What Causes Insulin Resistance? Lipid Overload
By Dr. Cyrus Khambatta
Cyrus Khambatta. 在加州大学伯克利分校获得营养生物化学博士学位，并获得斯坦福大学机械工程学士学位。他在22岁时被诊断出患有1型糖尿病，在此后的11年里，他一直在研究胰岛细胞衰竭和胰岛素抵抗。Khambatta 热衷于营养学和锻炼，通过MangoMan营养疗法和健身指导，教授逆转糖尿病的根源——胰岛素抵抗而不是治疗高血糖症状的原则，实现对血糖波动的高度控制。
胰岛素抵抗是与2型糖尿病相关的最常见的一个状况, 现在越来越多的证据揭示了事实, 胰岛素抵抗是许多以前认为与血糖无关的疾病,包括(但不限于)心脏病、糖尿病、动脉粥样硬化、代谢综合征、肥胖和癌症的共同主线。
胰岛素抵抗是人体多种组织对胰岛素（Insulin) 的作用产生抵抗的一种状态。简单地说，当组织对胰岛素反应迟钝时，就会产生胰岛素抵抗(Insulin Resistance)。
这堵墙存在的原因有很多，并且受到经济力量的严重影响，这些经济力量从糖尿病等终身性疾病获得好处。你可能听说过“治愈疾病赚不到钱 There is no money in the cure”这句话。这是一种真实的说法，而这种做法是将拯救生命的信息传不到从需要的人手上。
然而，尽管如此，实验室环境中的研究人员使用一种简单的技术，却能轻易地在实验室动物体内诱导出胰岛素抵抗 。 尽管无休止的学术争论，有一件事是清楚的——如果你想在实验动物或人类身上诱导胰岛素抵抗，最有效和可重复的方法很简单:
胰岛素抵抗是由脂质超载(Lipid Overload or Fat Overload) 引起的，或者由高脂肪饮食引起的，或者是由于缺乏运动导致的脂肪“燃烧”不足所致。
胰岛素抵抗原因1:高脂肪饮食 (High Fat Diet)
在一些研究中，研究人员使用高脂肪 （High Fat Diet ) 和高蔗糖(蔗糖)的饮食 (High Sucrose Diet)，以确保肌肉和肝脏都变得非常胰岛素抵抗。原因很简单:
摄入大量的膳食脂肪会导致肌肉和肝脏的脂质超载和胰岛素抵抗。蔗糖(白糖) (High Sucrose Diet) 也会增加肝脏的胰岛素抵抗。
“长时间暴露于骨骼肌和肌细胞中，高水平的脂肪酸会导致严重的胰岛素抵抗(2,3)。在不同类型的脂肪酸中，饱和的长链脂肪酸，如棕榈酸和硬脂酸被证明是胰岛素抵抗的有效诱导因子(4,5)。我们(4,6 - 8)和其他(2,9-12)建议了几种机制来解释饱和脂肪酸是如何影响胰岛素作用的，如Randle循环，细胞内脂质衍生物的积累(二酰基甘油和神经酰胺)，氧化应激，基因转录的调节，炎症和线粒体功能障碍。在本综述中，我们讨论了支持这些机制参与饱和脂肪酸对胰岛素敏感性调节的证据，并提出在脂肪酸水平升高的条件下发现的线粒体功能障碍在胰岛素抵抗的发病机制中起着中心作用(13)。
胰岛素抵抗原因# 2: 假的碳水化合物 （Fake Carbohydrates)
胰岛素抵抗原因# 3: 缺少锻炼
What Causes Insulin Resistance? Lipid Overload
Over the past year I have interacted with hundreds of people with diabetes, and have come to learn one very important lesson that has changed my view of diabetes altogether. This realization came to me early on in my career as a nutrition and fitness coach for people with diabetes, and continues to hold true.
While insulin resistance is a condition that is most commonly associated with type 2 diabetes, an increasing body of evidence is now shedding light on the fact that insulin resistance is a common thread that underlies many health conditions previously unassociated with blood sugar, including (but not limited to) heart disease, diabetes, atherosclerosis, the metabolic syndrome, obesity and cancer.
What that means is simple: insulin resistance significantly increases your risk for the development of a collection of health conditions that can significantly reduce your quality of life and decrease your life expectancy.
Watch this video for a synopsis of the causes of insulin resistance:
What is insulin and why should you care?
Insulin is a hormone which is released by the pancreas in response to rising blood glucose. When you consume carbohydrates, the glucose that enters the bloodstream knocks on the door of the beta cells in the pancreas as a signal to make insulin.
Insulin serves as the key that unlocks the door to allow glucose to enter body tissues. Insulin tells your cells “Yoo hoo! Pick up this glucose. It’s all over the place.”
Without insulin, cells in the liver, muscle, and fat have a difficult time vacuuming up glucose from the blood. These tissues are capable to vacuuming up only a small percentage (5-10%) of the glucose in circulation without the help of insulin. When insulin is present, the amount of glucose that can be transported into tissues significantly increases, allowing tissues to be properly fed, and keeping blood glucose concentrations in the normal range. The system looks like this:
What is insulin resistance?
Insulin resistance is a condition in which multiple tissues in the human body become resistant to the effects of insulin. Simply stated, insulin resistance occurs when tissues become “dumb” to insulin.
As a result of insulin resistance, the pancreas is forced to secrete increasing amounts of insulin, resulting in a condition known as hyperinsulinemia.
Hyperinsulinemia is a dangerous condition for many tissues, simply because elevated insulin concentrations in the blood act as potent signals for cell growth. More insulin means more tissue growth. More tissue growth often results in increased fatness, increased cell replication rates and a significant increase in the risk for cancer. Many studies have now begun to uncover the link between insulin resistance and cancer, and one such study states the following:
"Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients (1)."
How much do scientists know about insulin resistance?
There is a significant amount of confusion about what actually causes insulin resistance, and in my life as a type 1 diabetic as well as my career as a research scientist, I have come to realize that life-saving information about insulin resistance is poorly understood.
There exists a large wall between what the research world understands about insulin resistance and what the general public understands about insulin resistance. Unfortunately, excellent research does no good if the information is not put in the hands of those who need it. This is certainly the case with insulin resistance. The picture looks something like this:
This wall exists for a number of reasons, and is heavily influenced by economic forces that profit on lifelong health conditions like diabetes. You may have heard the phrase “there is no money in the cure.” This is a true statement, and this practice is what keeps life-saving information out of the hands of those who need it.
What causes insulin resistance?
Researchers debate the causal mechanisms of insulin resistance tirelessly, day after day, and travel thousands of miles to attend large conferences to flex their scientific muscles. They propose every mechanism you can imagine, and blame every tissue you can think of, from the pancreas to the muscle to the liver to the brain to your blood.
To say that insulin resistance has a single cause is a misnomer. To say that insulin resistance is a complex metabolic condition is much more accurate.
Despite this, however, researchers in the laboratory environment can induce insulin resistance in laboratory animals an in humans incredibly easily, using one simple technique. Regardless of the endless intellectual debate, one thing remains clear - if you want to induce insulin resistance in a laboratory animal or in a human, the most effective and repeatable way to do it is simple:
Insulin resistance is caused by lipid overload, resulting from either a high fat diet or insufficient fat “burning” through movement.
Insulin Resistance Cause #1: High Fat Diet
Visit almost any laboratory on the planet that studies insulin resistance in animals or in humans and you’ll notice one simple technique that achieves insulin resistance in a repeatable fashion – eating a diet high in fat. Not carbohydrates.
In some studies, researchers use a diet high in fat and high in sucrose (table sugar), to ensure that both the muscle and the liver become extremely insulin resistant. The reason for this is simple:
A high intake of dietary fat causes lipid overload and insulin resistance in the muscle and liver. Sucrose (white table sugar) also increases liver insulin resistance.
I am often asked whether there is any research to back up the claim that fatty acids cause insulin resistance. There is a considerable amount of research that justifies this notion, and this evidence clearly points to the fact that excess fatty acids are a potent cause of both muscular and liver insulin resistance. A simple literature search reveals statements like the following:
"Prolonged exposure of skeletal muscle and myocytes to high levels of fatty acids leads to severe insulin resistance(2,3). Among the different types of fatty acids, saturated long-chain fatty acids such as palmitic and stearic acids were demonstrated to be potent inducers of insulin resistance(4,5). Several mechanisms have been suggested by us(4,6–8) and others(2,9–12) to explain how saturated fatty acids impair insulin actions such as the Randle cycle, accumulation of intracellular lipid derivatives (diacylglycerol and ceramides), oxidative stress, modulation of gene transcription, inflammation and mitochondrial dysfunction. In the present review, we discuss evidence supporting the involvement of these mechanisms in the regulation of insulin sensitivity by saturated fatty acids and propose the mitochondrial dysfunction found in conditions of elevated fatty acid levels has a central role in the pathogenesis of insulin resistance(13)."
Saturated fatty acids are the most potent influencers of insulin resistance
Saturated fatty acids are derived mainly from animal sources, and have direct negative effects on the muscle and liver.
High concentrations of saturated fatty acids are found in the following animal foods:
Animal meat (beef, chicken, pork, turkey, duck, venison etc.),
Dairy products from cows, goats and sheep (milk, butter, sour cream, cream cheese, cheese)
Fish (cod, herring, salmon, sardines etc.)
In addition, high concentrations of saturated fats are found in some plant foods, including:
Nuts and seeds (brazil nuts, macadamia nuts, cashew nuts, pine nuts and sesame seeds)
Dried coconut meat
Hydrogenated vegetable oils
These direct effects of saturated fatty acid intake on muscle and liver include include:
Mitochondrial dysfunction in the muscle and liver
The production of free radicals in the muscle and liver
Cellular inflammation in the muscle and liver
When excess fat accumulates it the muscle and liver tissue, the ability of glucose to enter both tissues is significantly compromised. In another paper written about the effect of saturated fatty acids on tissue function, the authors state the following:
"An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid ‘spill over’ to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis)(14)."
Several investigators have shed light on the ability of fatty acids to induce low-grade inflammation, which acts as an initial step in a series of events leading to damaged blood vessels, liver disease, heart disease and hypertension:
"Elevated free fatty acid levels (due to obesity or to high-fat feeding) cause insulin resistance in skeletal muscle and liver, which contributes to the development of type 2 diabetes mellitus (T2DM), and produce low-grade inflammation, which contributes to the development of atherosclerotic vascular diseases and NAFLD (non-alcoholic fatty liver disease)(15)."
From a top-down view, a high fat diet induces insulin resistance in the following way:
Too often, the blame is placed on carbohydrates as the cause of insulin resistance despite the fact that the evidence clearly supports that excessive fat consumption causes excessive fat storage.
Insulin Resistance Cause #2:
I’ve talked extensively about the difference between REAL and FAKE carbohydrates, and gone into detail about the effects they have on tissues throughout your body. You can read about them in the article Carbohydrates are NOT Killing You: Part 1.
To save you from having to scroll through previous articles, let’s walk through the difference between REAL and FAKE carbohydrates once again.
What are REAL carbohydrates?
REAL carbohydrates come from mainly fruits and vegetables, and can be eaten in their whole, natural state with minimal cooking or processing. REAL carbohydrates are found mainly in plant foods, and come pre-packaged with a host of vitamins, minerals, antioxidants, fiber and water. Think of REAL carbohydrates as the types of foods that you would find if you were walking in the woods by yourself.
REAL carbohydrates have untold health benefits, and are absolutely required for optimal athletic performance, athletic recovery and preventing against lipid overload.
What are FAKE carbohydrates?
FAKE carbohydrates live in packages, bottles, cans and boxes. They are “refined” products that have been processed, manufactured and changed from their original and whole state. FAKE carbohydrates have been modified from their original state in order to make them edible and often times to make them taste sweet. FAKE carbohydrates include grains, cereals, pastas, rice, bread products and artificial sweeteners.
Consumption of FAKE carbohydrates can lead to disastrous health effects, including (but not limited to):
Increased appetite and overeating(16)
Increased fat synthesis in the liver(17,18)
Unwanted weight gain(16,17)
Insulin resistance, high blood sugar and diabetes(17–19)
The metabolic syndrome(18)
In the past decade, a large body of evidence has begun to uncover the potent effects of refined carbohydrates on decreased cardiovascular health, diabetes health, liver health and unwanted weight gain. Statements taken from these articles include:
"High fructose exposure during critical periods of development of the fetus, neonate and infant can act as an obesogen by affecting lifelong neuroendocrine function, appetite control, feeding behaviour, adipogenesis, fat distribution and metabolic systems. These changes ultimately favour the long-term development of obesity and associated metabolic risk (16)."
"High consumption of refined grains, particularly white rice, has been reported to be associated with a higher risk of type 2 diabetes…These results suggest that high consumption of rice and noodles may contribute to hyperglycaemia through greater insulin resistance and that this relationship is independent of adiposity and systemic inflammation (19)."
Insulin Resistance Cause #3:
Exercise is without doubt the most effective method of increasing insulin sensitivity, and is considered the gold-standard method of decreasing diabetes risk(20–27). There are three main reasons why exercise benefits insulin resistance in muscle tissue:
Exercise stimulates the muscle tissue to burn stored fat
Exercise stimulates the muscle tissue to accept glucose from the blood
Exercise allows the muscle to accept glucose without the help of insulin
Think of exercise as being the signal that increases the appetite of your muscle tissue to accept incoming glucose in the blood. Forcing the muscle to contract and elongate thousands of times in a short period of time increases it’s fat burning capabilities and also increases its willingness to store more glucose. As far as insulin resistance is concerned, this is a double whammy.
Exercise acts in both the short term and the long term, and leads to significant increases in the ability of the muscle tissue to respond to glucose in the blood.
"A single bout of exercise increases skeletal muscle glucose uptake via an insulin-independent mechanism that bypasses the typical insulin signalling defects associated with these conditions. However, this ‘insulin sensitizing’ effect is short-lived and disappears after ∼48 h. In contrast, repeated physical activity (i.e. exercise training) results in a persistent increase in insulin action in skeletal muscle from obese and insulin-resistant individuals (28)."
I am happy to see that exercise is now being prescribed as a treatment for insulin resistant individuals, regardless of whether they have diabetes or not. In many cases, those with prediabetes can stave off the transition to diabetes by adopting a regular exercise regimen to increase insulin sensitivity regularly.
"Accordingly, it is now well accepted that regular physical exercise offers an effective therapeutic intervention to improve insulin action in skeletal muscle in insulin-resistant individuals (29)."
Take Home Message
It is important to recognize that insulin resistance affects everyone, even those who show no symptoms of high blood sugar. In order to ensure that you remain insulin sensitive, regardless of your current health status (diabetic or non-diabetic), follow these three steps:
Consume a diet containing less than 15% of calories from fat
Minimize or eliminate your consumption of FAKE carbohydrates
Maintain a consistent exercise regimen with 3-4 sessions of cardiovascular exercise per week