「胰島素阻抗性」是代謝症候群的致病主因。愈來愈多的證據顯示，由肝臟產生的體液因子可能會影響胰島素標的組織之胰島素訊息傳遞，而這些肝臟合成/釋放的蛋白質（hepatokines，肝臟激素）包括視網醇結合蛋白4 (retinol-binding protein 4, RBP4)與胎球蛋白A (fetuin-A)。在本研究的設計架構中，首先我們探討RBP4在高血壓動物模式與人類受試者的病態生理學所扮演之角色。其次，我們探討血清fetuin-A濃度和不同血糖狀況病人間之相關性。最後，我們研究當糖尿病合併非酒精性脂肪肝疾病時對血清fetuin-A濃度之影響。
在第一部分的研究中，我們利用自發性高血壓大鼠（SHR）來探討RBP4與胰島素阻抗性間之關係。研究結果發現在7週大的SHR大鼠，其血清中RBP4濃度與肝臟及附睾脂肪組織中的RBP4表現量都比對照組WKY大鼠高，同時也伴隨著胰島素阻抗性的增加。而當給予SHR大鼠fenretinide藥物以增加尿中RBP4的排泄時，不僅可降低血清中RBP4的濃度，也可顯著改善胰島素阻抗性。此外，使用血管收縮素II受體阻斷劑(valsartan)治療SHR大鼠，除了可降低血壓外，同樣也可降低血清中RBP4濃度及改善胰島素阻抗性。這些結果顯示，RBP4在SHR大鼠的胰島素阻抗性的致病機轉中扮演重要角色。
在人體的初步早期研究中，我們發現在血糖正常且無胰島素阻抗性的肥胖受試者，血壓是血清中RBP4的獨立相關因子。因此，我們進一步探討血清中RBP4濃度與「高血壓前期」和「新診斷高血壓」間之關係。研究結果發現，在年齡和性別匹配的「正常血壓」、「高血壓前期」及「新診斷高血壓」三組受試者中，男性的血清RBP4濃度都高於女性。然而，血清RBP4濃度在「高血壓前期」及「新診斷高血壓」組並未比「正常血壓」組高。多元線性回歸分析結果發現，血清RBP4濃度與男性（p<0.05），估計腎絲球濾過率（eGFR）（p<0.05）及空腹血糖值（p<0.001）呈現獨立相關，但與「血壓」，「高血壓前期」和「新診斷高血壓」則沒有相關。由於 RBP4是一種低分子量蛋白質，可自由地經腎絲球濾出，隨後再完全吸收到近端腎小管中，因此我們的研究結果顯示，血壓對RBP4的影響遠小於腎功能的影響。這也是「高血壓前期」和「新診斷高血壓」對 RBP4濃度並無顯著影響的主因。
Fetuin-A是一種肝源性糖蛋白，在過去的研究發現fetuin-A會抑制胰島素的訊息傳遞，導致胰島素阻抗性的發生。研究也顯示，血清fetuin-A與與肝臟中脂肪含量成正相關；同時，在前瞻性研究中發現血清fetuin-A也可預測第2型糖尿病發生的風險。為了探討fetuin-A在血糖代謝異常的角色，我們延攬年齡和性別匹配的「正常血糖」（NGT）、「空腹血糖異常」（IFG）、「葡萄糖耐受性不良」（IGT）和「新診斷糖尿病」（NDD）且無非酒精性脂肪肝疾病（NAFLD）四組受試者。結果顯示，血清fetuin-A濃度在「葡萄糖耐受性不良」和「新診斷糖尿病」組顯著高於「正常血糖」組。多元線性回歸分析結果也發現，經調整年齡、人體測量學指標、血脂值、估計腎絲球濾過率、脂締素(adiponectin)、C -反應蛋白（CRP）與胰島素阻抗性指標（HOMA- IR）後，IGT（p<0.01）和NDD（p<0.01）仍與血清fetuin-A濃度呈現正相關，但年齡（p<0.05）則是負相關因素。
最後，我們發現當糖尿病併發NAFLD時，會明顯升高糖尿病患者血清fetuin-A濃度。即便在調整過其他心臟代謝危險因素（包括中心型肥胖、CRP、血脂值與脂締素）後，仍然具有統計上的顯著差異。因此，我們推測fetuin- A血清濃度的升高可能與併發糖尿病及非酒精性脂肪肝疾病之患者有較高的心血管疾病發病率有關。
綜言之，在本研究中，我們證明了肝臟和脂肪組織產生的RBP4在SHR大鼠胰島素阻抗性惡化的致病機轉中扮演重要角色。我們的研究結果也顯示，血管收縮素II受體阻斷劑(valsartan)的胰島素增敏作用與RBP4血中濃度減少有關。在人類研究中，我們發現在腎功能正常的「新診斷高血壓」、「高血壓前期」及「正常血壓」受試者血清RBP4濃度並無差異。同時，在調整過性別與心血管危險因素後，估計腎絲球濾過率仍與血清RBP4濃度獨立相關。此外，我們證明了無「非酒精性脂肪肝疾病」之「新診斷糖尿病」與「葡萄糖耐受性不良」組的受試者，血清fetuin-A濃度比「正常血糖」組高。我們的結果也顯示，當糖尿病併發NAFLD時，會進一步提升血清fetuin-A濃度。至於fetuin-A在脂肪肝和糖尿病患者相關的心血管疾病風險之角色，未來還需要前瞻性研究進一步研究及探討。

Insulin resistance (IR) is a fundamental component of metabolic syndrome. Growing evidence suggests that humoral factors produced by the liver may affect insulin signaling in insulin-responsive tissues. These liver synthesized/released-proteins are referred to as “hepatokines”, and include retinol binding protein 4 (RBP4) and fetuin-A. This study was designed to investigate the role of RBP4 in hypertensive human subjects and spontaneously hypertensive rats (SHR). In addition, we also investigated the relationship between serum fetuin-A concentrations and different glycemic status. Finally, we studied the combined effect of diabetes and nonalcoholic fatty liver disease (NAFLD) on serum fetuin-A levels.
In the first part of the study, we used SHR to evaluate the relationship between RBP4 levels and IR. We found that in SHR with developing hypertension, serum levels and expression of RBP4 in liver and epididymal adipose tissue were increased, accompanied by worsening of IR as compared with Wistar-Kyoto (WKY) control rats. Administration of fenretinide in SHR to increase urinary RBP4 excretion significantly decreased plasma RBP4 levels and improved IR. Moreover, treatment with valsartan markedly reduced blood pressure, circulating RBP4 levels, and IR in SHR. Valsartan also reversed the increase of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the decrease of type 4 glucose transporter (GLUT4) in adipose tissue. These results suggest that RBP4 contributes, at least partly, to the pathogenesis of IR in SHR.
In our early work on human subjects, we found that blood pressure is an independently associated factor of serum RBP4 in normoglycemic non-insulin-resistant obese subjects. Therefore, we further investigated the relationship among serum RBP4 levels and prehypertension and newly-diagnosed hypertension. We showed that among age- and sex-matched subjects with normotension, prehypertension, and hypertension, males had higher RBP4 levels than females. However, serum RBP4 levels were not increased in hypertensive and prehypertensive subjects as compared with normotensive subjects. In multivariate linear regression analysis, serum RBP4 was independently associated with male gender (p<0.05), estimated glomerular filtration rate (eGFR) (p<0.05), and fasting plasma glucose (p<0.001), but not with blood pressure, prehypertension, and hypertension. As RBP4 is a low-molecular weight protein which is freely filtered in the glomeruli and subsequently completely reabsorbed into proximal renal tubule, our results suggest that the effect of blood pressure on RBP4 is less than that of renal function. This may be the explanation for the insignificant effect of prehypertension and newly-diagnosed hypertension on RBP4 levels.
Fetuin-A is a liver-derived glycoprotein which inhibits insulin signaling. Previous studies have shown that serum fetuin-A concentrations positively correlate with liver fat and predict type 2 diabetes in prospective studies. To explore the role of fetuin-A in glycemic dysregulation, we recruited age- and sex-matched subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly-diagnosed diabetes (NDD) but without NAFLD in a case-control study. We found that the serum fetuin-A concentration was significantly higher in the NDD and IGT groups than NGT group. In multiple regression analysis, IGT (p<0.01) and NDD (p<0.01) were the positively associated factors of serum fetuin-A concentration, but age (p<0.05) was a negatively associated factor after adjusting for age, anthropometric indices, lipid profile, eGFR, adiponectin, C-reactive protein (CRP), and homeostasis model assessment (HOMA-IR). We thus conclude that IGT and NDD are positively associated with serum fetuin-A concentrations in subjects without NAFLD independent of cardiometabolic risk factors.
Finally, we demonstrated that the concurrence of NAFLD significantly increased fetuin-A concentrations in diabetic patients. This increase in fetuin-A concentration in diabetic patients with NAFLD is independent of several cardiometabolic risk factors, including central obesity, CRP, lipid profile, and adiponectin. We speculate the elevated fetuin-A levels may contribute significantly to the increased incidence of cardiovascular disease among subjects with both diabetes and NAFLD.
In conclusion, we demonstrate that in SHR rats with developing hypertension, the elevated levels of RBP4 secreted from liver and adipose tissue may play a pathophyiological role in the worsening of IR. Our findings also suggest that the insulin sensitizing effect of valsartan is associated with a decrease in circulating levels of RBP4. In human studies, we found that newly-diagnosed hypertensive, prehypertensive, and normotensive subjects with normal renal function had similar serum RBP4 levels and that eGFR is significantly related to serum RBP4 levels independent of gender and cardiovascular risk factors. In addition, we demonstrated that the subjects with NDD and IGT had higher serum fetuin-A concentrations than those with NGT in the population without NAFLD. Our data also suggested that concomitant NAFLD in diabetic patients further elevated serum fetuin-A concentrations independent of cardiovascular risk factors, CRP, and adiponectin. Future prospective studies are needed to establish the role of fetuin-A in the high cardiovascular risk associated with NAFLD and diabetes.

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