天然抗氧化劑α-硫辛酸現身：有望成為第二型糖尿病治療新利器

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α-硫辛酸（ALA）具有抗氧化、抗發炎、促進葡萄糖攝取等多重功效，研究指出可有效改善第二型糖尿病併發症，如神經病變、腎病與視網膜病變。結合生活型態調整與常規治療，ALA 有潛力提升糖尿病患者的整體療效與生活品質。

ALPHA-LIPOIC ACID IN TYPE 2 DIABETES MELLITUS: MECHANISMS, CLINICAL BENEFITS, AND IMPLEMENTATION IN THERAPY

第二型糖尿病中的 α-硫辛酸：機轉、臨床益處與治療應用

B DHARANI*, STEPHY SEBASTIAN, SUBA A
Department of Physiology, A.C.S. Medical College and Hospital, Dr. M.G.R. Educational and Research Institute, Chennai, Tamil Nadu, India.
*Corresponding author: B Dharani; Email: doctordharanibhaskaran@gmail.com

https://www.researchgate.net/publication/386532964_ALPHA-LIPOIC_ACID_IN_TYPE_2_DIABETES_MELLITUS_MECHANISMS_CLINICAL_BENEFITS_AND_IMPLEMENTATION_IN_THERAPY

ABSTRACT 摘要

Diabetes Mellitus (DM) encompasses a range of metabolic disorders marked by persistent high blood glucose levels. Type 2 Diabetes Mellitus (T2DM), the more common form of the disease is characterized by insulin resistance and partial insulin deficiency. The primary contributors to mortality and morbidity in diabetes are its vascular complications. Alpha-Lipoic Acid (ALA) is an antioxidant derived from caprylic acid and synthesized within the mitochondria. Extensive research shows that ALA aids in preventing and treating Diabetic Neuropathy (DN), lowers the risk of diabetes in at-risk individuals and is also beneficial for those with impaired glucose tolerance. Therefore, this review article aims to explore the different aspects of ALA and its beneficial effects on individuals with T2DM. A range of articles from databases such as Springer, Wiley, Web of Science, PubMed, Google Scholar, SCOPUS, Embase and Cochrane were examined. References from these articles were also analysed to broaden the search for pertinent reviews. Administering ALA in T2DM was found to have beneficial effects like anti-oxidant, anti-inflammatory, enhance glucose uptake, prevents diabetic neuropathy, neuroprotective, anti-obesity, cardio-protective, reno-protective, prevent diabetic retinopathy, anti-aging and improve metabolic parameters in Polycystic Ovary Syndrome (PCOS). Incorporating ALA into a comprehensive treatment plan, combined with lifestyle changes and standard therapies could improve patient outcome and enhance the quality of life for those managing T2DM and related conditions.

Keywords: Alpha Lipoic Acid, Type 2 Diabetes Mellitus, ALA, Diabetic Neuropathy, Antioxidant, Anti-inflammatory

糖尿病（DM）是一種以長期高血糖為特徵的代謝性疾病群。第二型糖尿病（T2DM）是最常見的形式，其特徵為胰島素阻抗和部分胰島素分泌不足。糖尿病死亡率與致病率的主要來源是其血管併發症。α-硫辛酸（Alpha-Lipoic Acid，ALA）是一種抗氧化劑，來自辛酸並在粒線體內合成。大量研究指出，ALA 可預防與治療糖尿病神經病變（DN），降低高風險人群罹患糖尿病的風險，並對於葡萄糖耐受受損者也具益處。因此，本篇綜述旨在探討 ALA 的不同面向及其對第二型糖尿病患者的益處。本研究檢索 Springer、Wiley、Web of Science、PubMed、Google Scholar、SCOPUS、Embase 與 Cochrane 等資料庫中的文獻，並分析文獻中的參考資料以擴大綜合性回顧的涵蓋範圍。研究指出，在第二型糖尿病中使用 ALA 可帶來多項益處，包括抗氧化、抗發炎、促進葡萄糖攝取、預防糖尿病神經病變、神經保護、抗肥胖、心血管保護、腎臟保護、預防糖尿病視網膜病變、抗老化，並改善多囊性卵巢症候群（PCOS）的代謝參數。將 ALA 納入綜合性治療計畫，並結合生活型態改變與標準療法，可望改善病患的治療結果並提升其生活品質，對於第二型糖尿病及相關疾病的管理具有臨床意義。

關鍵詞： α-硫辛酸、第二型糖尿病、ALA、糖尿病神經病變、抗氧化、抗發炎

INTRODUCTION 

Diabetes mellitus (DM) encompasses a range of metabolic disorders marked by persistent high blood glucose levels which may stem from problems with insulin production, insulin action, or both. The main categories of diabetes include type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). T1DM is an autoimmune disorder in which the body’s immune system targets and destroys the insulin-producing beta cells in the pancreas, resulting in no insulin production. T2DM is the most common type, typically arising in adults but increasingly being identified in younger individuals. It is characterized by insulin resistance and a partial deficiency of insulin often associated with obesity, physical inactivity, and various environmental and genetic factors. GDM develops during pregnancy, resulting in higher blood sugar levels that can affect both the mother and the baby. Insulin is a polypeptide hormone produced by the beta cells in the islets of Langerhans in the pancreas. Its primary roles include regulating blood glucose levels, facilitating the assimilation of glucose, and promoting its utilization within the body.

DM is recognized as one of the most rapidly increasing and prevalent diseases globally. By 2045, it is estimated to impact approximately 693 million adults. The primary contributors to mortality and morbidity in diabetes are its vascular complications, which encompass both macrovascular and microvascular issues. The disease also imposes a substantial economic burden on both developing and developed nations.

Diabetic neuropathy (DN) is a prevalent complication of T2DM and presents in various forms, including symmetric sensorimotor neuropathy, autonomic neuropathy, mononeuropathy, mononeuritis multiplex, polyradiculopathy, and plexopathy. Diabetic symmetric polyneuropathy (DSPN) is estimated to affect 29% of individuals with T1DM and 35% of those with T2DM in Asia, and approximately 30% of the global population with diabetes.

Alpha-lipoic acid (ALA) is an antioxidant derived from caprylic acid and synthesized within the mitochondria. Studies have shown that nutritional supplementation with ALA may be an effective preventive strategy for managing diabetic complications. Research has shown that ALA enhances nitric oxide-mediated endothelium-dependent vasodilation in diabetic patients and improves microcirculation in those with DSPN.

In the 1950s, experimental studies demonstrated that ALA, a naturally occurring compound, could prevent the onset of alloxan diabetes in rats. The use of oral ALA for DN was first reported in the 1960s. Klein et al in 1975 documented the treatment of 100 patients with DN using oral ALA. ALA is a powerful antioxidant utilized in the treatment of DN because it helps prevent neuronal lipid peroxidation. It was found to have anti-diabetic effect which is linked to its partial inhibition of siteI inflammation. Its anti-inflammatory properties are attributed to its capacity to scavenge oxygen radicals and inhibit nitric oxide production.

There is strong research evidence indicating that ALA has beneficial effects in diabetes, especially in the prevention and treatment of DN. It may also aid in preventing diabetes in individuals at risk. The current expert opinions suggest that ALA could be beneficial for patients with impaired glucose tolerance. Therefore, this review article aims to explore the different aspects of ALA and its beneficial effects on individuals with T2DM.

糖尿病（Diabetes Mellitus, DM）涵蓋一系列以長期高血糖為特徵的代謝性疾病，其可能源於胰島素產生異常、胰島素作用異常，或兩者皆有。目前糖尿病主要分為第一型糖尿病（T1DM）、第二型糖尿病（T2DM）與妊娠糖尿病（GDM）三大類。第一型糖尿病是一種自體免疫疾病，身體的免疫系統會攻擊並破壞胰臟中負責製造胰島素的β細胞，導致無法產生胰島素。第二型糖尿病是最常見的類型，通常出現在成年人身上，但現在也越來越常見於年輕族群。其特徵是胰島素阻抗與部分胰島素缺乏，通常與肥胖、缺乏運動及多種環境與遺傳因素有關。妊娠糖尿病則發生於懷孕期間，會導致血糖升高，影響母體與胎兒健康。胰島素是一種由胰臟蘭氏小島中的β細胞所分泌的多肽激素，主要功能包括調節血糖濃度、幫助葡萄糖吸收與促進其在體內的利用。

糖尿病已被認為是全球增加最快、最普遍的疾病之一。預估到2045年，全球將有約6億9300萬名成人受到影響。糖尿病造成死亡與併發症的主要因素是血管相關問題，包含大血管與小血管併發症。此外，糖尿病也對已開發與開發中國家造成重大經濟負擔。

糖尿病神經病變（Diabetic Neuropathy, DN）是第二型糖尿病常見的併發症之一，可呈現多種型態，包括對稱性感覺運動神經病變、自主神經病變、單一神經病變、多發性單神經病變、神經根病變與神經叢病變等。其中對稱性多發性神經病變（DSPN）是最常見的型態，估計亞洲地區約有29%的第一型糖尿病患者與35%的第二型糖尿病患者受到影響，而在全球糖尿病患者中，約有30%患有此類病變。

**α-硫辛酸（ALA）**是一種從辛酸衍生並於粒線體內合成的抗氧化劑。研究顯示，營養補充 ALA 可能是一種有效的糖尿病併發症預防策略。ALA 能促進一氧化氮介導的血管內皮擴張作用，並改善糖尿病患者，特別是患有對稱性多發性神經病變（DSPN）者的微循環功能。

1950 年代的實驗研究證實，ALA 作為一種天然化合物，能預防大鼠罹患由 alloxan 誘發的糖尿病。口服 ALA 用於治療糖尿病神經病變（DN）最早在 1960 年代被報導。1975 年，Klein 等人記錄了以口服 ALA 治療 100 位 DN 病患的情形。ALA 是一種強效抗氧化劑，能抑制神經脂質過氧化，因此在治療 DN 中具有重要應用。研究發現，ALA 具有抗糖尿病作用，與其對炎症部位（尤其是 siteI）部分抑制有關。ALA 的抗發炎特性也來自其清除活性氧與抑制一氧化氮產生的能力。

大量研究證據指出，ALA 對糖尿病，尤其在預防與治療糖尿病神經病變方面有正向效果。它也可能有助於預防高風險人群罹患糖尿病。目前的專家觀點認為，ALA 對於葡萄糖耐受受損的病患可能具有潛在益處。因此，本篇綜述旨在探討 ALA 的各種面向及其對第二型糖尿病患者的正向影響。

METHODS

A range of articles from databases such as Springer, Wiley, Web of Science, PubMed, Google Scholar, SCOPUS, Embase, and Cochrane were examined. References from these articles were also analyzed to broaden the search for pertinent reviews. Each article was reviewed in detail about the significance of their findings.

本研究檢索了多個資料庫中的文獻，包括 Springer、Wiley、Web of Science、PubMed、Google Scholar、SCOPUS、Embase 與 Cochrane。並進一步分析這些文獻中的參考資料，以擴大對相關綜述的搜尋範圍。每篇文章皆進行詳細審閱，以掌握其研究結果的重要性。

RESULTS AND DISCUSSION
結果與討論

T2DM may remain undetected in its early stages due to its gradual progression and often asymptomatic nature, with symptoms sometimes manifesting only as mild hyperglycemia. More noticeable signs such as increased thirst, weight loss, blurred vision, and impaired growth typically emerge later. The development of T2DM is frequently associated with lifestyle issues such as poor diet, aging, physical inactivity, a family history of diabetes, obesity, previous gestational diabetes in women, and related health conditions such as atherosclerosis, hypertension, and dyslipidemia.

第二型糖尿病（T2DM）在早期可能不易察覺，因其進展緩慢且常無明顯症狀，僅表現為輕度高血糖。較明顯的症狀如口渴增加、體重減輕、視力模糊及生長遲緩等，通常在疾病後期才出現。T2DM 的發展常與生活型態問題有關，例如飲食不良、年齡老化、身體活動量不足、有糖尿病家族史、肥胖、女性曾有妊娠糖尿病，以及動脈硬化、高血壓與血脂異常等相關健康問題。

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The pathophysiology of T2DM is characterized by both insulin deficiency and insulin resistance. These conditions are associated with elevated inflammatory cytokines in the plasma and high fatty acid levels, which impair glucose transport into target cells, increase fat breakdown, and boost hepatic glucose production. This results in hyperglycemia, which is further exacerbated by excessive glucagon secretion from α cells and insufficient insulin production from β cells of pancreas.

T2DM 的病理生理特徵包括胰島素分泌不足與胰島素阻抗。這些狀況會引起血漿中發炎細胞激素增加與脂肪酸濃度上升，導致葡萄糖進入目標細胞受阻、脂肪分解增加，以及肝臟葡萄糖產生上升，進而造成高血糖。高血糖進一步受到胰臟α細胞分泌升高的升糖素與β細胞胰島素分泌不足的加劇。

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Understanding of T2DM has progressed from identifying a combination of pancreatic β-cell dysfunction with impaired insulin secretion and insulin resistance (IR) to a more comprehensive model that now includes hepatic gluconeogenesis. Recently, the “ominous octet” framework has been introduced, adding factors such as incretin defects, abnormal adipocyte metabolism, increased renal glucose reabsorption, elevated glucagon levels, neurotransmitter imbalances, and disrupted central appetite control. Further refinements with the “dirty dozen” concept, which incorporates additional elements such as dopamine, vitamin D, testosterone, and the renin-angiotensin system thereby offering a more nuanced view of the disease.

對T2DM的理解已從β細胞功能障礙與胰島素分泌不足加上胰島素阻抗的簡單組合，發展至涵蓋肝糖異生的綜合性模型。近期提出的「可怕八重奏」理論，將病因擴展至腸促胰素缺陷、脂肪細胞代謝異常、腎臟葡萄糖再吸收上升、升糖素濃度增加、神經傳導物質失衡與中樞食慾控制障礙。後續的「骯髒十二項」概念更納入多巴胺、維生素D、睪固酮與腎素-血管張力素系統，提供對此疾病更細緻的理解。

ALA plays a crucial role in several enzymatic processes. ALA exists in both R- and S-enantiomeric forms. However, only R-lipoic acid is attached to conserved lysine residues through an amide linkage, making this isoform essential as a cofactor in biological enzymes. ALA functions as a cofactor for the activity of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. It is also essential for the oxidative decarboxylation of pyruvate to acetyl-CoA, a crucial step connecting glycolysis to the citric acid cycle (CAC). Overall bioavailability of ALA can vary depending on whether it is consumed as a free acid or a salt, and whether it is taken with or without a meal. Pharmacokinetically, ALA has an oral bioavailability of about 30% due to its near lability, significant pre-systemic elimination, and hepatic first-pass metabolism.

α-硫辛酸（ALA）在多種酵素反應中扮演重要角色。ALA 有 R 型與 S 型兩種鏡像異構物，但僅有 R 型硫辛酸能透過醯胺鍵與保守的離胺酸殘基結合，成為生物酵素的輔酶。ALA 是丙酮酸脫氫酶與α-酮戊二酸脫氫酶等酵素的輔酶，並參與丙酮酸氧化脫羧生成乙醯輔酶A，這是糖解作用連接至檸檬酸循環的關鍵步驟。ALA 的整體生物可利用率依其攝取形式（游離酸或鹽類）、是否與食物同服而有所不同。藥物動力學研究顯示其口服生物可利用率約為30%，主要因其不穩定、經過顯著的首渡效應與肝臟代謝所致。

ALA can be found in common dietary sources such as muscle meats, kidney, heart, and liver, while smaller quantities are present in fruits and vegetables. Although ALA can be found in normal dietary sources, significant amounts are unlikely to be consumed in a typical diet. Instead, ALA supplements are commonly available in doses between 50 and 600 mg/day, with varying absorption efficiency. Research shows its bioavailability differs from plasma following these supplements.

ALA 可從日常飲食中攝取，例如肌肉肉類、腎臟、心臟與肝臟等動物性來源中含量較多，水果與蔬菜則含量甚微。雖然ALA可由飲食中攝取，然而實際攝取量通常不足，因此多以營養補充品形式提供，每日劑量介於50至600毫克，吸收效率因人而異。研究也顯示ALA補充劑的血漿中生物可利用率具有變異性。

BENEFICIAL ACTIONS OF ALA IN DIABETES
ALA 在糖尿病中的有益作用

The oxidized form of lipoic acid (LA) and its reduced form (DHLA) form a redox pair. DHLA has stronger antioxidant properties than LA. DHLA has a redox potential of –320 mV, compared to –240 mV for the reduced form of vitamin C and –220 mV for vitamin E. ALA scavenges various free radicals including superoxide, peroxyl, and hydroxyl radicals. It also regenerates other antioxidants including vitamins C and E, and glutathione. Their functions include neutralizing Reactive Oxygen Species (ROS), regenerating both consumed and endogenous antioxidants such as vitamins C and E, GSH binding metals, and repairing oxidized proteins, regulating gene transcription, and modulating the activation of Nuclear Factor-kappa B (NF-κB).

硫辛酸（LA）及其還原型（DHLA）構成一對氧化還原對，DHLA 的抗氧化能力強於 LA。本對的氧化還原電位為 –320 mV，相較之下，維生素C還原型為 –240 mV，維生素E 為 –220 mV。ALA 可清除多種自由基，例如超氧陰離子、過氧自由基與氫氧自由基，也能再生其他抗氧化劑如維生素C、E與穀胱甘肽（GSH）。ALA 的作用包括中和活性氧（ROS）、再生內生與外來抗氧化劑、與金屬離子結合、修復氧化蛋白質、調節基因轉錄與抑制 NF-κB 活化等。

Reactive Oxygen Species (ROS) and reactive nitrogen species are byproducts of cellular metabolism and can activate prooxidases such as NADPH-oxidase, myeloperoxidase, and nitric oxide synthase. Excess ROS production in diabetes pathogenesis can lead to damage within the host body. Moreover, reactive oxygen and nitrogen species (ROS/RNS) induce oxidative stress by acting as signaling messengers in various cell death pathways, immune activation, and autophagy. Free radicals also can generate secondary radicals, thereby increasing oxidative stress and toxicity. Therefore, it is essential to maintain redox homeostasis to prevent such damage. Redox homeostasis is upheld by an internal defense system that includes enzymes such as superoxide dismutase, catalase, and glutathione peroxidase as well as molecules such as ascorbate, bilirubin, flavonoids, coenzyme Q, and uric acid. ALA is produced within the human body to act as an antioxidant, protecting cells from damage and assisting in the regeneration of other antioxidants such as vitamins C and E. In addition, ALA may lower blood levels of various inflammatory markers such as IL-6 and ICAM-1. The recommended dosage of ALA is 300–600 mg daily and up to 1,200 mg has been tolerated in humans taking 600 mg per day for up to 7 months.

活性氧（ROS）與活性氮（RNS）是細胞代謝過程中的副產物，會活化 NADPH 氧化酶、髓過氧化酶與一氧化氮合酶等氧化酶。糖尿病患者體內產生過多 ROS，會對身體造成損害。此外，ROS/RNS 還會作為細胞死亡、免疫活化與自噬等訊息路徑中的信使分子，誘發氧化壓力並增加毒性。維持氧化還原平衡對防止這些傷害極為重要。人體內部的防禦系統，包括超氧歧化酶、過氧化氫酶與穀胱甘肽過氧化酶，以及維生素C、膽紅素、黃酮類、輔酶Q與尿酸等小分子，可維持此平衡。ALA 也由人體自行合成，具有抗氧化能力，可保護細胞免受傷害並協助再生其他抗氧化物如維生素C與E。此外，ALA 還可降低發炎指標如 IL-6 與 ICAM-1。建議每日攝取量為300–600毫克，研究顯示每天服用600毫克連續7個月亦為人體所耐受。

ALA enhances the expression of glucose transport protein 4 (GLUT4) from its storage site in the Golgi apparatus to the cell membrane, thereby increasing glucose uptake by lowering the number of GLUT4 transporters on the surface. Evidence from cell culture studies supports the involvement of insulin-mediated PI3K activity in ALA-induced glucose uptake, with these being sustained even when PI3K inhibitors are present. Further data and relevant evidence is needed to confirm the role of GLUT4 translocation in improving glucose disposal with ALA administration.

ALA 可促進葡萄糖轉運蛋白4（GLUT4）由高基氏體儲存處移動至細胞膜表面，藉此提升葡萄糖的攝取。ALA 能降低細胞表面的 GLUT4 數量，進一步刺激葡萄糖內移。細胞培養研究證實此過程涉及胰島素介導的 PI3K 活性，即使存在 PI3K 抑制劑，ALA 仍可維持其效應。然而，尚需更多數據與相關證據來確認 ALA 是否能透過促進 GLUT4 移位來改善葡萄糖利用。

When ROS accumulation vastly beyond the capacity of these endogenous defenses occurs, oxidative stress increases. This elevated oxidative stress has been linked to the development of peripheral neuropathy in diabetes.

當體內 ROS 累積超過內源性防禦系統所能處理的範圍時，氧化壓力便會大幅升高。這種氧化壓力的增加與糖尿病周邊神經病變的發展有密切關聯。

In 2012, Mijnhout carried out a meta-analysis that analyzed four studies with an overall participant count of 513 patients. The findings revealed that intravenous administration of ALA at one daily dose for 3 weeks significantly reduced the total symptom score (TSS). However, the analysis did not assess the impact of oral ALA. Another study indicated that intravenous ALA administration for 2 weeks led to more favorable results in nerve conduction velocity (NCV) and improved symptoms. The mean reduction in TSS and the treatment of 510 type 2 diabetic patients who had low HbA1c with fewer than 25 non-serious side effects compared favorably with placebo. The findings were comparable with oral ALA group which included 460 diabetic patients with high HbA1c and received active infusion. ALA reduced TSS by 24–25% in both oral and IV groups which was considerably higher than the placebo group.

2012 年，Mijnhout 進行一項涵蓋四個研究、總共513位受試者的統合分析，結果顯示，ALA 靜脈注射連續使用三週後，可顯著降低總症狀評分（TSS）。然而，該分析並未評估口服 ALA 的效果。另有研究指出，ALA 靜脈注射兩週能顯著改善神經傳導速度（NCV）並減輕症狀。對於510位第二型糖尿病且 HbA1c 較低的患者，TSS 顯著下降且不良反應少於25例，效果優於安慰劑。該結果與另一組使用口服 ALA 的糖尿病患者（460人，HbA1c 較高且接受主動治療）相似，口服與靜脈注射組的 TSS 均降低約24–25%，遠優於安慰劑組。

ALA was shown to assist in preserving the degeneration of dorsal root ganglion and to protect against myelin degeneration and uncoupling proteins 1 (UCP1). This regulation promotes anti-apoptotic mechanisms in changes causing cell death in neurons.

研究指出，ALA 有助於抑制背根神經節的退化，並能預防髓鞘變性及解偶聯蛋白1（UCP1）失調。此一調節作用可促進抗細胞凋亡機制，減緩導致神經元死亡的病理變化。

A clinical study has found that ALA supplementation can lead to reduction in body weight and BMI among obese individuals. A dosage of 180 mg/day of ALA resulted in modest weight loss among obese individuals. ALA energy elicited a rapid clinical response in obese and pre-obese patients by reducing plasma levels of pro-inflammatory cytokines. Notably, there was a significant decrease in circulating TNF-α levels following treatment. In addition, genes at the central role of IL-6 in mediating inflammatory pathways, like the significant reduction in circulating IL-6 levels post-treatment, is a crucial factor in the clinical improvement of pre-obese and obese patients and in the prevention of chronic diseases.

臨床研究發現，補充ALA有助於減少肥胖者的體重與BMI。每日服用180毫克ALA可使肥胖患者出現輕度體重減輕。ALA可快速降低肥胖與前肥胖患者體內的促發炎細胞激素濃度，特別是腫瘤壞死因子α（TNF-α）濃度顯著下降。此外，IL-6作為發炎反應的關鍵調節因子，其基因表現與治療後血中IL-6濃度顯著下降，也對肥胖與前肥胖患者的臨床改善及慢性疾病的預防具有關鍵作用。

It has been found that macrophages, smooth muscle cells, and ROS scavenger receptors on monocytes excessively ingest oxidized LDL, leading to lipid buildup and the formation of atherosclerotic plaques. Increased oxidative stress and inflammation generates hydroxyl radicals, peroxides, and superoxides in the endothelium which promotes the progression of cardiovascular diseases. DHLA is noted for its ability to modulate blood lipids, protect against LDL oxidation, and influence hypertension. This suggests that ALA could potentially serve as a supportive agent against cardiovascular diseases (CVD).

研究發現，巨噬細胞、平滑肌細胞及單核球上的ROS清除受體會過度攝取氧化低密度脂蛋白（LDL），造成脂質堆積與動脈粥樣斑塊的形成。氧化壓力與發炎會在血管內皮中產生氫氧自由基、過氧化物與超氧自由基，進一步加速心血管疾病的進展。還原型ALA（DHLA）具有調節血脂、保護LDL不被氧化及調節高血壓的能力，顯示ALA可望作為心血管疾病的輔助治療劑。

T2DM is the major cause of chronic kidney disease (CKD). Diabetic kidney disease (DKD) is marked by reduced glomerular filtration, proteinuria, and renal fibrosis. It is well established that mitochondrial dysfunction plays a role in DKD, making them vulnerable to effects of free radicals and combining the condition. Hyperglycemia, ROS, and oxidative stress can lead to significant kidney damage. Evidence suggests that ALA plays a significant role in mitigating these damages through inhibition of oxidative stress, inflammation, and upregulating antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2).

第二型糖尿病（T2DM）是慢性腎臟病（CKD）的主要病因。糖尿病腎病（DKD）的特徵為腎絲球過濾率下降、蛋白尿與腎臟纖維化。研究證實，粒線體功能障礙在DKD中扮演重要角色，使其更易受到自由基損傷。高血糖、ROS與氧化壓力會導致腎臟嚴重損傷。研究顯示，ALA能透過抑制氧化壓力與發炎反應，並上調抗氧化轉錄因子Nrf2來達到腎臟保護效果。

Studies have shown that ALA (600 mg/day) alone or in combination with coenzyme Q10 or vitamin E (900–1000 mg/day) and N-acetylcysteine (600–1200 mg/day) may benefit early-stage patients of diabetic nephropathy. These supplements improve kidney function and reduce TGF-β1 expression in mesangial cells. ALA alleviates proteinuria by lowering TGF-β and fibronectin levels. It was found that ALA supports podocyte linkage and adherens junctions through stabilizing p38 MAPK signaling pathways. By targeting NF-κB and reducing the release of inflammatory cytokines, it has been shown that ALA enhances glomerular integrity. Myoinositol oxygenase (MIOX), which is upregulated in DKD, a producer of lipid peroxidation, is widely used as an indicator in ALA nephroprotective studies.

研究指出，每日補充ALA 600毫克，單獨使用或搭配輔酶Q10或維生素E（每日900–1000毫克）及N-乙醯半胱胺酸（600–1200毫克），對糖尿病腎病早期患者有益。這些補充劑能改善腎功能，降低系膜細胞中TGF-β1的表現。ALA 亦可透過抑制TGF-β與纖維連接蛋白來減少蛋白尿。ALA能穩定p38 MAPK訊號通路，進而支持足細胞間連接與黏附連接。ALA亦可抑制NF-κB並降低發炎細胞激素的釋放，強化腎絲球結構。肌醇氧化酶（MIOX）在糖尿病腎病中表現上升，與脂質過氧化產生有關，常被作為ALA腎保護研究的重要指標。

In developed countries, the most common and prevalent cause of blindness is due to diabetic retinopathy (DR), especially among working-age adults. Within 5 years of diagnosis, 50% of patients with T2DM might show progression of DR. ALA prevents DR by inhibiting Oxidized Receptor-1, reducing VEGF, and Nrf2 expression, and thereby as well as reducing oxidative stress. It also attenuates nuclear factor-kappa B (NF-κB) and AP-1–associated signaling in retinal ganglion cells. Clinical trials in prediabetic patients and patients with DR have demonstrated that ALA combined with Centrum and vitamins can protect retinal cells and reduce inflammation in diabetic patients.

在已開發國家，糖尿病視網膜病變（DR）是導致失明最常見與普遍的原因，尤其在工作年齡族群中。診斷後五年內，有高達50%的第二型糖尿病患者可能出現DR進展。ALA 可透過抑制氧化受體1（Oxidized Receptor-1）、降低血管內皮生長因子（VEGF）與Nrf2表現，進而減少氧化壓力。ALA 也可抑制視網膜神經節細胞中的NF-κB與AP-1訊號傳遞。臨床試驗顯示，ALA 與綜合維他命（Centrum）聯合使用能保護視網膜細胞並降低糖尿病患者的發炎反應。

In polycystic ovary syndrome (PCOS), ALA also reduces oxidative damage and insulin resistance. In a study involving 90 obese patients with PCOS, the combination of ALA (600 mg/day) and myo-inositol (1 mg/day) improved hormonal and metabolic parameters including insulin sensitivity. 12-week supplementation of ALA (600 mg/day) enhances metabolic functions in all PCOS patients, particularly benefiting those at high risk for non-alcoholic fatty liver disease (NAFLD) and predisposed to diabetes.

在多囊性卵巢症候群（PCOS）中，ALA 同樣具有減少氧化傷害與改善胰島素阻抗的作用。一項針對90位肥胖PCOS患者的研究發現，ALA（每日600毫克）與肌醇（每日1毫克）聯合補充可改善荷爾蒙與代謝參數，包括提升胰島素敏感性。為期12週的ALA補充（每日600毫克）可全面提升PCOS患者的代謝功能，特別有助於預防非酒精性脂肪肝（NAFLD）與糖尿病高風險族群。

Oxidative stress was found to be the process involved in cellular aging and age-related organ dysfunction. Antioxidants might decrease the likelihood of certain heart conditions and may also offer anti-aging benefits. ALA can target aging pathways in pancreatic islet cells through its antioxidant properties.

研究顯示，氧化壓力是細胞老化與老化相關器官功能障礙的關鍵機制。抗氧化劑有助於降低心臟疾病的發生機率，亦可能具有抗老化功效。ALA 可藉由其抗氧化特性，作用於胰島細胞的老化路徑以延緩衰老

Rare instances, also known as insulin autoimmune syndrome (IAS), is characterized by high insulin levels and low plasma glucose in non-diabetic individuals. This rare form of autoimmune hypoglycemia is triggered by sulfhydryl-containing medications that stimulate the production of insulin autoantibodies. In recent studies, ALA has been cited as one of the causative factors of IAS. Consequently, caution is advised when considering ALA supplementation given its association with this condition.

ALA 可能引發極罕見的不良反應，即胰島素自體免疫症候群（IAS），該症狀表現為非糖尿病患者體內胰島素濃度升高但血糖濃度過低。這種自體免疫性低血糖常由含硫氫基的藥物誘發，刺激胰島素自體抗體的生成。近年研究指出，ALA 可能是引發 IAS 的潛在因素，因此在補充 ALA 時應特別謹慎。

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Previous studies have shown that doses up to 2400 mg for adults are well tolerated without any adverse effects. However, higher doses may provide only additional nutritional or therapeutic benefits and hence should not be recommended. Daily oral supplementation of 600 mg of ALA during pregnancy has not been associated with adverse effects for either mothers or newborns, but it is strongly advised to avoid use without medical supervision.

過去研究顯示，成人服用最高達2400毫克ALA皆無明顯不良反應。但高劑量未必帶來更多營養或療效，因此不建議使用。孕期每日補充600毫克口服ALA並未對母體或新生兒造成不良影響，但仍強烈建議應在醫療專業人員監督下使用。

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Studies on primates have shown that excessively high doses of ALA can cause hepatic lesions, suggesting that very high intakes over long periods may lead to toxicity. The most common side effect of ALA is gastrointestinal issues, including reactions such as rashes, hives, vomiting, or severe stomach pain. Patients may also experience bloating, diarrhea, and weight loss.

靈長類動物研究顯示，長期過量攝取ALA可能造成肝損傷，顯示其具有潛在毒性。ALA 最常見的不良反應為腸胃不適，包括皮疹、蕁麻疹、嘔吐或腹部劇痛。部分患者亦可能出現腹脹、腹瀉與體重下降等反應。

Conclusion
結論

This systematic review of ALA has highlighted its various beneficial therapeutic applications in T2DM. ALA represents a multifunctional therapeutic agent supporting redox homeostasis and mitochondrial health in metabolic disease. Figure 1 explains various mechanisms by which ALA exerts its benefits in type 2 diabetes, including improving insulin sensitivity, glucose metabolism, and reducing ROS, TGF-β, and other related inflammatory and fibrotic pathways. Recent studies confirm ALA’s efficacy in preventing or reversing diabetic complications by notably mitigating oxidative stress which plays a pivotal role in T2DM progression. ALA supplementation in combination with other antioxidants (e.g., coenzyme Q10, N-acetylcysteine, or vitamin E) may enhance its therapeutic effects by targeting multiple signaling cascades such as NF-κB, PI3K/Akt, or TGF-β/SMAD, further supporting its role in managing chronic inflammation in T2DM.

本系統性回顧總結ALA在第二型糖尿病中的多重治療潛力。ALA 是一種具多功能的治療劑，可維持氧化還原平衡、保護粒線體健康，並改善代謝病症。圖一說明ALA在糖尿病中發揮功效的多種機制，包括提升胰島素敏感性、改善葡萄糖代謝、降低活性氧（ROS）、轉化生長因子β（TGF-β）與其他發炎與纖維化途徑。近期研究證實，ALA在預防與逆轉糖尿病併發症方面具有療效，主要是因為其可顯著減輕氧化壓力，而氧化壓力是T2DM進展的關鍵因素。ALA 若與其他抗氧化劑（如輔酶Q10、N-乙醯半胱胺酸或維生素E）聯合補充，可透過調節多條訊號傳導途徑如NF-κB、PI3K/Akt 或 TGF-β/SMAD，進一步強化其對慢性發炎的控制效益。

圖一：α-硫辛酸於第二型糖尿病中之有益作用摘要

Associated with T2DM, the enhancement of glucose uptake through increased GLUT-4 transporter expression on the cell surface offers a direct benefit for glycemic control, making ALA a valuable adjunct in diabetes management.

在第二型糖尿病中，ALA 可藉由提升細胞表面 GLUT-4 輸送蛋白的表現來促進葡萄糖攝取，有助於血糖控制，成為糖尿病治療的重要輔助因子。

In the realm of T2DM, ALA has demonstrated efficacy in reducing oxidative stress on nerves, preventing apoptosis, and preserving the integrity of DRG. Its neuroprotective properties are bolstered by its ability to regulate proinflammatory cytokines, inhibit NF-κB, and enhance signaling pathways such as TrkA/p75NTR and the p-AKT/AKT pathway, all of which contributes to nerve health and function.

ALA 在第二型糖尿病領域中，顯示出可減輕神經氧化壓力、抑制細胞凋亡與維護背根神經節（DRG）完整性的療效。其神經保護作用與其調節促發炎細胞激素、抑制NF-κB 及促進 TrkA/p75NTR 和 p-AKT/AKT 等訊號傳導路徑有關，從而維護神經健康與功能。

ALA also shows promise in addressing obesity-related concerns by reducing TNF and IL-6, while its cardioprotective and renoprotective effects, evidenced by decreased LDL oxidation, reduced pro-inflammatory markers, and improved mitochondrial function, highlight its broader therapeutic potential.

ALA 亦可藉由降低腫瘤壞死因子（TNF）與白細胞介素-6（IL-6）來改善肥胖相關問題；其心臟與腎臟保護作用則反映在LDL氧化減少、促發炎指標降低與粒線體功能改善等表現，展現其更廣泛的治療潛力。

Furthermore, its role in mitigating DR through inhibition of specific glycosylation processes and NF-κB underscores its importance in preventing long-term complications. In addition to these benefits, ALA has demonstrated efficacy in reducing oxidative damage and insulin resistance in PCOS, suggesting a versatile role in metabolic disorders beyond diabetes. Its anti-aging properties further complement its therapeutic profile.

此外，ALA 透過抑制特定糖化過程與 NF-κB 活性來緩解糖尿病視網膜病變（DR），凸顯其對長期併發症的預防價值。ALA 也被證實能減少多囊性卵巢症候群（PCOS）中的氧化損傷與胰島素阻抗，顯示其在代謝疾病中的廣泛應用潛力；其抗老化特性亦為其治療優勢之一。

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While the evidence supporting ALA’s benefits is robust, continued research is essential to fully establish its efficacy, optimal dosing, and long-term safety. Future studies should focus on validating these effects through large-scale, well-designed clinical trials to confirm ALA’s role as a therapeutic adjunct in T2DM. Early treatment regimens integrating ALA into a multi-tiered approach, alongside lifestyle modifications and conventional therapies may enhance patient outcomes and improve quality of life for individuals managing T2DM and its associated conditions.

儘管ALA療效已有強力證據支持，但仍需持續研究以明確其治療效益、最佳劑量與長期安全性。未來研究應透過大規模、嚴謹設計的臨床試驗來驗證其作用。若能在早期治療策略中納入ALA，搭配生活型態調整與常規療法，將有助於提升糖尿病患者的治療成效與生活品質。

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