2型糖尿病的功能医学干预（2）

DISCUSSION

Diabetes, an epidemic disease, is a disorder of glucose metabolism that is damaging to every tissue in the body. As such, diabetes is a gateway disease, being associated with cardiovascular and kidney disease, dementia, retinopathy and numerous other conditions. Not surprisingly, morbidity, mortality and cost to society of this preventable illness are extremely high.

讨论

糖尿病，是由于糖代谢紊乱引起的疾病，它会损害身体的每一个部分，就好像糖尿病是一个连接体，它经常伴随着心血管疾病、肾病、痴呆、视网膜病变和其他疾病等一起发生。糖尿病的发病率、死亡率是非常高的，而且预防糖尿病的发生也需要付出很大的成本。

As with most complex, chronic conditions, the development of DMII involves environmental exposure coupled with genetic predisposition. It is clear that DMII is strongly associated with physical inactivity, obesity, low HDL levels, excessive alcohol intake, stress and poor dietary choices. Organotoxin exposures, including persistent organic pollutants (POPs), polychlorinated biphenyls and bispheno1A，among others，have also been associated with DMll，and individuals eating a typical diabetogenic diet of highly refined，Processed foods are at Particular risk for exposure，Identifying genetics has been a more elusive Path however variants in the transcription factor 7-like2 (TCF7LZ) gene，involved in insulin exocytosis，have been shown to be associated with an almost 30%increased risk of DM 2 in certain populations.

与大多数慢性复杂性疾病相同，2型糖尿病的发展涉及环境曝露和遗传易感性，显而易见的是，2型糖尿病通常与缺乏锻炼、肥胖、HDL偏低、过度饮酒，不良饮食习惯密切相关。另外，毒素的曝露包括持久性有机污染物（POPs）、多氯联苯和双酚A等也会造成2型糖尿病的发生。不良的饮食习惯尤其是精加工的食品是最有可能导致糖尿病发生的因素。目前对于遗传鉴别仍不能确定，但转录因子（TCF7LZ）已被证实与30%的人群患糖尿病风险增加是有关的。

As shown in her family history, CK demonstrated a strong genetic predisposition toward heart disease and diabetes. Environmental risk factors antecedent to her diagnoses included a high stress，sedentary lifestyle with excessive sugar and alcohol intake. Further , her waist-hip ratio，considered to be a more sensitive marker of cardiovascular risk than body一mass index.

如CK的家族病史所示，她表现出心脏病和糖尿病的强烈的遗传倾向，环境风险因素包括压力过大、久坐、过多的酒精和糖分的摄入等，另外，腰臀比是一个比BMI更为敏感的指标，也会增加糖尿病发生的几率。

As indicated in Figure l，hemoglobin AIC，blood and urinary glucose were all markedly elevated despite being on glyburide and metformin Looking at the high一normal insulin level in relation to the Pronounced elevation of blood and urinary glucose suggested that the Pancreas was unable to Produce enough insulin to overcome resistance Allowed to continue，CK would likely have required exogenous insulin at some Point in the future. CK、use of the beta一blocker metoprolol could:150 have been contributing to the dysglycemia.，BuN， creatinine，and urinary microalbumin were within normal limits，demonstrating intact kidney function.

如检测结果所示，尽管服用格列本脲和二甲双胍药物，但是她的血红蛋白、血糖和尿糖指标还是非常高，表明胰腺无法产生足够的胰岛素，CK以后可能会需要外源性胰岛素。使用β受体阻滞剂--美托洛尔药物可能会导致血糖代谢障碍。血尿素氮、肌酐和尿微量蛋白均在正常范围，证明肾脏功能尚未被破坏。

An elevated AIT，and an AIT/AST ratio of>1 may be early indications of non-alcoholic fatty liver disease(NASH)，which is associated with type 2 diabetes. Medications including atorvastatin may increase liver enzymes.While the thyroid Panel findings were within normal limits，a TSH>2.5 has been considered indicative of subclinical hypothyroidism，Subclinical hypothyroidism occurs with significantly greater frequency in type 2 diabetics，and may contribute to dyslipidemia.

CK的检测结果中，ALT升高，ALT/AST＞1，可能是患有非酒精性脂肪性肝病，这种病与2型糖尿病相关。包括阿托伐在内的药物可能提升肝酶。甲状腺检测数据在正常范围，但TSH＞2.5被认为是亚临床甲减的指征，亚临床甲减在2型糖尿病患者中的发生率明显更高，并可能导致血脂异常。

The lipid panel，including LDL，HDL and triglycrides, was with in normal limits. However，a Closer inspection of cholesterol Particle quantity and size demonstrated significantly different risk picture. .Elevated total LDL Particle quantity， despite normal LDL-C, is associated with increased risk for cardiovascular disease in type 2 diabetics. The markedly elevated lipoprotein is indicative of increased risk for vascular disease，particularly in diabetics. Further，Lpa  is not controlled by statin therapy.  Thus, individuals with type 2 diabetes with pharmaceutically controlled levels of total cholesterol may continue to have an increased risk of cardiac and cerebrovascular events based on size quantity, and type of lipoproteins present.

脂质检查中，LDL、HDL和甘油三脂测量数值均在正常范围内，然而，胆固醇颗粒的数量和大小表现出风险倾向，尽管LDL-C正常，但偏高的LDL颗粒数量与2型糖尿病患心血管疾病风险增加有关。显著升高的脂蛋白表明血管疾病的风险增加，特别是对于糖尿病患者。此外，LP(a)不受他汀类药物的控制。因此，即使依赖药物控制胆固醇水平的2型糖尿病患者，基于脂蛋白颗粒大小和数量的异常，仍存在心脑血管疾病增加的风险。

Vitamin D has been found lower in type 2 diabetics as compared to type 1, and inversely correlated with BMI.

和1型糖尿病相比，2型糖尿病患者更容易缺乏维生素D，和BMI指数呈负相关。

Biotin deficiency is associated with impaired glucose tolerance and utilization of glucose. Biotin upregulates genes involved in lowering blood sugar, including pancreatic and hepatic glucokinase enzymes." CK also demonstrated significant elevation of two alpha-keto acids, both of which have been shown to normalize in some cases with high-dose thiamine, and may be lowered with pantothenic acid, niacin, riboflavin, and alphalipoic acid. Finally, while the level of the B functional marker methylmalonic acid was normal, B should be periodically monitored because CK was taking metformin, which has been shown to deplete this nutrient in certain individuals.

生物素缺乏通常是和耐糖量异常和葡萄糖利用能力有关，生物素上调参与降低血糖的基因表达，包括胰腺和肝脏葡萄糖激酶。CK的报告也显示出两种α-酮酸显著升高，在某些情况下可通过使用高剂量的硫胺素使之恢复正常，虽然B族维生素标记物甲基丙二醛水平正常，但也应该定期检测。由于CK服用二甲双胍，已被证实此类药物会消耗维生素B族。

There are several possible reasons for CK's lactate elevation. An elevated blood lactate/pyruvate ratio was shown to occur in individuals on statin therapy, demonstrating a mitochondropathy and lactate is likely elevated compromised cellular respiration. It is hypothesized that urinary in diabetic patients, as plasma lactate has been shown to be. Furthermore, metformin has been shown to increase serum lactate levels.

CK的乳酸水平增高可能由几种原因造成，接受他汀类药物治疗的个体中血清乳酸/丙酮酸比值升高表明线粒体功能受损，从而损害细胞呼吸功能，二甲双胍也可以提升血清乳酸的水平

Also found were high urinary ketoses ((β-Hydroxybutyrate), evidence for increased fatty acid beta oxidation due to insulin resistance. HMG was also mildly elevated, suggesting inhibition of HMG-CoA reductase enzyme, which was expected given CK's use of the pharmaceutical inhibitor, atorvastatin. HMG-CoA reductase is the rate-limiting enzyme in cholesterol and CoQ10 synthesis. CoQ10 deficiency has been shown to occur in statin users. In cell studies, statin exposure causes increased oxidative DNA damage, early cell death, decreased ATP production and CoQ10 deficiency.'， Taken together, the elevated lactate along with the HMG elevation may have been associated with inadequate CoQ10 availability compromising cellular respiration, causing subclinical mitochondropathy. As discussed below , the high level of Lipid peroxidation is further evidence for mitochondrial dysfunction.

我们还发现，CK报告显示高尿酮酸（β-羟基丁酸），由于胰岛素抵抗导致脂肪酸β氧化增加，HMG也轻度升高，CK使用抑制性药物阿托伐他汀后抑制了HMG-CoA还原酶（是胆固醇和辅酶Q10合成中的限速酶），已发现的使用他汀类药物可导致辅酶Q10缺乏，另外，在细胞研究中，他汀药物还会增加DNA氧化损伤，早期细胞死亡，ATP产生下降。乳酸升高和HMG升高可能与辅酶Q10不足有关，影响细胞呼吸，导致亚临床线粒体病变。总之，高水平的脂质过氧化进一步证实线粒体功能障碍。

Omega-3 fatty acids EPA and DHA were within normal limits, but the omega-6 fatty acid AA was elevated, providing the substrate for eicosanoid inflammatory compounds. Insulin stimulates the production of AA through up-regulation of delta-5 desaturase. AA elevation has been associated with insulin resistance.

Omega-3脂肪酸中EPA和DHA水平都在正常范围内，但是Omega-6脂肪酸AA升高，为类花生酸炎性化合物提供底物，胰岛素通过上调δ-5去饱和酶刺激AA产生，AA升高与胰岛素抵抗有关。

The element insufficiencies may have contributed to the pathogenesis of CK's complaints. In brief, chromium is involved in cellular glucose uptake via potentiating insulin receptor tyrosine kinase. Indeed, elevated blood sugar itself has been proposed as a surrogate marker for chromium deficiency." Vanadium is believed to be involved in lipid and glucose metabolism.'' Selenium is a cofactor in multiple enzymes involved in glutathione and thyroid metabolism, and thus low selenium status may be contributing to increased oxidative stress (see below) as well as the mild thyroid dysfunction. Magnesium is a cofactor for some 375 enzymes, including those involved in glucose and insulin regulation. It also plays a role in modulating blood pressure by supporting smooth muscle relaxation.4' Magnesium is frequently found to be low in diabetics. Multiple essential element deficiencies also suggest compromised digestion and absorption in addition to poor dietary intake.

某些营养元素不足可能是导致CK出现2型糖尿病的发病机制，简而言之，铬通过增强葡萄糖受体酪氨酸激酶参与细胞葡萄糖摄取，事实上，血糖升高本身已被提议作为缺铬的指标。钒被认为与脂质和葡萄糖代谢有关。硒是多种酶的辅因子，参与谷胱甘肽和甲状腺代谢，所以硒含量过低会导致氧化应激增加和轻度的甲状腺功能障碍。镁是375种酶的辅因子，包括参与葡萄糖和胰岛素调节的酶，镁还通过支持平滑肌松弛来调节血压。在糖尿病患者中，镁缺乏是很常见的。除了从膳食中摄入不足以外，多种营养元素缺乏也表明患者消化吸收功能受损。

The elevated lipid peroxides were indicative of oxidative damage to cell membranes, which occurs with greater frequency in diabetic individuals. An association between glycemic control, A1C and lipid peroxides has been demonstrated in individuals with type 2 diabetes.`" Mitochondropathy has also been associated with increased reactive oxidative species and CoQ10 deficiency.

脂质过氧化物升高提示对细胞膜的氧化损伤，其在糖尿病个体中发生的频率更高。控制血糖、糖化血红蛋白和脂质过氧化物这三项指标之间的关联已在患有2型糖尿病个体中得到证实，线粒体病变也与增加的反应性氧化物质和辅酶Q10缺乏有关。

As discussed above, the plan for CK was based on the laboratory findings and included aggressive nutrient intervention with attention to glucose metabolism, oxidative stress, lipid abnormalities, nutrient deficiencies, and subclinical mitochondropathy Diet and exercise were important components of the plan.

如上所述，基于实验室的检测结果，CK的干预计划包括营养干预，着眼于改善葡萄糖代谢、氧化应激、脂质异常、营养缺乏和亚临床线粒体病变，另外，配合饮食疗法和运动疗法来加强治疗效果。

On follow-up, CK presented with improved energy, reduced sugar cravings, decreased blood pressure, and a 20-pound weight-loss. She was inspired by her progress to continue exercising consistently and to focus on a healthy diet. Her follow-up laboratory data inflected her commitment: glucose and A1C were both significantly improved. Though not yet in the normal range, A1C did meet guidelines for those with type 2 diabetes. Her follow-up plan included stopping glyburide, metoprolol (which has been contribute to dysglycemia) and reducing metformin.

在CK的随访中可以发现，她逐渐感到精神充沛，富有活力，也不再喜欢吃甜食，血压下降了，同时体重减少了20磅。她为自己身体状况的改善感到非常高兴，而且还会继续加强锻炼，注意保持健康的饮食习惯。从检查报告数据中可以看出，她的葡萄糖和糖化血红蛋白均有所改善，尽管还没有到正常范围，但是对于2型糖尿病患者来说，这种结果已经是非常好的了。在她的后续计划中，需要停用格列本脲和美托洛尔药物，并减少二甲双胍服用量。

At her nine-month follow-up visit, CK reported her average blood sugar to be 91 and total weight loss of 30 pounds. Her sleep apnea was resolved. She was pleased with her progress, and inspired to lose 15 additional pounds, which she intended to do by increasing her routine with a personal trainer. She would continue to work with the clinician to her goals.

在九个月的跟踪随访中，CK的平均血糖为91，体重减掉了30磅，睡眠呼吸暂停症状也有了改善，她对治疗效果非常满意，希望通过训练再减掉15磅，而且继续配合医生进行下一步的治疗。

It is important to note that CK's weight loss may have been assisted by the resolution of her sleep apnea, as poor sleep quality is associated with weight gain or difficulty in losing weight. Also, the relatively slow rate of weight loss (30 pounds over nine months) by CK may have minimized exposure to stored organotoxins liberated from adipose tissue, making the process of weight reduction safer.  Recent research has demonstrated a highly significant increase in the blood level of key fat-soluble toxins during weight loss.suggesting that a slower pace of weight loss may reduce toxic exposure."These toxins, including polychlorinated biphenyls (PCBs) hexachlorobenzene(HCB), and p,p'-dichlorophenyldichloro ethylene (DDE) are ubiquitous microcontaminants that are lipid soluble and accumulate in stored fat. Assessment of organotoxin status may be indicated prior to and during weight reduction programs.

值得注意的是，CK的体重减轻可能有助于解决睡眠呼吸暂停，因为睡眠质量差与体重增加或减肥困难是相关的，此外，CK相对缓慢的减重（九个多月的时间减掉30磅），可以最大限度的减少从脂肪组织存储的毒素曝露，使减重的过程更安全。最新研究表明，体重减轻期间脂溶性毒素的血液浓度显著增加，包括多氯联苯、六氯苯和乙烯等普遍存在的污染物，具有脂溶性并可在脂肪中累积，所以，建议在减肥之前和期间对于毒素状态进行评估和监测。

CK ‘s nine-month follow-up laboratory data continued to reflect improvement Blood sugar was at 111, down from an original 312. Liver enzymes were at normal levels and her TSH was also improved at 1.6，It showed significant improvement with HDL at a robust 68. While still elevated at 288, Lp(a) had dropped considerably from the original measurement of 423. Vitamin D was sufficient,Urinary organic acids also showed improvement, although beta-Hydroxyisovalerate continued to be elevated, despite aggressive supplementation. Biotin is primarily produced by bacteria in the GI tract. Ongoing deficiency despite supplementation suggested possible GI imbalance. Lactate and B hydroxybutyrate were both within normal ranges, suggesting improved insulin sensitivity and mitochondrial function.

从CK九个月的随访数据中，可以看出她的身体状况有了明显的改善，血糖由从前的312降到111，肝酶趋于正常，TSH也提高至1.6，高密度脂蛋白增加至68，LP（a）尽管还是偏高，但也从原来的423下降到了228，维生素D含量达到了正常标准，有机尿酸指标也得到改善，虽然给予了补充，但β-羟基异戊酸仍偏高，除使用补充剂以外，生物素主要是由细菌在胃肠道产生的，持续的缺乏表明肠道菌群仍存在失衡。其中乳酸盐和乙羟基丁酸酯数值均在正常范围内，这有助于改善胰岛素敏感性和线粒体功能。

CONCLUSION

It is difficult to overstate the diabetes epidemic and its associated ramifications. Diabetes is one of the top seven causes of death in the United States, and is associated with six of the top ten causes of death. In 2007, one of every five U.S. healthcare dollars was spent caring for someone diagnosed with diabetes. According to the world Health Organization, over 220 million people worldwide now have diabetes, and deaths from diabetes are expected to double by the year 2030. However, 90% of DMII is likely preventable through lifestyle changes alone.

结论

关于糖尿病的流行性及其相关疾病，让人不得不引起重视，糖尿病在美国是七大致死病因之一，并与排名前十的死亡原因其中六个相关，在2007年，医疗保健费用的五分之一用于照护糖尿病患者，根据世界卫生组织统计，目前全球有超过2.2亿人患有糖尿病，预计到2030年因糖尿病死亡人数将会翻倍，但是通过改变生活方式，有90%的2型糖尿病患者是可以得到有效预防的。

Excess body weight is a strong independent risk factor in diabetes, and some one in three Americans (including children) is obese or overweight.' Obesity and DMII have been closely linked to organotoxins , exposure to which is greatly increased in those who follow the typical standard American diet.z' Successful pharmacological control of DMII is achieved in fewer than 50% of all patients.' Alternatives in combating this disease are therefore urgently needed.

体重过重是糖尿病的一个非常强大的独立风险因素，三分之一的美国人（包括儿童）肥胖或超重。肥胖和2型糖尿病都与人体器官毒素蓄积密切相关，而典型的美国饮食又大大增加了这项几率。只有不到50%的糖尿病患者成功用药物控制病症，因此还需要更加有效的替代干预的方法出现。

It is well-established that lifestyle intervention can significantly reduce the incidence of DMII. As evidenced by the above statistics, however, these interventions are infrequently used. DMII might be considered a socio-political disease, since the advent of government-subsidized foods such as wheat, soy, and high-fructose. corn syrup has led to increased consumption of processed foods and simple carbohydrates, resulting in the twin epidemics of obesity and DM2. This suggests that the solution to involvement not dissimilar to that which occurred the epidemic will require government involvement not dissimilar to that which occurred with the tobacco industry. Moreover, the technological revolution has contributed to the onset of a more sedentary lifestyle, also contributing to the disease incidence.

众所周知，生活方式干预可以显著降低2型糖尿病的发生率，然而，也正如上述统计数据所证明的，这些干预治疗方法是很少被采纳的。2型糖尿病是一种社会性的疾病，因为政府补贴的食物通常是不利于糖尿病患者的，比如小麦、大豆、高糖水果和玉米糖浆等，可以导致肥胖和2型糖尿病的双重流行。这表明，与一般流行病不同的是，此项解决方案需要政府的参与。此外，随着科技的发展，大多数人选择久坐不动的生活方式，这也是导致糖尿病发生率上升的一个重要原因。

As in the case of CK, patient education, inspiration and self-awareness are essential factors needed to alter the diabetes epidemic. Laboratory assessment of disease risk and nutrient status guided the development of safe interventions that involved individualized diet, nutrient and lifestyle changes. Individualized therapies and education may be the key inspirational tools required to turn around the epidemic of DMII. Innovations in group treatment and sustainable behavior change are critical to help stem the rising tide of cost and suffering attributable to type 2 diabetes.

正如CK的案例，健康教育、激励和自我意识的改变是干预糖尿病的必需因素，疾病风险和营养状况的实验室评估对于实施安全的干预方案有指导性意义，涉及个性化饮食、营养和生活方式的改变。个性化治疗、教育可能是扭转2型糖尿病的关键启发工具，创新的团体治疗和可持续行为的改变更有利于减少2型糖尿病带来的成本和痛苦