等。PPAR-γ也會影響脂肪細胞激素的分泌如增加adiponectin, 減少TNF-α, IL-6等的分泌。PPAR-γ agonists (Thiazolidinedione, TZD)臨床上被用來治療第2型糖尿病病患、經由改善胰島素的阻抗性來達到控制血糖的目標。所以我們研究經過TZD藥物治療後臨床上的第2型糖尿病病患血液中adiponectin, RBP4等細胞激素的變化如何，是否和胰島素阻抗性及抗發炎反應有相關性。
在這一系列的研究中，我們發現RBP4上升對於第2型糖尿病病患的胰島素阻抗性的確有相關，在經過TZD藥物的治療後也有意義的改善。而臨床上影響RBP4的高低除了血糖的控制外、糖尿病腎病變的情形、腎功能的好壞及尿酸的高低都有相關性。細胞學的研究中也發現RBP4會經由STRA6進入細胞內，藉由CRBP-I/JAK2/STAT5等路徑影響細胞的凋亡。在長期追蹤觀察後、我們也發現TZD類的藥物使用會影響糖尿病病患中的紅血球數目輕微下降並且造成體重的顯著上升。在停止TZD藥物的10個月後體重有明顯下降但紅血球的數目仍然沒有恢復，這個效果應該和骨骼的造血功能被TZD藥物所抑制有關，而且這個影響至少持續10個月以上。
在我們這一系列的研究中，我們專注在第2型糖尿病病患的PPAR-γ藥物治療作用中、並以脂肪細胞激素RBP4作為研究的標的。我們的研究顯示RBP4在糖尿病腎病變的患者身上有正相關、腎功能越差、尿酸濃度越高則RBP4的濃度就越高。在第2型糖尿病病患使用pioglitazone®治療會降低血中的RBP4濃度、也會改善病患的胰島素阻抗性。長期使用pioglitazone®的治療則會造成病患的血色素、紅血球數目的輕微降低，這個效果應該是透過抑制骨骼的造血系統。換句話說，長期使用pioglitazone®治療的第2型糖尿病病患體內造血系統會被輕微的抑制。這些經驗可以提供臨床醫師在治療第2型糖尿病患者時的一個參考。

關鍵字

糖尿病 ； 胰島素阻抗性 ； PPAR-γ ； thiazolidinedione ； RBP4 ； 脂聯素 ； 脂肪激素

並列摘要

Diabetes Mellitus (DM) is a major issue of public health around the world. The pathophysiological factors of type 2 DM are diverse, including the genetic and environmental factors. The insulin resistance, abdominal obesity, and sick of adipose tissue have major effects on metabolic syndrome and they play an important role in contributing to type 2 DM.
We focus on serum retinol-binding protein 4 (RBP4) secreted mainly by adipocytes, and study its effect on insulin resistance clinically. We analyze the differences of RBP4 in patients with or without type 2 DM, and the interactions with other clinical factors. The RBP4 also regulates STRA6/CRBP-I/JAK2/STAT5 pathway and causes cell apoptosis in vitro.
PPAR-γ agonists can improve insulin resistance, affect the differentiations of adipocytes, and reduce the inflammations of endothelial cells and slow the progression of diabetic nephropathy. We study the effects of PPAR-γ on serum RBP4 and adiponectin in our type 2 diabetic patients.
Thiazolidinedione(TZD) is a PPAR-γ agonist, and is widely used to treat type 2 DM in recent years for controlling the blood glucose through enhancing insulin sensitivity. Pioglitazone® is one of the TZDs and its common side effects are body weight gain, congestive heart failure, lower legs edema and etc. In 2011, FDA warned the higher risk of developing bladder cancer in men and atypical bone fracture in women after long term treatments of pioglitazone® in patients with type 2 DM by meta-analysis announced in mid-2011. Some of our patients withdrew pioglitazone® treatment since that time. So, we designed a prospective study to observe the long-term effects in our type 2 DM patients treated with pioglitazone® and who withdrew pioglitazone® treatment.
Our results showed that the increase of RBP4 correlates with the increase of insulin resistance in our diabetic patients; and the serum RBP4 is decreased after treatment of pioglitazone 30mg/day for 3 months. The serum RBP4 is correlated to the stages of diabetic nephropathy and also correlated with renal function and uric acid level in our clinical findings.
The side effects of pioglitazone® treatment including body weight gain, decreases of RBC, hemoglobin (Hb), and hematocrit (Hct) in type 2 diabetic patients. After stopping pioglitazone® treatment for 10 months, the body weight gain reversed but surprisingly, RBC, Hb and Hct did not. It implies that pioglitazone causes bone marrow suppression and this effect persisted more than 10 months. This finding provokes us to seriously consider the persistent effects of PPAR-γ agonist on the hematopoietic system in type 2 diabetic patients.
In these series study, we study the PPAR-γ effects in our type 2 DM, and focus on adipocytokine, RBP4. The serum RBP4 is correlated with diabetic nephropathy stage, renal function and serum uric acid level. Pioglitazone, a PPAR-γ agonist, can decrease RBP4 level in type 2 DM and increase insulin sensitivity. Long term PPAR-γ treatment also causes tiny but significantly reduction of hematopoietic system and reduces RBC, Hb and Hct level in type 2 DM. These findings can provide the additional information to treat our type 2 diabetic patients in clinical practice.

並列關鍵字

diabetes ； insulin resistance ； PPAR-γ ； thiazolidinedione ； RBP4 ； adiponectin ； adipocytokine

參考文獻

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