This edition of Pursuing Health Pearls will build on our last edition about COVID-19 and our Health. In that edition, we revealed that only 12.2% of our population is optimally metabolically healthy, and a lot of metabolic dysfunction goes undiagnosed.

Good metabolic health is a state of being in which the biochemical processes in the body that regulate blood sugar and lipids are operating normally. There are many definitions of metabolic dysfunction, but all involve abnormal regulation of blood sugar and lipids as well as systemic inflammation. If metabolic dysfunction is left unaddressed, it can ultimately lead to a range of common chronic diseases and causes of death such as hypertension, diabetes, heart disease, and stroke.

Here, we’ll review how metabolic dysfunction develops, what is actually happening in our bodies that sets the stage for chronic disease, and how to assess metabolic health so that this dysfunction can be detected and addressed early.

Diagnosing Metabolic Dysfunction

There is no single test for metabolic dysfunction, but there are many different signs and symptoms which we can assess to determine whether it is present. Some of these indicators have been grouped together to define a condition called metabolic syndrome. Metabolic syndrome is a grouping of five different risk factors that, when present, raise the risk of heart disease and other health problems, such as diabetes and stroke. Any one of these risk factors may be present by itself, but they tend to occur together. Having at least three of the five risk factors is consistent with a diagnosis of metabolic syndrome. The risk factors include:

• A waist measurement of 35 inches or more for women or 40 inches or more for men
• Triglycerides of 150 mg/dL or higher (or being on medicine to treat high triglycerides)
• HDL cholesterol level of less than 50 mg/dL for women or  less than 40 mg/dL for men (or being on medicine to treat low HDL cholesterol)
• Blood pressure of 130/85 mmHg or higher (or being on medicine to treat high blood pressure)
• A fasting blood sugar level of 100 mg/dL or higher (or being on medicine to treat high blood sugar)

Metabolic syndrome has a prevalence of 24% in US adults and 43% in US adults older than 60 years. In other words, 24% of adults and 43% of adults over 60 in the US have at least 3 of the above five risk factors. The NHANES (National Health and Nutrition Examination Survey) from 2009-2016 showed that only 12.2% of American adults have zero of these five criteria. In other words only 12.2% of American adults are considered to have optimal metabolic health. In this study an even more stringent blood pressure criteria was used of <120/80, which is considered a “normal” blood pressure.

The risk factors listed above have discrete cutoffs, but of course our bodies behave on a continuum. It’s important to look at the big picture of what these numbers mean and their trends over time.

Development of Metabolic Syndrome

Now that we’ve defined metabolic syndrome, we’ll review how it develops. What causes the process of normal metabolism to become dysfunctional, and how does it progress?

Excess Carbohydrate Intake

In the simplest terms, the process starts with increased carbohydrate consumption. Increased carbohydrate consumption leads to increased sugar circulating in the bloodstream, and a storage hormone called insulin is released. Normally, insulin signals cells to take up the blood sugar and store it in muscles, fat cells, and the liver so that it can be used later when energy is needed.

Visceral Adiposity

When there is excess sugar circulating and the muscles are full, then the insulin directs the glucose to be stored in fat cells as fat. Over time, this can lead to increased body fat or obesity. In particular, increased fat cells in the abdomen around our organs (called visceral adiposity) is what contributes to increased abdominal circumference, one of the hallmarks of metabolic syndrome discussed above. This visceral fat contains fat tissue that is very metabolically active and releases more than 50 different molecules called adipocytokines. Secretion of these molecules leads to increased inflammation and also contributes to insulin resistance, which we’ll define shortly.

Insulin Resistance

It’s important to note that the level of sugar in our bloodstream is tightly regulated by insulin and other hormones, because very high or very low levels of sugar in the blood can be dangerous. So, if there is continued excess carbohydrate intake and elevated blood sugar, large amounts of insulin are required in order to keep storing blood sugar in the tissues. Eventually this can lead to a state of insulin resistance, which is where the cells don’t respond to the insulin as well. It takes more and more insulin to get the cells to receive the signal and take in sugar for storage. There are other factors that play a role in insulin resistance, too, and can make a person more or less susceptible to this state in the context of high carbohydrate intake. For example, a person’s genetics, sleep deprivation, inactivity, exposure to toxins, and stress can all contribute to increased blood sugar levels and/or insulin resistance.

Lipid Abnormalities 

Insulin resistance usually occurs first in the muscle, which then drives excess glucose to the liver. The liver then uses excess blood sugar for increased production of VLDL, (a type of lipid transport molecule), as well as elevated blood triglycerides and decreased blood HDL. This is why elevated triglycerides and low HDL are also hallmarks of metabolic syndrome. The fat cells then become insulin resistant too. Because they are not picking up the signal from insulin to store energy, they start behaving as if they are starving, and they start breaking down the stored fat. As a result, the fat cells release this stored fat into the bloodstream and deliver it to the liver, where the liver uses it to start making more glucose which further contributes to the problem.

Hyperinsulinemia

In the end, all key insulin-responsive tissues (liver, skeletal muscle, fat tissue) become insulin resistant and the body has to use higher and higher levels of insulin in order to break through the resistance and get the sugar out of the blood and stored in these tissues. This means there is a high circulating level of insulin in the bloodstream which is a state called hyperinsulinemia. Hyperinsulinemia leads to increased production of inflammatory markers further leading to a state of systemic inflammation that characterizes metabolic syndrome.

Elevated Blood Sugar

Insulin is normally produced in a part of the pancreas called the beta cells. Eventually the pancreas gets so tired out from having to make so much insulin that these cells start to die off. Less insulin is then produced and blood sugar can’t be stored in the tissues as efficiently, so the concentration of sugar in the blood rises. The end result is a metabolic catastrophe known as diabetes. This is why elevated blood sugar is another hallmark of metabolic syndrome.

Please note that a lot has happened up until this point before the blood sugar even becomes elevated, which is usually the way prediabetes or diabetes is initially detected. For example, decline in beta cell function has been noted to begin as early as 12 years before the diagnosis of diabetes. This process of metabolic dysfunction can be taking place for many years before it may be apparent on a test of blood sugar.

Elevated Blood Pressure

High circulating levels of glucose and insulin coupled with inflammation also contribute to elevated blood pressure. Insulin resistance can lead to hypertension through increased oxidative stress, increased production of chemicals that cause the blood vessels to constrict and reduction in levels of chemicals that cause the blood vessels to relax. Hyperinsulinemia also activates a hormonal system called the Renin-Angiotensin-Aldosterone System which leads to salt retention and increased blood pressure. This is why elevated blood pressure is another hallmark of metabolic syndrome.

Vascular Damage

The dysregulated glucose and lipid metabolism in addition to systemic inflammation also eventually leads to damage of the large and small arteries. In the large arteries, this leads to what is called macrovascular damage, or increased inflammation and development of plaques in the artery walls. As the plaques grow they can restrict blood flow or rupture and cause blockages in arteries in places such as the heart or brain, leading to heart attacks or strokes. The same thing can happen in the legs leading to peripheral artery disease.

In addition, exposure of the small arteries to high levels of blood sugar, oxidative stress, and other inflammatory compounds leads to decreased blood flow to the eyes (leading to blindness), to the kidneys (leading to kidney failure and eventually dialysis), and to the nerves (leading to impotence and diabetic foot disorders which include severe infections leading to amputation). These are known as microvascular complications of metabolic syndrome.

Gut Microbiome

The gut microbiome is also emerging as an important player in the development of systemic inflammation and metabolic dysfunction, which is also strongly affected by the food we eat, stress, sleep, and exercise.

Physiology of Insulin Signaling in Metabolic Syndrome

Assessing Metabolic Health

Now that we’ve covered what metabolic dysfunction is and how it progresses from a silent process to life-threatening disease, we’ll review how to assess metabolic health. Below, we’ll review how to assess each of the five hallmarks of metabolic syndrome, as well as systemic inflammation.

Body Composition

Because lean muscle tissue and fat tissue act very differently from a metabolic and hormonal perspective it is important to assess the presence of each. There are many different ways to estimate body composition and the presence of fat mass, and each has strengths and limitations. We’ll cover some of the most commonly used methods below:

• Body Mass Index (BMI): This a measurement of Weight (kg) / Height (m)^2. There are BMI calculators that can be used to easily perform this calculation if weight and height are known. The advantage of this measure is that extensive national reference data establishing the relationship between BMI, body fat, and risk of illness and early death exists. In adults, BMI levels above 25 are associated with an increased risk and are considered overweight. BMI levels above 30 indicate obesity and are associated with even higher risk. We do have to use caution with this measure though, because it does not distinguish between fat mass and muscle mass. This means that a well-muscled athlete may have a higher BMI but may not carry the same associated increased risk as someone with the same weight but more fat mass.
• Abdominal Circumference: Abdominal or waist circumference of 35 inches or more for women or 40 inches or more for men provides one of the criteria for the definition of metabolic syndrome. Remember that fat deposited in the abdomen seems to be more inflammatory and more closely associated with the development of metabolic disease than fat deposited elsewhere, called subcutaneous fat (typically fat in arms, legs, hips, etc). This measurement is taken as the circumference around the abdomen at the level of the top of the hip bones, or what is called the iliac crest.
• Waist to Hip Ratio: A ratio of the abdominal or waist circumference described above to the circumference at the hips is called the waist to hip ratio, which also provides an estimate of increased metabolic risk. Most men with a ratio greater than 1.0 and women with a ratio greater than 0.85 are at high risk for cardiovascular disease, diabetes, and cancers. Some argue that these abdominal measurements are better discriminators of cardiovascular risk factors than BMI. Again, this is probably due to the increased association of visceral or abdominal fat with metabolic disease than subcutaneous fat elsewhere in the body.

Table from IFM Cardiometabolic Advanced Practice Module. Source: Ford ES, et el 2002. 

• Skinfold Measurements: Skinfold measurements with calipers are commonly used, but are not ideal because they predominantly measure subcutaneous fat rather than the visceral abdominal fat which carries the strongest association with increased metabolic risk.
• Body Fat Percentage: All of the measurements discussed above have the advantage that they are easy to obtain: all you need is a measuring tape and maybe a scale. They are good crude ways to estimate total body and abdominal fat which is known to be associated with increased metabolic risk. But, in order to really assess total body fat there are more advanced imaging methods that can be used. The methods below are used to estimate the percentage of body weight composed of fat mass vs. lean mass (muscle and organs), and in some cases where that fat mass is distributed in the body (abdominal vs. subcutaneous). The 1999-2004 NHANES survey compared body fat percentage cutoffs to BMI cutoffs and identified body fat percentage cutoffs that were associated with increased metabolic risk. These differed by age, sex, and race so it’s difficult to generalize what body fat percentage is considered “normal” without knowing an individual’s background. On average for men, body fat percentages above 25% were associated with the same risk of a BMI of 25 or being overweight, and above 30% were associated with the same risk of a BMI of 30 or being obese. For women, body fat percentages above 38% were associated with the same risk as a BMI of 25 or being overweight, and body fat percentages over 42% were associated with the same risk of a BMI of 30 or obesity. The table below shows more specifics based on age, sex, and race:

Body fat percentage cutoffs in reference to BMI and cardiovascular risk

• Below are some of the ways body fat percentage can be measured:
  • Bioimpedance Analysis (BIA): BIA measures bioelectrical impedance and estimates total body water, fat-free mass, and fat mass by measuring the resistance of the body as a conductor to a very small alternating electrical current. These are the devices used by standing on a scale and/or holding on to handles such as an InBody machine. Overall, these measurements give a good approximation of fat-free mass (muscles and organs), and fat mass.
  • Body Density: There are two ways to measure body density using either water or air:
    • Hydrodensitometry is commonly called “underwater weighing” and is an accurate way of measuring body fat percentage.
    • Air Displacement Plethysmography uses air displacement to measure the body’s density. This method which is used by devices such as the BodPod, is preferred to underwater methods by most people, but does result in higher mean % body fat than underwater weighing.
  • Dual Energy X-ray Absorptiometry (DEXA): DEXA is the most popular method for quantifying fat, lean, and bone tissues. It uses two separate low energy x-rays to assess total body fat and soft tissue and bone mineral density. This is a relatively cheap and convenient way to assess body composition and is what has been used to collect data in the National Health and Nutrition Examination Survey (NHANES). DEXA has long been thought of as a gold- standard, but a recent study comparing DEXA, air densitometry, and BIA showed that all three methods were comparable, although air densitometry and BIA underestimated percent body fat compared to DEXA.

   

Blood Pressure

Although a blood pressure >130/85 or being on medication to treat high blood pressure was a criteria for metabolic syndrome, remember that blood pressure exists on a continuum, and increased cardiovascular risks have been identified at even lower blood pressures than 135/85. Below are the stages of hypertension:

Definitions of elevated blood pressure

The risk for cardiovascular disease increases as average blood pressure readings increase. Notably, a 20 point increase in systolic blood pressure (top number) and 10 point increase in diastolic blood pressure (bottom number) are each associated with a doubling in the risk of death from stroke, heart disease, or other vascular disease. In those over age 30, higher blood pressures are associated with increased risk for cardiovascular disease, heart attacks, heart failure, stroke, peripheral artery disease, and aneurysms. It is important to follow the correct protocol when measuring blood pressure in order to obtain accurate readings.

Glucose and Insulin

There are several ways to test for elevated levels of blood sugar. These methods are described next, and cutoffs of each that define prediabetes and diabetes by the American Diabetes Association and World Health Organization are included in the table below.

• • Fasting Blood Sugar: This is a blood test for the level of sugar or glucose in the blood after an 8-12 hour fast.
  • Hemoglobin A1c: Red blood cells live for about three months, and as they float around in the bloodstream, sugar sticks to them. We can measure the amount of sugar stuck to these cells through a measurement called the hemoglobin A1c. This gives us an  estimate of the average blood sugar over the last 3 months.
  • 2-hr Glucose Tolerance Test: After fasting, a patient drinks 75g of glucose and their blood sugar is checked one and two hours later. This gives an indication of how good the body is at storing the sugar that was just consumed.

Definitions of Prediabetes and Diabetes

As we discussed earlier, a hallmark of type 2 diabetes is a decline in beta cell function, which begins as early as 12 years before diagnosis and continues throughout the disease process. Insulin resistance and hyperinsulinemia can be occurring for many years before the blood sugars or hemoglobin A1c start to look abnormal. One way to assess for hyperinsulinemia is by using an oral glucose tolerance test in which both insulin and glucose are measured fasting, and at 1 and 2 hour intervals after drinking 75g of glucose.

Dyslipidemia

Elevated triglycerides > 150 mg/dL and low HDL <50 mg/dL for women and <40 mg/dL for men are also criteria for metabolic syndrome. These can be measured in a basic lipid panel, which is a blood test that also contains total cholesterol, and LDL.

The triglyceride/HDL ratio has also been proposed as a marker of insulin resistance. One study suggests a ratio of >2.75 in men and >1.65 in women to be highly predictive of metabolic syndrome (1, 2).

There are also more advanced lipid measurements which look at particle size and lipoproteins. In particular, apoB ≥ 130mg/dL and lp(a) > 50mg/dL are associated with increased cardiovascular risk and are considered cardiovascular disease risk enhancers.

Systemic Inflammation

Finally, we’ve talked about how metabolic syndrome is associated with chronic, low-grade systemic inflammation. Elevation in many different inflammatory markers has been observed, but as of yet very few are used clinically. High sensitivity CRP (hsCRP) is one marker that is used, and has been associated with increased risk for future cardiovascular illness and death independent of other cardiovascular risk factors. We also touched on this briefly in our Pursuing Health Pearls Episode 140 about cholesterol and statins, where hsCRP ≥ 2.0 mg/L was considered to be a cardiovascular risk enhancer.

Lifestyle Factors that Drive Metabolic Health

Reversing metabolic dysfunction is possible by implementing healthy lifestyle factors below:

• Focusing on a nutrient-rich, whole-foods diet, low in carbohydrates and especially refined carbohydrates and sugar
• Getting regular exercise, including bouts of high intensity exercise
• Reducing and learning how to manage the physical impacts of stress
• Getting enough good quality sleep

Weight loss is often a focus when it comes to metabolic syndrome, and a sustained weight loss greater than 10% has been shown to be enough to reverse glucose intolerance, high blood pressure, and several lipid abnormalities. However, we really don’t like to focus on weight, because we see weight as just another symptom of this metabolic dysfunction. Instead, we like to think about excess weight like high blood pressure or high cholesterol. Giving our bodies the ingredients necessary for optimal metabolic health listed above will often lead to weight loss as a result.

Wrapping it Up...

We’ve covered a lot of ground. We talked about the prevalence of metabolic dysfunction and how it is characterised by abnormal glucose and lipid metabolism and chronic systemic inflammation. We then talked about how metabolic dysfunction is diagnosed, and how it develops insidiously over many years.

There is no one test in order to assess metabolic dysfunction but looking at many different symptoms and biomarkers can identify early signs of metabolic dysfunction such as glucose and insulin regulation, body composition, blood pressure, lipids, and systemic inflammatory markers like hsCRP.

At the end of the day, the goal is to detect metabolic dysfunction early and then make adjustments to lifestyle factors (diet, exercise, sleep and stress) in order to reverse the process before it manifests as chronic diseases such as hypertension, dyslipidemia, and type 2 diabetes or life-altering complications such as kidney failure, blindness, and limb amputations or even death from stroke or heart attack.

Disclaimer: This podcast is for general information only, and does not provide medical advice. We recommend that you seek assistance from your personal physician for any health conditions or concerns.