Impaired nicotinamide adenine dinucleotide (NAD(+) ) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment.
Impaired nicotinamide adenine dinucleotide (NAD(+) ) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment.
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尼古丁酰胺腺嘌呤二核苷酸（NAD（+））代谢受损，糖尿病和糖尿病组织：与烟酰胺相关的化合物治疗的影响。
DOI：
10.1111/jdi.13303
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发表时间：
2020-11
影响因子：
3.2
通讯作者：
Ido Y
中科院分区：
文献类型：
--
作者：
Fan L;Cacicedo JM;Ido Y
在糖尿病组织中发现的生化异常之一是由过量底物（通过多元醇途径的葡萄糖、游离脂肪酸和乳酸盐）氧化引起的细胞溶质氧化还原形式的烟酰胺腺嘌呤二核苷酸比率（NAD+/NADH，也称为假性缺氧）降低。随后，由于多聚腺嘌呤核苷酸二磷酸核糖聚合酶的激活（主要在1型糖尿病中）或腺嘌呤核苷酸一磷酸活化蛋白激酶的抑制（在2型糖尿病中），NAD+水平下降。因此，通过烟酰胺相关化合物补充NAD+水平可能是有益的。然而，这些化合物也增加引起氧化应激的烟酰胺催化剂。这对于糖尿病患者尤其麻烦，因为他们在烟酰胺磷酸核糖转移酶和磷酸核糖焦磷酸水平上的烟酰胺补救途径反应受损，这通过以下机制发生。首先，磷酸戊糖途径的磷酸核糖焦磷酸合成受到血浆硫胺素和转酮醇酶活性降低的影响。第二，烟酰胺磷酸核糖转移酶表达降低，因为腺苷一磷酸活化蛋白激酶活性降低，这发生在2型糖尿病中。腺苷一磷酸活化蛋白激酶抑制是由蛋白激酶C和D1的活化引起的，这是由于假性缺氧和脂肪酸水平升高引起的二酰基甘油合成增强所致。在这方面，应谨慎给予烟酰胺相关化合物治疗糖尿病。为了最大限度地降低风险并最大限度地提高获益，烟酰胺相关化合物应与胰岛素增敏剂（用于2型糖尿病）、多酚、苯磷硫胺、乙酰左旋肉碱和醛糖还原酶抑制剂一起服用。这些方案的疗效可以通过测量血清NAD+和尿烟酰胺催化剂来监测。糖尿病引起烟酰胺腺嘌呤二核苷酸代谢失调，其特征在于通过生化异常增加烟酰胺腺嘌呤二核苷酸的消耗以产生烟酰胺，并减少烟酰胺向烟酰胺腺嘌呤二核苷酸的转化（补救级联），这被假定为糖尿病并发症的病因。这会导致烟酰胺催化剂的产生增加，这可能会导致氧化应激。对于糖尿病患者，纠正这些异常后，烟酰胺相关化合物（如烟酰胺核苷和烟酰胺单核苷酸）可能有用。
One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+/NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate‐ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate‐activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide‐related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate‐activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate‐activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide‐related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide‐related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl‐L‐carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites. Diabetes causes nicotinamide adenine dinucleotide metabolism dysregulation characterized by increasing consumption of nicotinamide adenine dinucleotide to produce nicotinamide and decreasing conversion of nicotinamide to nicotinamide adenine dinucleotide (salvage cascade) by biochemical abnormalities, which have been postulated for the etiology of diabetic complications. This results in increasing production of nicotinamide catabolites, which might cause oxidative stress. For diabetes patients, nicotinamide‐related compounds, such as nicotinamide riboside and nicotinamide mononucleotide might be useful after correcting these abnormalities.