2型糖尿病的功能医学干预（1）

A diabetic is diagnosed in the United States every 20 seconds. Diabetes mellitus (DM) is the seventh leading cause of death in the United States, with type 2 diabetes mellitus(DM2) accounting for 90 to 95% of all diabetes. Significant comorbidities include heart disease, hypertension, respiratory infection, kidney disease, stroke, retinopathy, neuropathy, and dementia, of which all except the last three are among the top ten causes of death in the U.S. These comorbidities are all linked by common underlying mechanisms. Treating the underlying causes and mechanisms can prevent or reverse most of these comorbidities. Pre-diabetes was found in more than 40% of the population between 1988 and 1994, and 7% of all adolescents have been diagnosed with impaired fasting glucose. The estimated annual cost to society of diabetes-rated concerns in the U S. is $218 billion. Hypoglycemic medications，while very important in minimizing diabetic-associated sequelae, have long carried risks. Most recently rosiglitazone (Avandia) was shown to increase risk of myocardial infarction by 43%,which is a concern in any population, but particularly so in a group already vulnerable to cardiovascular(CV) events.

在美国，平均每20秒就会检查出一名糖尿病患者，而且糖尿病被认定为致死的第七大原因（美国），尤其是2型糖尿病患者，高达糖尿病总人群的90%~95%。糖尿病的显著症状包括：心脏病、高血压、呼吸道感染、肾脏疾病、中风、视网膜病变、神经病变和老年痴呆，除最后三种疾病以外，其他疾病都会导致死亡。所有并发症都是由常见的不良机制所引起的，但通过干预可以预防或缓解。在1988年到1994年间，有40%的人在糖尿病前期就会被检查出来，甚至7%的青少年被诊断出血糖出现问题。在美国，据估计每年就诊糖尿病的所有人群需要的花费高达2180亿美元。尽管服用那些使后遗症最小化的降糖药物，但是长期使用还是会危害身体。最近罗格列酮（温亚迪）显示，有43%的糖尿病病人患有心肌梗塞，这是一个相当大的数字，这种疾病在心脑血管疾病中是非常危险的。

Lifestyle intervention has been shown to reduce the incidence of diabetes by 71 % in those 60 years of age and older, and by 58%. in all adults. Such findings strongly suggest that diabetes, while subject to genetic influence, is primarily a disease of lifestyle choice and increasingly environmental toxicity.

在60岁或以上的人群中，生活方式干预可以使糖尿病发生率降低至71%，而在中年人中降低至58%。从这些数据中，我们可以看出糖尿病和遗传有关，但主要还是受生活方式和环境毒素等因素的影响。

案例分析

CK, a 56-year-old female presented to the clinic with type 2 diabetes(DMII),obesity, high blood pressure, elevated cholesterol and sleep apnea. CK was diagnosed with diabetes in 1999 and was prescribed glyburide and metformin. She did not regularly test her blood sugar, although she did attempt to adhere to a healthy diet, including oatmeal for breakfast, chicken and other lean protein with salads for lunch and dinner. However, she craved sugary foods and consumed much candy and ice cream at night. She generally felt ravenous before lunch and dinner, and experienced nausea and mood swings when she waited too long to eat. She also had wine with dinner most nights. These habits provided palliation for her high-stress job as a university professor and researcher.

CK，一名56岁的女性，被诊断为2型糖尿病。她身材偏胖，患有高血压、高胆固醇和睡眠呼吸暂停症。在1999年，CK就被查出有糖尿病，当时医生开的处方药是格列苯脲和二甲双胍。尽管她一直坚持健康的饮食方式，比如早晨吃燕麦，午饭或晚饭吃鸡肉、其他瘦肉或沙拉，但是，并没有定期测血糖，甚至，她晚上还吃甜食、糖果和冰激凌。在吃午饭和晚饭之前，她总是感觉非常饿，甚至由于太久没吃饭感到恶心和情绪波动。大多数晚餐时，她还会饮用一些酒。所有这些习惯使她作为一个大学教授每日高强度的工作状态可以得到一些缓解。

CK was diagnosed with hypertension in 1997, for which she took metoprolol and amlodipine/benazepril. She did not monitor her blood pressure levels regularly. She was diagnosed with hyperlipidemia in 2003 for which she took atorvastatin. CK had sleep apnea for years, but did not use a CPAP machine. She experienced occasional constipation. She felt well in the mornings, and meditated daily for 15 minutes, but was frequently sleepy after lunch and dinner.

CK在1997年被诊断出高血压，为此她定期服用美托洛尔和氨氯地平或贝那普利等药物，但她并没有定期测量血压。在2003年，她被查出有高血脂症，开始服用阿托伐他汀药物。CK已经有多年的睡眠呼吸暂停的状况，但没有使用呼吸机。偶尔出现便秘。一般早晨的时候她感觉自己状态良好，每天坚持十五分钟的静坐，但在午饭或者晚饭后感到困倦。

CK's past medical history was unremarkable, with the exception of mononucleosis at age 16.CK's father died at 55 years of age from a cerebrovascular accident. He also had coronary artery disease. CK's father was adopted, and therefore extended paternal family history was unknown. CK's mother died at 70 years of age. She was diagnosed with type 2 diabetes and heart disease. CK has no siblings. CK's maternal aunts have type 2 diabetes.

除了16岁时曾患有单核细胞增多症以外，CK的既往病史不是很明确，CK的父亲55岁时由于脑血管疾病去世，同时还患有冠心病。由于CK的父亲是被领养的，所以家族病史无从调查。CK的母亲患有2型糖尿病和心脏病，70岁去世。CK没有兄弟姐妹。CK的姨妈也有2型糖尿病。

CK did not smoke. She meditated for 15 minutes each morning. She took a one-per- day multivitamin and mineral supplement. She traveled a great deal for work and went out 1 to 2 nights per week. CK generally did not exercise, but did some limited walking during vacations.

CK从不吸烟，每天早晨坚持15分钟的静坐，补充维生素和矿物质。她经常旅行，每周出去一两天，她通常不太爱运动，仅在放假的时候散散步。

CK's significant physical exam findings included a blood pressure of 160/104 (left arm seated) and a heart rate of 94 beats per minute. She weighed 190 pounds and was 5'2" tall. Her body mass index (BMI) was 34.7, considered obese, and her waist-to-hip ratio (WEIR) was slightly above optimal at 0.89.

CK的体检报告结果中，血压：160/104mmHg，心率：94次/分，体重：190磅，身高：5英尺2英寸，BMI：34.7，腰臀比：0.89，由以上数据可以诊断为肥胖。

Laboratory tests ordered and rationale:

1. Fasting insulin, hemoglobin A1C, urinalysis*, metabolic panel*, thyroid panel, hs-CRP and fibrinogen: Comprehensive, standard laboratory assessments for DMII and associated inflammation.

2. Lipids, lipoprotein subclasses with lipoprotein (a): Lipid subclass assessment may be a more sensitive predictor of cardiovascular risk in metabolic syndrome than a standard lipid assay. Lp(a) is an independent risk marker for cardiovascular disease that is not responsive to statin therapy.

3. Vitamin D: Low levels are associated with increased inflammation and increased incidence of numerous diseases.R

4. Multi-profile metabolic panel*: A comprehensive assessment including organic acids, fatty acids, amino acids, fat soluble vitamins, essential elements and oxidative stress markers; assists in detecting individual etiopathogenesis factors and in individualizing treatment plans.

5. Stool test: Assessment of GI microbial status and GI function. Imbalances may be associated with glycemic regulation and obesity.

实验室检查结果：

1.空腹血胰岛素、糖化血红蛋白、尿常规、代谢评估、甲状腺、超敏C反应蛋白、纤维蛋白原：通过以上检测可以全面综合诊断出她是否患有2型糖尿病或相关炎症。检测结果显示尽管CK接受了降糖治疗，但胰岛素抵抗的许多标志物偏高，ALT升高提示早期非酒精性脂肪肝，甲状腺指标尽管不是最理想的，还在正常范围以内，其他指标如肾功能指标、纤维蛋白原、微量白蛋白等均在正常范围。

2型糖尿病的功能医学干预（1）

图1：临床实验室检测结果

2.脂质和脂蛋白检测：亚类脂质检测比其他标准脂质测定更能准确检查是否有代谢综合征心血管疾病，Lp（a）是心血管疾病的独立风险标志物，对他汀类药物治疗无反应。检测结果显示：LP(a)升高，HDL和LDL颗粒指标异常表明存在代谢综合征。

2型糖尿病的功能医学干预（1）

图2：脂蛋白分型检测结果

3.维生素D检测：如果水平太低则表明会有炎症或其他疾病的发生。CK维生素D结果偏低。

2型糖尿病的功能医学干预（1）

图3：维生素D检测结果

4.代谢水平评估：这个检测比较全面，包括有机酸、脂肪酸、氨基酸、脂溶性维生素、营养元素和氧化应激标志物，这些都有助于找出发病原因。有机酸检测结果显示：B族维生素标记物β-羟基异戊酸酯是生物素不足的敏感和特异性标记物，α-酮酸升高与硫胺素需求增加有关，也能表明需要烟酸、泛酸、核黄素和硫辛酸。线粒体标记物中乳酸盐、羟基丁酸等升高提示存在线粒体功能障碍。另外，红细胞营养元素的检测发现均处于较低水平。

2型糖尿病的功能医学干预（1）

图4：有机酸&脂肪酸&营养元素&脂质标记物检测结果

5.粪便检测：检测胃肠道微生物状况和胃肠道功能，如胃肠道功能失衡也会引起肥胖。

Initial Assessment

Type 2 diabetes

Obesity

Hypertension

Hyperlipidemia

Sleep apnea

Subclinical fatty liver disease

Subclinical hypothyroidism

Hypovitaminosis D

Mitochondropathy

Oxidative stress

初步评估

2型糖尿病

肥胖

高血压

高脂血症

睡眠呼吸暂停

亚临床性脂肪肝

亚临床甲减

维生素D缺乏

氧化应激

Initial Plan

Dietary Intervention

Begin low carbohydrate/low glycemic diet; have protein with each meal. Chew food adequately, eat slowly and allow digestion time. Protein-based snacks in afternoon

初步治疗计划

饮食干预

每餐食用含有蛋白质的低碳水化合物或者低糖量食物，细嚼慢咽有助消化，下午食用含有蛋白质的零食。

Lifestyle Intervention

Increase exercise-begin interval training.

Monitor fasting blood sugar and 2 hour post prandial blood sugar QD·

Sleep apnea: Recommend mandibular repositioning appliance and home sleep study

生活方式干预

增加运动量，进行间歇性训练

每日餐后两小时测血糖

对于睡眠呼吸暂停状况，建议使用下颌复位校正仪器

Nutrient Support

Nutrients for glucose metabolism (chromium, vanadium, alpha-lipoic acid (ALA), n-acetyl cysteine (NAC), biotin, banaba leaf extract, Gymnema sylvester)，1 packet PO BID

Fiber complex (konjac mannan, sodium alginate, xanthan gum), 4 capsules before meals with water

Medicinal food containing rice protein powder, medium chain triglycerides,vitamins and minerals specific for hepatic function, 2 scoops QAM (mix/blend with ice, unsweetened soy milk and berries; add 2 TBSP ground flax.)

Nutrients for mitochondria support (including: magnesium, CoQ10, creatine, acetyl-carnitine), 1 tab PO BID

EPA/DHA 720 mg, 2 Gelcaps PO BID

CoQ10 100 mg, l tab PO BID

R-alpha-lipoic acid (R-ALA) 100 mg, l cap PO QD

Cinnamon (Cinnamomum burmannii) extract, 2 caps PO BID

Biotin 8 mg, l capsule

Vitamin D3 10,000 IU, daily

营养干预

支持血糖代谢的补充剂（含铬、钒、α-硫辛酸、N-乙酰半胱氨酸、生物素、大花紫薇叶提取物、匙羹藤属植物），1包，口服，BID

纤维复合物（魔芋甘露聚糖、海藻酸钠、黄原胶），四粒，餐前服

医疗食品包括大米蛋白粉、中链甘油三酯、维生素和具有护肝功能的矿物元素（用水混合或者可以加冰、无糖豆浆和浆果，添加两匙亚麻籽油）。

线粒体支持的营养物质包括镁、辅酶Q10、肌酸、左旋肉碱，一粒，QD

EPA/DHA，720mg，两粒，BID

辅酶Q10,100mg，一粒，BID

α-硫辛酸100mg，一粒，QD

肉桂，两粒，BID

生物素8mg，一粒，QD

维他命D3,10，000IU/天

Discontinue:

Multivitamin mineral formula

停止使用：

维生素矿物质配方

Medication

Niacin sustained release 500 mg, l tablet

药物治疗：

烟酸缓释500mg，1粒

Continue:

Atorvastatin 10 mg, l tab

Glyburide 5 mg, l tab QD

Metformin 500 mg, l tab TID

Metoprolol 25 mg 1 tab QD

Lotrel 10 mg-20 mg, 1 cap QD

Aspirin 81 mg, l tab QD

继续服用：

阿托伐他汀10mg，1粒

格列苯脲5mg，QD

二甲双胍500mg，1粒，TID

美托洛尔25mg，1粒，QD

氨氯地平10~20mg，1粒，QD

阿司匹林81mg，1粒，QD

Follow-up Laboratory Tests Ordered:

Hemoglobin AIC

Fasting blood glucose

Urinary microalbumin

后期需要检查项目：

1. 血红蛋白

2. 空腹血糖

3. 尿微量白蛋白

Treatment plan rationale:

Intensive dietary intervention was recommended to reduce glycemic load and increase phytonutrient density, in combination with addressing meal timing and frequency. A regular exercise program was initiated to improve insulin sensitivity and increase V02max and mitochondria) number and efficiency. Supplementation of glucose metabolism-supportive nutrients was initiated, including a specifically-designed product with chromium, vanadium, alpha-lipoic acid (ALA), NAC, biotin, and botanicals banaba leaf and Gymnema sylvestre. Extra biotin was also given, based on research using higher doses in insulin resistance (IR), and the significant biotin deficiency identified .All nutrients prescribed have shown efficacy in improving insulin sensitivity in human trials. Additional lipoic acid was also given in the form of R-ALA, which may be more potent than ALA," and may therefore be more effective for IR. A fiber complex including Konjac-mannan (KJM) was initiated. KJM has been shown to improve insulin sensitivity.' Fiber is also a demonstrated hypolipidemic agent.'`' KJM may have similar promise. A proprietary rice protein and nutrient-based medicinal food was given. Research suggests this medicinal food benefits hepatic function, and was therefore prescribed for the suspected subclinical fatty liver.20 the medicinal food contains B vitamins and essential elements, both found to be insufficient in this patient .The anti-inflammatory fatty acids EPA and DHA have been shown to reduce the pro-inflammatory fatty acid arachidonic acid, which was found to be elevated . Both fatty acids also have demonstrated benefit in hypertriglyceridemia.' Mitochondrial supportive nutrients, including CoQ10, creative, carnitine, and magnesium were started based on the organic acid findings and high lipid peroxide level ,which suggested an oxidative stress picture and mitochondropathy. Niacin has been shown to effectively reduce lipids, including Lp(a), which was found to be very high. Atorvastatin, which CK was taking, has not been shown effective at lowering Lp(a).Vitamin D was given for the identified deficiency .The multivitamin and mineral formula was stopped because it didn't supply enough of the specific nutrients required.

干预计划的原理

建议进行强化饮食干预措施，以减少血糖负荷，增加植物营养素密度，控制饮食时间和饮食的频度。规律运动，以提高胰岛素敏感性和增加摄氧量。补充支持葡萄糖代谢的营养素，其中包括铬、钒、α-硫辛酸、生物素和植物大花紫薇叶和匙羹藤等成分，有研究表明使用大剂量的生物素可以对胰岛素抵抗有帮助，其他营养素也可以对改善胰岛素敏感性起作用。硫辛酸以R-ALA形式给予，比ALA形式更加有效。纤维复合物包括魔芋甘露聚糖，同样可以提升胰岛素敏感性，也有降血脂的作用。研究表明，含有大米蛋白质医疗食品对肝功能有益，因此可用来干预亚临床性脂肪肝，这种医疗食品还含有维生素B族和其他一些患者体内缺乏的必需元素。抗炎脂肪酸EPA和DHA可以降低促炎性脂肪酸花生四烯酸，对于高甘油三酯血症也是有益的。线粒体支持的营养物质，包括辅酶Q10、肌酸、肉碱和镁等。在CK的案例中，我们可以看出阿托伐他汀对降低脂蛋白LP(a)并没有发挥作用。另外，检测表明CK缺乏维生素D，所以给予相应补充。由于综合维生素和矿物质补充剂并不能满足CK的特殊营养需求，所以停用。

Four-Month Follow-up

After making dietary changes and taking supplements, CK reported improvement in energy particularly in the mid-afternoon and evening. Her morning blood sugar average was 90. She noted that her skin was clearer. Protein-based afternoon snacks were very helpful in improving mood and energy, and reducing cravings. Fiber was helping with bowel movements. She was exercising on treadmill 30 minutes per day on most days. Her weight loss was at 20 lbs. Her sleep apnea resolved without any interventions. She was very leased with her progress.

四个月随访

在改变饮食结构和服用营养补充剂后，CK在午后和晚间明显感觉有活力了，她每天早晨的平均血糖数值为90mg/dL，觉得自己的皮肤变好了。午后摄入含有蛋白质的零食和减少吸烟量也可以有助她增加能量，变得身心愉悦，精力充沛。含纤维的食物可以改善她的便秘状况，每天跑步30分钟，体重也下降了20磅，而且在没有使用任何仪器的条件下，睡眠质量也有所改善。

CK's diet consisted primarily of organic or cleaner sources of protein (lean meats, fish, eggs, and protein powder), low glycemic snack bars, nuts, seeds, legumes, fresh fruit, vegetables, and some whole grains. When she started the program, she was inspired to clean out her kitchen cabinets of all unhealthy foods. She then stocked up at the natural foods market, buying a greater variety of foods. CK admitted that she allowed the diet perfectly for one week, and then began to cheat. When she did so, she noticed that certain foods caused symptoms. In particular, she thought that dairy and sugary foods significantly worsened her afternoon fatigue.

CK的饮食结构主要包括蛋白质或者有机食物（瘦肉、鱼肉、鸡蛋和蛋白粉），低糖零食、坚果、豆类、新鲜蔬果和全麦食品。当她开始进行饮食计划后，把厨房里所有不健康的食物都清理掉了，然后开始去菜市场买大量的健康果蔬，坚持一周后，CK开始有所放松，但是当她摄入某些特定食物，尤其是乳制品和甜食时，就马上感到午后疲劳加重了。

She reported that it was difficult to maintain dietary changes when traveling, and noticed at her blood sugar was significantly higher after flying, reaching 180 on a recent trip. CK was confessed to being addicted to buffet foods, and decided to limit eating out.

她说外出时很难坚持健康的饮食习惯，同时会发现血糖的迅速增高，在最近一次测量中血糖量竟然高达180mg/dL。CK承认自己又开始沉迷于不健康的食物，所以她决定不再外出就餐。

CK's physical exam findings showed great improvement: blood pressure:. 127/79, left arm seated (previous reading: 160/104); heart rats per minute79 (previous rate: 94) weight 170 lbs (previous weight: 190 lbs);BMI 32.66 (previous:34.7); waist-to-hip ratio.0. 86 (previous ratio: 0.89).

CK的体检报告结果相较之前有了很大的改善。血压为127/79mmHg，（以前是160/104mmHg）；心率79次/分（以前是94次/分）；体重为170磅（以前是190磅）；BMI为32.66（之前是34.7）；腰臀比为0.86（之前是0.89）。

Four-Month Follow-up Plan

Dietary Intervention

Keep daily food journal

Include Brassica vegetables at least 3 times per week; daily is best. Examples: arugula, watercress, cabbage, radish, broccoli sprouts, broccoli, and Brussels sprouts

15 minutes walking if she overeats in a restaurant, followed by blood sugar check

Travel food suggestions:

Dehydrated bean soups

Canned wild salmon

Fresh fruit

Nuts/seeds

Organic fiber bars

Medicinal food: store individual servings in plastic bags for easy access

四个月随访计划

饮食干预

坚持记录饮食日志。

每周至少食用芸薹属蔬菜三次，如果每天食用效果更佳。芸薹属蔬菜包括：芝麻菜、西洋菜、白菜、萝卜、花椰菜、西兰花和甘蓝等。

如果外出就餐，测量血糖并散步15分钟以消耗热量。

外出吃饭建议：

      •    脱水豆类汤

      •    野生鲑鱼罐头

      •    新鲜水果

      •    坚果/种籽

      •    有机纤维食物

      •    医疗食品：按照每次食用量分装

Medications and nutrient therapy

Continue supplements as directed

Reduce metformin dosage to 500 mg BID

Discontinue glyburide

Discontinue metoprolol (has been shown to raise blood glucose2')

Organic acids

药物和营养干预

继续遵医嘱摄入营养补充剂

减少二甲双胍服用量直至每次500mg

停用格列本脲

停用美托洛尔（有升糖作用）

继续监测血糖

Continue to monitor blood sugar

Laboratory tests ordered (to be completed prior to next office visit):

Hemoglobin A1C, metabolic panel, thyroid panel

Lipids, lipoprotein subclasses and lipoprotein (a)

Vitamin D

复查项目

糖化血红蛋白，代谢评估，甲状腺评估

脂质、脂蛋白亚型

维生素D

有机酸

Treatment plan rationale:

Dietary suggestions for travel were given. Hypoglycemic medications were reduced based on laboratory findings that demonstrated significant improvement in glucose control. Metoprolol was stopped because it has been shown to elevate blood glucose, and CK's blood pressure was significantly improved.

治疗方案：

制定外出饮食计划，由于血糖控制显著改善，减少降糖药物，停用可以升糖的美托洛尔，CK的血压也开始趋近正常。

Nine一Month Follow-up

CK reported a 30 1b weight loss and stated that her average fasting blood sugar was 91. Her cravings were minimal. She reported no sleep apnea and no colds or other health problems since the start of treatment. She wanted to lose another 15 lbs, after which she would completely discontinue glyburide and metformin. She started working with a trainer on interval and strength training two times a week. CK complained of being very busy with work-related travel, though in general she felt empowered in life and health. She described herself as being at a magical point, happy and enjoying her life.

九个月随访

CK 已经减了30磅，平均血糖91mg/dL。自从干预以后，没有出现睡眠呼吸暂停、感冒或者其它病症。停用格列本脲和二甲双胍之后，CK希望再减15磅。她每周进行两次间歇和力量训练。虽然之前曾抱怨工作忙碌，经常出差，但总得来说，她觉得自己的生活和健康都有所提升， 她形容现在处于神奇的境遇，快乐并享受人生。

复查结果如图5、6所示，血糖和A1C指标得到改善，ALT、AST趋向正常，尽管T3相较之前偏低，TSH指标好转。脂质指标变化很大，维生素D已补充至正常水平。尽管补充了大剂量的营养素，有机酸代谢中B族维生素指标仍存在异常，线粒体标记物提示胰岛素敏感性和线粒体功能改善。

2型糖尿病的功能医学干预（1）

图5：临床指标&脂蛋白分型

2型糖尿病的功能医学干预（1）

图6：维生素D&有机酸检测结果

Nine一Month Follow-up Plan

Increase exercise as planned

Continue interventions as directed

九个月随访计划

提高运动量

继续遵医嘱执行干预计划

未完待续，请继续关注下期：功能医学辅助干预II型糖尿病案例分析（下）——机理分析

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