In the quest to understand the causes and early symptoms of diabetes and other chronic diseases, metabolic inflammation often comes up. What is it, and what is its role in the early onset of these diseases? This article delves into the definition of the term, its presentation, and likely effects.

1. What is metabolic syndrome?

The occurrence of metabolic syndrome has been on the rise in both developed and developing countries. It can be described as a group of disorders including glucose intolerance, central obesity, hypertension and lipid malfunctions present in various forms, depending upon the combination of the different components of the syndrome. Metabolic syndrome has been generally accepted to increase the risk for the development of Type 2 diabetes, cardiovascular disease, stroke, and cancer.

2. What is Inflammation?

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. Immune signaling molecules called cytokines orchestrate inflammatory response when the harmful stimuli are detected. The inflammatory responses caused by both pathogens and wounding can cause damage to cells and tissue which in turn can induce further inflammatory responses.

The primary duty of inflammation is to isolate or rapidly destroy the underlying source of the disturbance, remove damaged tissue and then restore tissue homeostasis. Excessive inflammation can have adverse effects, resulting in collateral damage and disease.

3. Inflammation and metabolic syndrome

Metabolism can be described as the whole range of biochemical processes that occur within a living organism. Without a doubt, the relationship between inflammation and metabolism is complex. Several explanations have been proposed to explain the origin of the metabolic syndrome. Some consider an initial insulin-resistant state progressing to the other components, while others view obesity as the main initiator of the syndrome.

More recently, the chronic low-grade inflammatory condition that often accompanies the metabolic syndrome has been implicated as a major factor both at the beginning of the metabolic syndrome and its associated pathophysiological consequences.

The inflammatory state that accompanies the metabolic syndrome does not completely fit into the classical definition of acute or chronic inflammation as it is not accompanied by infection; there is no massive tissue injury and the dimension of the inflammatory activation is also not large. It is therefore often called ‘low grade’ chronic inflammation or ‘meta-inflammation’, meaning metabolically-triggered inflammation or even ‘para-inflammation’ an intermediate state between basal and inflammatory states. Whatever the term used, the inflammatory process that characterizes the metabolic syndrome has its own unique features but its causes are far from being fully understood.

4. Inflammation and its outcomes

Despite it being an essential response to infection and tissue injury, inflammation has also been associated with several pathological processes. Excessive acute inflammation causes tissue damage and non-resolving inflammation leads to chronic tissue malfunction, suggesting a delicate balance between the rapid and effective response to distresses in tissue homeostasis and the collateral damage on tissue function.

As a cluster, obesity, raised fasting plasma glucose, high cholesterol and hypertension comprise the metabolic syndrome. We will have an in-depth discussion on some of these conditions in relation to metabolic inflammation:

            4.1 Obesity

Obesity is characterized by a low-grade chronic state of inflammation in which the level of pro-inflammatory cytokines such as TNF-α, IL-6, and CRP are increased. It is a state in which there is an over-accumulation of subcutaneous and/or abdominal adipose tissue.

This adipose tissue is no longer considered inert and mainly devoted to storing energy; it is emerging as an active tissue in the regulation of physiological and pathological processes, including immunity and inflammation. Adipose tissue is also implicated in the development of chronic metabolic diseases such as type 2 diabetes mellitus or cardiovascular disease.

Obesity can, therefore, be caused by inflammatory and metabolic diseases. Diet or dietary patterns as well as play critical roles in obesity and other pathophysiological conditions. It is therefore recommended for one to have a healthy diet and other nutrients that are generally considered to be beneficial.

              4.2 Type 2 Diabetes Mellitus

Diabetes Type 2 is a disease of insulin resistance, where people produce too much insulin and their receptors don’t work. They become insulin resistant and the inflammation arises from excessive insulin.

It has been known for a while that there are higher levels of inflammation in the bodies of individuals with type 2 diabetes. The levels of certain inflammatory chemicals called cytokines are much higher in people with type 2 diabetes than in people who do not have diabetes.

The development of Type 2 diabetes is to a large extent driven by obesity and inactivity. Excess body fat, especially in the abdomen, leads to continuous (chronic), low levels of abnormal inflammation that alters insulin’s action and production. Chronic levels of free fatty acids and glucose as a result of insulin resistance induce further inflammation, which results in increased cell death and impaired insulin secretion. This, in turn, prompts the progression from obesity and insulin resistance to full-blown Type 2 Diabetes.

As type 2 diabetes starts to develop, the body becomes less sensitive to insulin and the resulting insulin resistance also leads to inflammation. A vicious cycle can result, with more inflammation causing more insulin resistance and vice versa. Blood sugar levels creep higher and higher, eventually resulting in hyperglycemia and other more serious effects of T2DM.

               4.3 Atherosclerosis

Heart disease is currently one of the major causes of morbidity and mortality facing humanity. Such a paradigm shift in disease patterns over the last century has been facilitated by the alarming global incidence of obesity and type 2 diabetes. Lately, there is an increasing focus on inflammation as one of the key factors in the pathophysiology of these disorders.

Early metabolic abnormalities that include weight gain, insulin resistance, and prehypertension and irregular blood lipid levels seem to have a complex relationship with diseases of the cardiovascular system.

Obesity increases the chances of diabetes, high blood pressure, pro-thrombotic state, and abnormal lipid presence. While inflammation and insulin resistance have direct antagonistic effects on the cardiac muscle, these metabolic irregularities as a whole lead to cardiovascular problems; warranting a multifaceted therapeutic and precautionary method of approach for the ‘Cardiovascular Metabolic Syndrome’ holistically.

              4.4  Non-alcoholic Fatty Liver Disease

Non-alcoholic Fatty Liver Disease is the predominant cause of liver disease. Its prevalence reaches 30% of the population and up to 75–100% in people with obesity. Different degrees of severity characterize this disease. A great majority of patients do not display any symptoms. However, nearly 20% eventually progress to develop chronic hepatic inflammation which can lead to early hypertension, cirrhosis, cancer of the liver, and increased mortality.

NAFLD is linked to overweight or obesity, Insulin resistance ( in which your cells don’t take up sugar in response to the hormone insulin), high blood sugar (hyperglycemia, indicating prediabetes or type 2 diabetes) and high levels of fats, particularly triglycerides, in the blood.

Although this is one of the most prevalent metabolic anomalies in humans, what triggers the inflammation has remained elusive.

5. What then can be done?

The appearance of chronic diseases such as type 2 diabetes, atherosclerosis, non- alcoholic liver diseases, and gout seems to be fairly recent. Taking into account the generally late onset of these diseases in the life of an affected individual, the causes and effects of the inflammation-induced metabolic disease need to be looked at in-depth considering increased life expectancy and the Western lifestyle.

Understanding inflammation as a critical component of metabolic syndrome can shed some light on what metabolic inflammation is and how it very likely plays a significant role in the onset of these chronic diseases. In turn, care can be taken to prevent or arrest metabolic inflammation before it causes serious harm.

References

1.   NCBI ( 2007): Cardiovascular metabolic syndrome – an interplay of, obesity, inflammation, diabetes, and coronary heart disease. Retrieved from. https://www.ncbi.nlm.nih.gov/pubmed/17391148

2.   Current Research in Nutrition and Food Science (2015): Inflammation and Metabolic Syndrome- An Overview. Retrieved from http://www.foodandnutritionjournal.org/volume3number3/inflammation-and-metabolic-syndrome-an-overview/

3.    NCBI (2011): Inflammation and the Metabolic Syndrome. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210244/

4.    NCBI (2013): Obesity, Inflammation, and Diet. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819692/

5.    WebMD: Diabetes and Inflammation. Retrieved from https://www.webmd.com/diabetes/type-2-diabetes-guide/inflammation-and-diabetes#1

6.   Wikipedia: Inflammation. Retrieved from https://en.wikipedia.org/wiki/Inflammation

We have been looking at metabolic inflammation and its role in the development of obesity, diabetes and other chronic diseases. Does overnutrition contribute to metabolic inflammation? How?

1. Some background on overnutrition….

It is estimated that by 2020, two-thirds of the global burden of the disease will be due to chronic non-communicable diseases, most of which are associated with diet. While hunger is a tremendous global health concern that cannot be minimized, overnutrition should similarly be given concentrated attention. Malnutrition affects up-to 1 billion people. Even though undernutrition is the main cause of malnutrition, people who are overweight could also be malnourished.

The “double burden of malnutrition” is a term coined by the World Health Organization (WHO) to describe a situation which is characterized by “the coexistence of undernutrition along with overweight and obesity, or diet-related non-communicable diseases, within individuals, households and populations, and across the life course. Globally, the problem is not the availability of food resources, but the allocation and consumption of food.

1. What is overnutrition?

Overnutrition is defined as the overconsumption of nutrients and food to the point at which health is adversely affected. Overnutrition can develop into obesity, which increases the risk of serious health conditions, including cardiovascular disease, hypertension, cancer, and type-2 diabetes.

Until recently, overnutrition had been viewed as a problem that only affected developed nations. However, this has been reviewed to affect most populations. The prevalence of obesity is increasing in developing countries with the introduction of fast food and refined sugars.

While once considered the disease of the rich, low-income groups in richer countries are also being affected by this condition.

2. What is overnutrition induced inflammation?

Inflammation is a biological response launched by the immune system against dangerous assaults that threaten the integrity and normal physiology of an organism. Chronic nutrient overload causes an increase in adipose irregularities in that, if adipose tissue expandability is low, there will be an increased presence of thickened tissue. This condition would lead to a pro-inflammatory state that can trigger insulin resistance, the release of macrophage chemoattractant proteins, and in chronic inflammation, even the death of the thickened adipose tissue itself. This creates cyclic an action that extends the insulin resistance to all adipose tissue.

An important characteristic of overnutrition-induced diseases is chronic low-grade inflammation caused by nutritional excess. Overnutrition-induced inflammation is thought to occur in the brain and thus plays an extensive and steering role in overnutrition-induced diseases.

3. Overnutrition and the metabolic syndrome

The metabolic syndrome is a constellation of metabolic risk factors including high cholesterol, elevated blood pressure, insulin resistance, and elevated serum glucose, a pro-inflammatory state, and a prothrombotic state.

Most persons with metabolic syndrome are obese and usually have abdominal obesity. Generally, obesity is a reflection of overnutrition. A current view is that when adipose tissue fails to store all excess nutrients as triglyceride, lipid begins to accumulate in various tissues (eg, muscle, liver, pancreas, and heart). The foundation of the metabolic syndrome thus appears to be overnutrition, that is, more nutrient intake than can be safely disposed of by lipid oxidation.

When obesity is present, adipose tissue becomes inflamed. This inflammation may result in a pro-inflammatory state, which could contribute to both ASCVD and diabetes.

4. What is carbohydrate overnutrition?

Most evidence supports the concept that fatty acids represent the final common pathway to tissue nutrient overload. Less attention has been given to the possible negative effects of excessive intake of carbohydrates.

Chronic overstimulation of insulin secretion induced by dietary carbohydrates could have the following adverse effects:

• The β-cell function may be impaired by chronic glucotoxicity
• Carbohydrate-induced hyperinsulinemia may suppress muscle insulin sensitivity.

Furthermore, high-carbohydrate intakes can prompt lipogenesis in the liver; fatty acids produced in this way can feed into the final common pathway of ectopic lipid accumulation. There is thus a need to look further into the role of carbohydrate overnutrition in the development of the metabolic syndrome.

5. What factors Contribute to Overnutrition?

Obesity in the United States has reached startling heights. The National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC) estimated that in 2015-2016, the prevalence of obesity in the United States was 39.8% in adults and 18.5% in youth.

While obvious factors including genetics, drugs, and other medical conditions may contribute to obesity, the behavior is perhaps the most common contributor. Healthy weight on an individual level is associated with a healthy diet and regular physical activity. Restaurants serve incredibly caloric meals, with some meals containing as much as 2,000 calories. The sedentary lifestyle practiced by most adds to the epidemic.

Unfortunately, this obesogenic culture has spread to other nations, including many developing countries. China, for example, now has more than 5,000 Kentucky Fried Chicken (KFC) restaurants in 1,100 cities. Similarly, McDonald’s expects to have 4,500 restaurants in China by 2022, up from 2,500 in 2017. A growing number of Chinese households also own television sets, personal vehicles, and other technologies that reduce physical activity and facilitate weight gain.

It is of note that economic inequality in developing nations is a primary cause of both overnutrition and undernutrition. Studies conducted in India show that income inequality had the same effect on the risk of being overweight as it did on the risk of being underweight; specifically, for each standard deviation increase in income inequality, the odds of being underweight increased by 19% and the odds of being obese increased by 21%.

While some people have the resources to purchase amounts of food beyond their daily caloric requirements, others cannot meet their recommended caloric intake. However, increasing numbers of poor people are becoming overweight in more nations, as these individuals consume affordably, yet highly caloric meals, such as fast food and processed foods.

6. What then should be done to avoid overnutrition?

An approach to understanding the effects of overnutrition on the metabolic profile is through overfeeding studies. These indicate that overnutrition produces a deterioration of metabolic status. Variability in individual response is, however, is expected. Such investigations are potentially useful for identifying those who are particularly susceptible to the development of metabolic risk factors.

The host of genetic factors likely acts at tissue levels to influence the response to nutrient excess. Different people may react differently to the accumulation of fat. However, overnutrition is generally considered to trigger metabolic disorders and predispose one to chronic conditions like Type 2 Diabetes. When choosing what to eat, one should be careful to ensure they choose balanced meals rich in fiber and nutrients and avoid the modern-day fast-food craze, as there cost of bad eating is too high.

References

1. Unite for Sight (2018): Module 4: Overnutrition. Retrieved from http://www.uniteforsight.org/hunger/module4
2. NCBI (2009): From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19171470
3. NCBI(2013): Neuroinflammation in Overnutrition-induced Diseases. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389772/
4. American Federation for Medical Research (2016): Overnutrition, ectopic lipid, and metabolic syndrome. Retrieved from https://jim.bmj.com/content/jim/64/6/1082.full.pdf 
5. NCBI (2009): From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19171470

Risk factors, the following factors increase your chances of developing insulin resistance metabolic inflammation:

Ethnicity may be a genetic factor or a lifestyle factor.

All of these diseases are increased when you develop Insulin Resistance & Metabolic Inflammation

Prevention: 

A healthy lifestyle prevents conditions that cause metabolic syndrome:

• Eat only when really hungry, don’t snack.
• Get at least 30 minutes of physical activity per day.
• Eat real food and avoid all processed foods.
• Avoid sugars and artificial sweeteners.
• Avoid industrial seed oils.
• Maintain a healthy weight and build muscle.
• Sleep well.
• Avoid screens.
• Have real friends.
• Don’t smoke.

Obesity is a disease that has plagued the modern-day man in recent times. Access to highly processed foods and a decrease in physical activity are key contributors to this ailment. Researchers are hard at work looking into what other underlying factors lead to obesity, especially given its relationship with the onset of Type 2 Diabetes, Cardiovascular diseases, and liver disease. We will take an in-depth look at metabolic inflammation and its role in the onset of obesity in this article. Let’s dive in.

1. What is obesity?

Obesity is characterized by a low-grade chronic state of inflammation in which the level of pro-inflammatory cytokines such as TNF-α, IL-6, and CRP are increased. It is a state in which there is an over-accumulation of subcutaneous and/or abdominal adipose tissue. This adipose tissue is no longer considered inert and mainly devoted to storing energy; it is emerging as an active tissue in the regulation of physiological and pathological processes, including immunity and inflammation.

Obesity is diagnosed when your body mass index (BMI) is 30 or higher. To determine your body mass index, divide your weight in pounds by your height in inches squared and multiply by 703. Or divide your weight in kilograms by your height in meters squared.

BMI	Weight status
Below 18.5	Underweight
18.5-24.9	Normal
25.0-29.9	Overweight
30.0 and higher	Obesity

For most people, BMI provides a reasonable estimate of body fat. However, BMI doesn’t directly measure body fat, so some people, such as muscular athletes, may have a BMI in the obesity category even though they don’t have excess body fat.

2. What is Diabesity?

‘Diabesity’ is the term for diabetes occurring in the context of obesity. This form of obesity-dependent diabetes has emerged as a major public health problem in recent times. Though it is basically explained by insulin resistance and pancreatic beta-cell dysfunction, new patterns have evolved to explain these modifications in the context of the modern spates of obesity and diabetes.

3. Is obesity an inflammatory condition?

The connection between obesity and inflammation has been often come up in debate in the recent past. Unbeknownst to many, the link between these conditions was made decades ago. Over a century ago, high doses of a class of anti-inflammatory compounds including aspirin called salicylates were used to treat Type 2 diabetes. In some cases, the symptoms of diabetes totally disappeared. Unfortunately, this treatment was discontinued due to the serious side effects caused by the high doses of salicylates.

We will now look at the questions of our topic today in-depth; Does obesity cause inflammation, or is inflammation caused by something secondary to obesity (like high blood sugar or triglycerides)? How about diabesity? Does diabesity cause inflammation, or does inflammation cause diabesity? How and why does the body initiate an inflammatory response to diabesity? Let us tackle each item separately.

4. How does Inflammation Cause Diabesity?

We look at some lines of evidence that show that inflammation directly causes obesity and diabesity.

• The development of diabesity has been shown to follow inflammation. Raised levels of inflammatory cytokines predict impending weight gain. In a study carried out, the infusion of inflammatory cytokines into healthy, normal-weight mice caused insulin resistance. This concept is also illustrated by the fact that people with other chronic inflammatory conditions are at higher risk of developing Type2 Diabetes, for example, about one-third of chronic Hepatitis C patients develop T2DM, and those with rheumatoid arthritis are also at higher risk.
• In obesity, inflammation has been noted to start in the fat cells themselves. As fat mass expands, inflammation increases. An explanation for this may be the dysfunction of the mitochondria (the “power plant” of our cells) caused by the increased stress obesity puts on cellular function. Another mechanism may be oxidative stress. As more glucose is delivered to the fat cells, they produce an excess of reactive oxygen species (ROS) which in turn starts an inflammatory cascade within the cell.
• Further, inflammation of the fat tissue causes insulin resistance, which is the primary feature of T2DM. TNF-α, a cytokine (small protein) released during the inflammatory response, has been repeatedly shown to cause insulin resistance. Several other proteins involved with inflammation, such as MCP-1 and C-Reactive protein, have also been shown to cause insulin resistance.
• Also, inflammation of the brain (specifically the hypothalamus) causes leptin resistance, which often precedes and accompanies insulin resistance and T2DM. Leptin is a hormone that regulates appetite and metabolism. It does this through its effect on the hypothalamus. When the hypothalamus becomes resistant to leptin, glucose and fat metabolism are impaired and weight gain and insulin resistance result.
• When there is inflammation of the gut, there arises leptin and insulin resistance. This may occur via an increase in lipopolysaccharide (LPS), an endotoxin produced by Gram-negative bacteria in the gut. LPS has been shown to cause inflammation, insulin resistance in the liver and weight gain.

5. How does Diabesity Cause Inflammation?

In the past, fat was considered an inactive tissue with no biological action. It wasn’t considered for much other than storing energy. It has now emerged that fat tissue is a metabolically active endocrine organ that secretes hormones and inflammatory cytokines such as IL-6 and TNF-α. This metabolic activity of fat is the key to understanding its role in diabesity.

6. Why would obesity cause inflammation?

The first theory is that obesity-induced inflammation a protective mechanism that prevents the body from losing mobility or fitness. Fat storage is an anabolic process, which means it builds up the organs and tissues. Inflammation, on the other hand, is a catabolic process. Catabolism breaks down organs and tissues. It’s possible that the activation of catabolism via inflammation is the body’s attempt to keep weight within acceptable bounds. Evidence that experimentally induced local inflammation in fat tissue improves insulin resistance and causes weight loss supports this theory.

The second theory is that obesity-induced inflammation is simply a malfunction that was never selected against human evolution. Obesity and its related disorders have been extremely rare throughout human history, and have only become common in the past 40 years. The surplus of modern, processed foods that accompanies diabesity is also a relatively new phenomenon. It’s possible that the stresses of obesity are similar enough to the stresses of an infection that the body reacts to obesity in the same way it would to an infection: via inflammation. Supporting this theory is evidence that the same intracellular, inflammatory stress pathways are activated in both obesity and infection.

7. Tackling Inflammation in the control of diabesity

We can, therefore, conclude that inflammation is both the cause and the result of diabesity. Once obesity and/or insulin resistance have been established, each can further stimulate the production of inflammatory cytokines, forming a vicious cycle of inflammation and diabesity.
Reduction of inflammation is a major key in preventing and treating diabesity. Focusing exclusively on regulating blood sugar and fat hormones without addressing other potential causes of inflammation is bound to produce inferior results.

References

1.    NCBI (2003): Diabesity: an inflammatory metabolic condition. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14598860

2.    NCBI (2013): Obesity, Inflammation, and Diet. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819692/

3.    NCBI(2006): Inflammation and insulin resistance. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483173/

4.    Chris Kessler (2019): How Inflammation Makes You Fat and Diabetic (And Vice Versa). Retrieved from https://chriskresser.com/how-inflammation-makes-you-fat-and-diabetic-and-vice-versa/

In previous articles, I have discussed the role of metabolic Inflammation in obesity and diabetes. Today, we will narrow down to the specifics of what insulin resistance is, its effects and how metabolic inflammation increases the chances of one developing it.

1. What is Insulin resistance?

Approximately 30% of Americans, and up to 50% in the 60 years and over the bracket, have a silent blood sugar problem known as insulin resistance. Insulin resistance increases the risk for prediabetes, Type 2 diabetes and a host of other serious health problems, including heart attacks, strokes, and cancer.

What therefore is Insulin Resistance? It is when cells in your muscles, body fat and liver start repelling or ignoring the signal being sent out by the hormone, insulin—which is to take glucose from the bloodstream into our cells for breakdown or storage. Glucose, commonly called blood sugar, is the body’s main source of fuel.

1. How does Insulin Resistance Develop?

Some factors that determine insulin resistance are aging and ethnicity but the driving forces seem to be excess body weight, too much belly fat, a lack of exercise, smoking, and even sleep depravity.

With time, and as the insulin resistance develops, more insulin is produced by your body as it tries to fight back. After an accumulated period of time, several years even, the beta cells in your pancreas get worn out because of all the extra work and can no longer keep pace with the increased demand for insulin. Then – years after insulin resistance stealthily started – your blood sugar may spike and you may manifest prediabetes or type 2 diabetes. You are also at risk of developing the non-alcoholic fatty liver disease (NAFLD), a condition that increases your risk for liver damage and heart disease.

2. What are the Signs and Symptoms of Insulin Resistance?

Insulin resistance does not always manifest to the naked eye but here are some signs to look out for:

• A large waist. Experts say the best way to tell whether you’re at risk for insulin resistance involves a tape measure and moment of truth in front of the bathroom mirror. A waist that measures 35 inches or more for women, 40 or more for men (31.5 inches for women and 35.5 inches for men if you’re of Southeast Asian, Chinese or Japanese descent)6 increases the odds of insulin resistance and metabolic syndrome, which is also linked to insulin resistance.
• You have additional signs of metabolic syndrome. According to the National Institutes of Health, in addition to a large waist, if you have three or more of the following, you likely have metabolic syndrome, which creates insulin resistance.
• High triglycerides. Levels of 150 or higher or taking medication to treat high levels of these blood fats.
• Low HDLs. Low-density lipoprotein levels below 50 for women and 40 for men – or taking medication to raise low high-density lipoprotein (HDL) levels.
• High blood pressure. Readings of 130/85 mmHg or higher, or taking medication to control high blood pressure
• High blood sugar. Levels of 100-125 mg/dl (the prediabetes range) or over 125 (diabetes).
• High fasting blood sugar (or you’re on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.
• You develop dark skin patches. If insulin resistance is severe, you may have visible skin changes. These include patches of darkened skin on the back of your neck or on your elbows, knees, knuckles or armpits. This discoloration is called acanthosis nigricans.8

3. Chronic low-grade inflammation and the development of insulin resistance

As early as the 1950’s, there was epidemiological evidence suggesting a correlation between inflammation and insulin-resistant states such as obesity, but the mechanistic links were unknown. In the last decade, however, it has become increasingly evident that obesity and the concomitant development of inflammation are major components of insulin resistance. Studies in human obesity and insulin resistance have revealed a clear association between the chronic activation of pro-inflammatory signaling pathways and decreased insulin sensitivity. For example, elevated levels of tumor necrosis factor-α (TNF), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin-resistant states. In addition, the inflammatory marker C-reactive protein (CRP), a non-specific acute phase reactant, is commonly elevated in human insulin-resistant states. Also, experiments in naturally occurring rodent models of obesity, knockout and transgenic mice, as well as detailed studies of insulin signaling at the molecular level have begun to elucidate the mechanistic links between obesity-induced inflammation and insulin-resistant states.

4. What Health Conditions are Related to Insulin Resistance?

An estimated 87 million American adults have prediabetes; 30-50% will go on to develop full-blown type 2 diabetes. In addition, up to 80% of people with type 2 diabetes have NAFLD. But those aren’t the only threats posed by insulin resistance.

Thanks to years of high insulin levels followed by an onslaught of cell-damaging high blood sugar, people with insulin resistance, prediabetes, and type 2 diabetes are at high risk for cardiovascular disease. Insulin resistance doubles your risk for heart attack and stroke – and triples the odds that your heart attack or ‘brain attack’ will be deadly, according to the International Diabetes Federation.

Meanwhile, insulin resistance and metabolic syndrome are also linked with higher risk for cancers of the bladder, breast, colon, cervix, pancreas, prostate and uterus.11, 12  The connection: High insulin levels early in insulin resistance seem to fuel the growth of tumors and to suppress the body’s ability to protect itself by killing off malignant cells. 13

Research has also found a strong association between insulin resistance and memory function decline, increasing the risk of Alzheimer’s disease.

5. Can understand the causes of Insulin Resistance aid in future preventive approaches?

As obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, obesity is a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by over-nutrition which leads to lipid accumulation in adipocytes.

Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuations of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance.

References

1. NCBI (2007): Inflammation and Insulin Resistance. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246086/
2. Scientific American(2009): Does Inflammation Trigger Insulin Resistance and Diabetes? Retrieved from https://www.scientificamerican.com/article/inflammatory-clues/

3. NCBI (2006): Inflammation and Insulin Resistance. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483173/
4. org (2008): Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species. Retrieved from https://www.physiology.org/doi/full/10.1152/ajpregu.00561.2007
5. Hindawi (2015): Mechanisms Linking Inflammation to Insulin Resistance. Retrieved from https://www.hindawi.com/journals/ije/2015/508409/

6. Endocrineweb(2019): Insulin Resistance Causes and Symptoms. Retrieved from https://www.endocrineweb.com/conditions/type-2-diabetes/insulin-resistance-causes-symptoms

A growing body of data shows that type 2 diabetes is at least in part rooted in inflammation. The higher a person’s body mass index, the more pro-inflammatory macrophages they have in their adipose tissue, and the higher their chances of developing T2D. In this article, we will highlight the emerging role of inflammation in the pathophysiology of diabetes. We will also analyze the implicated inflammatory pathways and biomarkers of inflammation in diabetes and metabolic diseases.

1. The metabolic syndrome and metabolic Inflammation

Metabolic syndrome often precedes type 2 diabetes and cardiovascular disease. It is characterized by high blood pressure, a large waist circumference, elevated fasting glucose and triglycerides, and low HDL cholesterol.

Metabolic inflammation is currently a hot research topic, wherein peculiarities in metabolic and inflammatory pathways are looked into for their possible contribution to atherosclerosis, Type 2 diabetes and insulin resistance (IR). In MI, insulin signaling is impeded by inflammation caused by obesity. Metabolically activated macrophages are key cells in the process. They are believed to spike both pro- and anti-inflammatory pathways in reaction to lipid spillover from adipocytes.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. The main clinical diagnostic features are impaired glucose tolerance and hyperglycemia. These occur as the result of an absolute or relative insulin deficiency or resistance to its action. Chronic hyperglycemia associated with diabetes can result in end-organ dysfunction and failure which can involve the retina, kidneys, nerves, heart and blood vessels. There is a  clinical relationship between diabetes and atherosclerotic cardiovascular disease, with the risk for cardiovascular disease (CVD) being significantly elevated in patients with diabetes.

Typically, CVD occurs one to two decades earlier in people with diabetes, with the more aggressive, severe and diffuse distribution. The first WHO Global report on diabetes published in 2016 demonstrates that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults and this is expected to rise to 552 million by 2030. There is, therefore, a need for effective novel therapeutic approaches for the treatment and/or prevention of diabetes and atherosclerotic disease.

Various proposals and hypotheses have been developed to describe the mechanisms involved in the propagation of diabetes, mainly focusing on T2D. The increase in the prevalence of the condition has been related to well-recognized risk factors, such as the adoption of a western lifestyle, sedentary lives, lack of physical activity and an energy-dense diet.

Genetic predisposition, ethnicity, and aging are not modifiable risk factors for T2D. Other factors such as being overweight or obese, an unhealthy diet, insufficient physical activity and smoking are modifiable through behavioral and environmental changes. However, increasing evidence has shown that inflammatory pathways are common in both modifiable and non-modifiable factors.

2. When was inflammation first thought to cause diabetes?

Observational studies provided the first evidence for the possible association between inflammation and diabetes. Over a century ago, the administration of high doses of sodium salicylate led to decreased glycosuria in people with a suspected or definite diagnosis of diabetes.  Later studies on the role of inflammation in diabetes revealed that this hypoglycaemic action was related to the inhibition of the serine kinase IkappaB kinase-beta (IKKbeta), which correlates with the post-receptor action of insulin.

A landmark study to correlate inflammation with diabetes was conducted in animal models by Hotamisiligil et al., in 1993 and it revealed that the role of tumor necrosis factor-alpha (TNF-alpha) in obesity and particularly in insulin resistance and diabetes. Epidemiologic associations of inflammation with obesity and T2D were made when circulating concentrations of markers and mediators of inflammation and acute-phase reactants including fibrinogen, C-reactive protein, interleukin (IL)-6, plasminogen activator inhibitor-1, sialic acid, and white cells, have been shown to be elevated in these conditions.

Over the next decades, numerous studies on human and animal models provided further supporting evidence for the role of inflammation in the initiation and progression of diabetes. Accumulative evidence suggests that chronic activation of pro-inflammatory pathways in target cells of insulin action may contribute to obesity, insulin resistance and related metabolic disorders including T2D. The identification of potential pathways connecting inflammation to diabetes has produced growing interest in targeting inflammation to help prevent and control diabetes and related conditions, as well as improving risk stratification for diabetes by using inflammatory biomarkers as potential indexes.

3. What is the relationship between Metabolic Disorders and Inflammation in Type 2 Diabetes?

In several pathophysiological studies carried out, our understanding of insulin resistance and secretion in the course of disease onset and progression has been expanded. Subjects at risk of T2D display an initial state of insulin resistance compensated by hypersecretion of insulin in the beta cells. In the clinical course of the disease this pancreatic functional reserve is eventually unable to cope with the required insulin secretion and by the time diabetes is diagnosed, beta cells are no longer able to secrete enough insulin.

Although the relative contribution of beta-cell dysfunction and insulin resistance can vary in people with T2D, it is generally accepted that abnormal insulin sensitivity precedes the clinical diagnosis of diabetes by up to 15 years. Therefore, along with mechanistic studies investigating mechanisms forming the basis of insulin resistance, more recent research has also focused on the pathways leading to beta-cell failure.

4. Is there evidence of Inflammation in Other Organs in People with Type 2 Diabetes?

There is inconclusive evidence that the inflammatory state in T2D can spread to other organs such as the liver, the neural system and possibly skeletal muscle. More research is needed to support this evidence.

5. What are the Future Perspectives for the Treatment of Diabetes?

Below are some of the approaches currently being investigated.

1. Innovative approaches on T2D to gauge anti-inflammatory diets and moderate an individual’s microbiome are under study.
2. Clinical trials examining the effects of vitamin D supplementation on serum levels of inflammatory markers have provided inconsistent results, with no evidence of effects in most trials, or effects on selected markers in others.
3. There are also studies investigating whether antagonists of leukotriene production enzymes – 5-lipoxygenase (5-LO), 5-LO-activating protein and LTA4 hydrolase – or receptor binding BLT1 have cardiometabolic outcome benefits, however, these results have not yet been reported.
4. The potential for targeting cholinergic pathways, immune modulation or other mediators of inflammation such as JNK and toll-like receptors (TLRs) are also being researched.
    

6. What is the future of understanding metabolic inflammation as a cause of diabetes?

Given the increasing prevalence of diabetes, it is crucial that research focuses on its prevention as well as its treatment. Heart disease, metabolic syndrome and type 2 diabetes (T2D) all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral action.

An improved understanding of the mechanisms linking inflammation to diabetes and related complications has stimulated interest in targeting inflammatory pathways as part of the strategy to prevent or control diabetes and its complications.

T1D is considered to be more of an immunological response rather than a metabolic disorder and the preliminary results of trials using anti-inflammatory and immunomodulatory medication are promising. These treatments in combination with the possible use of stem cells to regenerate pancreatic beta cells could potentially be the key to the permanent treatment of T1D. Therefore, after a holistic review of the possible mechanisms that lead to T1D and T2D and the numerous already described inflammation pathways that are involved, it becomes more and more clear that future research should focus on simultaneous suppression of various inflammatory response pathways rather than focusing on one pathway at a time.

References

1. NCBI (2017): Nutritional modulation of metabolic inflammation. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28710289

2. EM-Consulte (2012): Inflammation and type 2 diabetes. Retrieved from https://www.em-consulte.com/en/article/735580

3. ECR (2019): The Role Of Inflammation In Diabetes: Current Concepts And Future Perspectives. Retrieved from https://www.ecrjournal.com/articles/role-inflammation-diabetes-concepts-future

The modern diet contains a large number of simple sugars. From bread to donuts, to carbonated drinks to chocolate, cookies, and candy, everywhere you look, temptation abounds. The potential impact on the health of diets rich in free sugars, and particularly fructose, is of major concern. Does the sugar we take have an impact on insulin resistance and obesity? In this article, we look at this risk and the effects of insulin resistance.

1. Sugar and Insulin resistance….

Sugar has a bittersweet reputation when it comes to health. It occurs naturally in all foods that contain carbohydrates, such as fruits and vegetables, grains, and dairy. Consuming whole foods that contain natural sugar is safe. Plant foods also have high amounts of fiber, essential minerals, and antioxidants, and dairy foods contain protein and calcium.

Where does the problem with sugar come about? Added sugar, which is usually extracted or synthesized ……

There is plenty of evidence to suggest that consuming too much sugar can have a negative effect on our metabolic health. Regular sugar consumption produces a constant release of the hormone insulin. Over a period of time, it can lead to serious problems, such as the synthesis of triglycerides, insulin resistance, fatty liver disease, type II diabetes, an increase in very-low-density lipoprotein (the bad kind of cholesterol), and the accumulation of fat on all tissues.

Added sugar intake may contribute to and certainly does exacerbate insulin resistance. For example, added sugar intake is associated with higher blood pressure, inflammation, weight gain, fatty liver disease, health issues that can lead to insulin resistance, and further exacerbation of these issues. Added sugars cater to particularly energy-hungry but metabolically inefficient cells, including senescent cells, cancerous cells, and even quickly proliferating pathogenic bacteria in the gut.

Several genetic and lifestyle factors can contribute to how likely you are to develop insulin resistance. But even if you have a genetic risk, you can help yourself with regular exercise, a balanced diet, avoidance of added dietary sugars, healthy sleep patterns, and stress reduction activities.

Risk factors for insulin resistance and prediabetes include:

• Obesity
• Aging
• physical inactivity
• high cholesterol
• blood pressure
• sleep disorders or circadian rhythm disruption

It is said that one in three Americans—including half of those age 60 and older— have insulin resistance.

2. What exactly is Insulin Resistance?

Insulin resistance is when cells in your muscles, body fat, and liver start resisting or ignoring the signal that the hormone insulin is trying to send out—which is to grab glucose out of the bloodstream and put it into our cells. Glucose, also known as blood sugar, is the body’s main source of fuel. We get glucose from grains, fruit, vegetables, dairy products, and drinks that bring break down into carbohydrates.

3. How does Insulin Resistance develop?

While genetics, aging, and ethnicity play roles in developing insulin sensitivity, the driving forces behind insulin resistance include excess body weight, too much belly fat, a lack of exercise, smoking, and even not getting enough sleep.

As insulin resistance develops, your body fights back by producing more insulin. Over months and years, the beta cells in your pancreas have been working so hard to make insulin get worn out and can no longer keep pace with the demand for more and more insulin. Then – years after insulin resistance silently began – your blood sugar may begin to rise, and you may develop prediabetes or type 2 diabetes. You may also develop non-alcoholic fatty liver disease (NAFLD), a growing problem associated with insulin resistance that boosts your risk for liver damage and heart disease.

4. What are the Signs and Symptoms of Insulin Resistance?

Insulin resistance can be triggered by a combination of factors linked to weight, age, genetics, being sedentary, and smoking.

– Polycystic ovary syndrome (PCOS): Insulin resistance can worsen the symptoms of PCOS, which can include irregular menstrual cycles, infertility, and periods that cause pain.

– A large waist. Experts say the best way to tell whether you’re at risk for insulin resistance involves a tape measure and a moment of truth in front of the bathroom mirror. A waist that measures 35 inches or more for women and 40 or more for men (31.5 inches for women and 35.5 inches for men if you’re of Southeast Asian, Chinese, or Japanese descent) increases the odds of insulin resistance and metabolic syndrome, which is also linked to insulin resistance.

– You have additional signs of metabolic syndrome. According to the National Institutes of Health, in addition to a large waist, if you have three or more of the following, you likely have metabolic syndrome, which creates insulin resistance.

• High triglycerides. Levels of 150 or higher, or taking medication to treat high levels of these blood fats.
• Low HDLs. Low-density lipoprotein levels below 50 for women and 40 for men – or taking medication to raise low high-density lipoprotein (HDL) levels.
• High blood pressure. Readings of 130/85 mmHg or higher or taking medication to control high blood pressure
• High blood sugar. Levels of 100-125 mg/dl (the prediabetes range) or over 125 (diabetes).
• High fasting blood sugar (or you’re on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.

– Acanthosis nigricans: This skin condition can develop in people with insulin resistance. It involves dark patches forming on the groin, armpits, and the back of the neck.

5. What health conditions are related to Insulin Resistance?

The most common health condition related to Insulin Resistance is prediabetes and the resultant Type 2 Diabetes. Insulin resistance also doubles your risk for heart attack and stroke – and triples the odds that your heart attack or ‘brain attack’ will be deadly.
Insulin resistance and metabolic syndrome are also linked with a higher risk for cancers of the bladder, breast, colon, cervix, pancreas, prostate, and uterus. This is because the high insulin levels early in insulin resistance seem to fuel the growth of tumors and suppress the body’s ability to protect itself by killing off malignant cells.

Furthermore, research has found a strong association between insulin resistance and memory function decline, increasing the risk of Alzheimer’s disease.

6. Can you prevent or reverse insulin resistance?

The good news is that, yes, insulin resistance can be prevented and also reversed in some cases. Here is what you can do:

• Get recommended amounts of physical activity and structured exercise
• Get adequate sleep
• eat when the sun is up(we are more insulin resistant at night and after a night of poor sleep, due to disrupted circadian rhythms that help regulate our metabolic state)
• Reducing stress and, therefore stress-related inflammation
• Maintaining a healthy weight
• Increasing your plant fiber intake.

All of the above can help improve your insulin sensitivity. It has been shown that combining both diet and exercise have the most impact on insulin sensitivity.

In a fascinating University of New Mexico School of Medicine, study published in the International Journal of Obesity, overweight people who lost 10% of their weight through diet plus exercise saw insulin sensitivity improve by an impressive 80%. Those who lost the same amount of weight through diet alone got a 38% increase. And those who simply got more exercise, but didn’t lose much weight, saw almost no shift in their level of insulin resistance.

Intermittent fasting is also another way in which you can reverse your insulin resistance. This is because it gives your body a break from insulin and glucose signaling pathways that promote cell proliferation and inflammation and may help increase insulin sensitivity.

7. What, therefore, is the relationship between sugar and Insulin Resistance?

There is an association between diets high in sugars (predominantly sucrose) and the risk of disease, and experimental studies have shown that high intakes of fructose (over 100 g/d) can reduce insulin sensitivity. However, somewhat lower intakes may affect serum TG. The mechanisms for such associations or effects have not been convincingly demonstrated.

References:

1. NCBI (2016): A review of recent evidence relating to sugars, insulin resistance, and diabetes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5174139/

2. Endocrineweb (2019): Insulin resistance causes and symptoms. Retrieved from https://www.endocrineweb.com/conditions/type-2-diabetes/insulin-resistance-causes-symptoms

3. Medical News Today (2019): What to know about insulin resistance. Retrieved from https://www.medicalnewstoday.com/articles/305567.php

4. The Sugar Movement (2016): Sugar vs Fat. Retrieved from https://thatsugarmovement.com/sugar-vs-fat/

5. Harvard Health Publishing (2017): The sweet danger of sugar. Retrieved from https://www.health.harvard.edu/heart-health/the-sweet-danger-of-sugar

6. NCBI (2014): Weight Loss, Exercise, or Both and Cardiometabolic Risk Factors in Obese Older Adults: Results of a Randomized Controlled Trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835728/

If Hippocrates the father of modern medicine is to be believed, “All disease begins in the gut”. The gastrointestinal tract with its microbiota is a complex, open, and integrated ecosystem. It is widely accepted that healthy gut microbiota is essential for optimal health. Imbalance in the gut flora could lead to one being vulnerable to a large spectrum of infectious and non-communicable diseases, including diabetes and obesity. There is an urgent need to develop efficient strategies to prevent and treat metabolic disorders such as diabetes and obesity. In this article, we will look at the implications of gut microbiota in diabesity and review ways of achieving optimal metabolic conditions.

1. What is Gut Microbiota and Gut Microbiome?

The gut microbiota is a collective term for the microbial community in the gut, whereas the gut microbiome is defined as the full collection of genes in the gut microbiota. The intestinal microbiota is known to be associated with metabolic syndrome and related comorbidities. Associated diseases including obesity, T2D, and fatty liver disease (NAFLD/NASH) all seem to be linked to altered microbial composition; however, causality has not been proven yet. This points to the potential causal and personalized role of the human gut microbiota in obesity and T2D is highly prioritized.

The gut microbiome contains an immense diversity of microorganisms, varying from bacteria as well as viruses, fungi, phages, protozoa, and archaea all colonizing our adult bodies. There is a proposed view that our microbiota is a microbial (endocrine) organ living symbiotically inside our gut. This has led to a new perspective suggesting multiple lineages capable of communicating with each other and shaping host immune-metabolism in several ways. Some of the capabilities of these “organ” are:

• The degradation of otherwise indigestible components of our diet
• harvesting of energy and nutrients
• shaping of the host immune system
• maintaining the integrity of the gut mucosal barrier
• xenobiotic metabolism

In this way, gut microbiota complement our biology in ways that are mutually beneficial.

The current research data regarding the precision/personalized nutrition suggest that dietary interventions, including administration of pre-, pro-, and syn-biotics, as well as antibiotic treatment should be individually tailored to prevent chronic diseases based on the genetic background, food and beverage consumption, nutrient intake, microbiome, metabolome, and other omic profiles.

2. The gut and diet….

Diet is essential in the composition and the function of the gut microbiota. Microbiota alters rapidly when exposed to great and fast changes in diet. Short-term dietary changes such as switching between plant- and meat-based diets, or adding more than 30 grams of fiber per day to the diet, or following a diet with different fat/fiber content can change the human gut microbiota in function and composition significantly in 48 hours.

Fiber-enriched diets have been shown to improve insulin resistance in lean and in obese subjects with diabetes. However, only long-term dietary habits are effective in shaping the composition of the gut microbiota as short-term dietary interventions failed to change the major features and classification of the microbiota.

3. What is the impact of Gut Microbiome in Insulin Resistance and Type 2 Diabetes?

When there is low diversity in the gut microbiome, there is a higher prevalence of obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and low-grade inflammation. Furthermore, low bacterial diversity was characterized by pro-inflammatory properties, suggested by the reduction in butyrate-producing bacteria and the increase in mucin-degrading bacteria. These characteristics potentially impair the gut integrity causing low-grade inflammation through endotoxemia. This low-grade inflammation of visceral adipose tissue may provide a link between obesity and insulin resistance.

Ethnic differences between human populations may also affect microbiota composition. Karlsson et al. compared data of T2D-associated metagenomes between Chinese and Swedish subjects with T2D, which indicated that different intestinal bacterial species were involved in similar metabolic functions. The authors were also able to distinguish subjects with T2D from healthy subjects, with a predictive power exceeding that of body mass index (BMI).

4. What is the effect of Gut Microbiota in Lipid Metabolism?

In recent decades, it has become clear that many metabolic, inflammatory, and innate immune mechanisms are also coordinated by (dietary-derived) lipids. The nutritional importance of dietary lipids is unequivocal.

Lipid accumulation in conjunction with low-grade inflammation is a pathophysiological hallmark of atherosclerosis. There is emerging evidence that the pathophysiology of atherosclerosis is related to interpersonal gut microbiome differences. Atherosclerosis seems to be related to TMAO, which is a new marker associated with increased risk of atherosclerosis and coronary artery disease.

Other key intestinal regulators of lipid and cholesterol metabolism are bile acids, which are involved in facilitating intestinal absorption and transport of diet-derived nutrients, vitamins, and lipids. Whereas bile production takes place in the liver (and is facilitated by products derived from lipid catabolism), 95% of all bile acids will be reabsorbed in the terminal ileum and subsequently re-absorbed by the liver, constituting the so-called enterohepatic circulation.

The intestinal microbiota is responsible for converting primary bile salt to secondary bile salts via bile acid de-hydroxylation. Although short courses of oral antibiotics affect intestinal microbiota composition and bile acid metabolism in humans, we found differential effects on glucose metabolism.

5. What effect does the Gut Microbiome have on Appetite?

Obesity is defined as an imbalance between energy intake (usually food intake) and energy expenditure. The brain is a key regulator in detecting alterations in energy balance and induces behavioral and metabolic responses to correct these alterations. The hypothalamus plays an important role in regulation of both food intake as well as energy homeostasis, receiving hormonal and (vagal) neuronal information from the periphery.

Changing the gut microbiome composition with prebiotics has also been shown to affect portal vein levels of other hormones including GLP-1, which in turn affected food intake, followed by a decrease in body weight and fat mass.

6. What are the Microbial Signatures in T2DM and Obesity?

Dysbiosis, which is the disruption of normal microbiota, has been described to be involved in a large spectrum of diseases, including diabetes, obesity, and insulin resistance, through disturbing the energy balance. It has therefore been suggested that the modulation of microbiota, either directly (by antimicrobials, diet, prebiotics and/or probiotics, stool transplant, microbial-derived signaling molecules or metabolites) or indirectly (e.g., immunotherapy) may contribute to the therapeutic management of these pathologies.

7. What is the Influence of Diet on Gut Microbiota in Diabetes and Obesity?

Diet is one of the major lifestyle factors involved in the genesis, prevention and control of diabetes, obesity and other cardiometabolic diseases, being also strongly linked to changes in microbiota. Many reports have shown that the genetic susceptibility to obesity may have interacted with an obesogenic environment (e.g., a major shift in dietary patterns influencing the gut microbiota, a sedentary lifestyle and physical inactivity) in determining the obesity epidemic. To date, there are many popular diets including Mediterranean, gluten-free, vegan, Western, omnivore, vegetarian. To date, most of these diets have been clearly linked to different microbiome profiles.

Following the industrial revolution, countries in the West underwent a nutritional transition from the traditional diet to a diet rich in heavily processed foods, fats, sugars, proteins, plus different additives, while remaining low in micronutrients and dietary fibers (also referred to as Western diet). These diets were deficient of dietary fibers, which are essential for gut health due to their role in stimulation of the growth and/or activity of certain beneficial microorganisms.

Conversely, people in traditional societies, with a fiber intake of almost 50–120 g/day harbor a much more diverse gut microbiota, which indicates good health. SCFAs are found in lower amounts in individuals consuming a Western diet. Western diet was correlated with a decrease in the total bacterial load and in beneficial commensals. On the other hand, subjects consuming vegan and vegetarian diets which are rich in fermentable plant-based foods were reported to have a microbiota characterized by a lower abundance of Bacteroides sp. and Bifidobacterium sp.

The Mediterranean diet (vegetables, moderate consumption of poultry, olive oil, cereals, legumes, winenuts, fish and a low amount of red meat, dairy products, and refined sugars) provides beneficial effects through the elevated content in mono-unsaturated and poly-unsaturated fatty acids, as well as high levels of antioxidants, fibers and vegetable protein content. The gut microbiota in individuals receiving Mediterranean diet is characterized by a high colonization by Lactobacillus sp., Bifidobacterium sp., and Prevotella sp., and low levels of Clostridium sp, species which are associated with weight loss, improvement of the lipid profile and decreased inflammation.

Dietary proteins have also been reported to be involved in shaping the microbiota. Individuals consuming a diet rich in beef had high levels of Bacteroides sp. and Clostridia and were low in Bifidobacterium adolescentis unlike individuals eating a meatless diet. Several studies have recently shown that diets including vegetarian whey/pea protein, and animal protein (meats, eggs, and cheese) are linked with microbial diversity. Consumption of animal-based protein was positively associated to a richness in bile-tolerant anaerobes, including Alistipes sp., Bilophila sp., and Bacteroides sp.

8. What are the Future Perspective on the Gut Microbiome?

Accumulating evidence suggests that gut microbiota plays a significant role in the initiation and progression of MS. The gut microbiota was proven to modulate plasma glucose, appetite, serum lipids and pro-inflammation. In addition, prebiotics or probiotics, which are widely used to manipulate the microbiota, can reduce low-grade intestinal inflammation and improve gut barrier integrity to reduce plasma glucose and serum lipid levels, induce weight loss and decrease insulin resistance. Based on these current achievements, the gut microbiota may be a potential therapeutic target for MS. However, clinical trials addressing the efficacy and efficiency of current or potential treatments on therapeutic applications in metabolic syndrome are needed.

Also, Individuals who are obese are likely to have an imbalance in gut microbiota composition. This possibility is a thrilling avenue for further research and possible novel treatment targets. However, because most studies have been undertaken in animals, direct translation of the findings to human is limited.

Prebiotics or other newly identified beneficial bacterial strains are potential interventions that will be used for treatment in the near future, and it will be important to evaluate their efficacy. Similarly, interventional studies with metabolites of microbiota will be performed (including SCFA butyrate supplementation) to evaluate if this compound has similar effects on food intake, energy expenditure, and improved metabolic features in humans.

The modifiable effects of the human gut microbiota on the development of metabolic syndrome make its handling a promising therapeutic approach. Analyzing and mapping individual microbial composition on a metagenomic level provides insight into specific targets for treatment and contributes to personalized therapeutic interventions.

References

1. Frontiers in Nutrition: Gut Microbiota, Host Organism, and Diet Trialogue in Diabetes and Obesity. Retrieved from https://www.frontiersin.org/articles/10.3389/fnut.2019.00021/full

2. NCBI (2018): The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013535/

3. NCBI (2017): Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655955/

Given that obesity and associated disorder type II diabetes mellitus have reached epidemic proportions worldwide, the development of efficient prevention and therapeutic interventions is a global public health interest. There is now a large body of evidence suggesting that the micro-organisms colonizing the human gut, known as gut microbiota, play a central role in human physiology and metabolism. Understanding how gut microbiota affects and regulates key metabolic functions such as glucose regulation and insulin resistance is an important health issue. We will highlight how prebiotic/probiotic interventions affect these bacterial processes and are now considered as promising approaches to treat obese and diabetic patients.

1. The gut microbiota of an obese person…

Obesity is a chronic, complex, and multifactorial disease representing the fifth leading cause of death in the world and accounting for almost 3.4 million deaths each year. Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease.

Microbiota is now recognized as a real functional “organ” due to its immense impact on human health and has become the subject of intensive research over recent years. The vast majority of microbes reside in the intestinal tract, where they influence host physiology by playing fundamentally important roles in digestion, nutrition, immune regulation, and metabolism.

Gut microbiota composition and activity can fluctuate over time and depend on different factors including genetics, sex, age, health status, and drug/antibiotic consumption. Over the last decade, a large number of publications have reported a prominent role of microbiota in metabolic diseases.

Notably, accumulated evidence suggests an association between a dysregulated gut microbiome and obesity, glycemic control impairment, and therefore T2DM pathophysiology.

2. Obesity, Diabetes, and Dysbiosis

The preservation a normal and healthy gut microbiota plays a critical role in maintaining good health. Alterations of both composition and function of the microbiota, termed dysbiosis, are common features of several pathologies including metabolic diseases such as obesity and T2DM.

A number of preclinical and clinical studies have attempted to describe the differences between gut microbiota in obese, compared to lean individuals and have reported that obesity is related to lower microbial diversity and greater depletion. In early obesity, microbiota studies report that an increase of body weight is associated with a microbiota shift.

Although T2DM is generally considered as an attribute to obesity, some studies have correlated glycemic control impairment and insulin resistance to specific gut microbiota composition. Furthermore, antidiabetic drugs liraglutide and metformin have been recently shown to significantly lower body weight and improve glucose metabolism while considerably modifying the composition of gut microbiota.

Liraglutide decreased obesity-related microbial phenotypes and increased lean-related phenotypes while metformin modifies the intestinal microbiota composition by inducing the growth of several bacteria.

There is proof that gut microbiota is involved in the beneficial glucose-lowering effects of antidiabetic agents and that it is a promising therapeutic target in T2DM and the glycemic control impairment context.

3. How can Gut Microbiota be moderated?

Through several mechanisms, gut bacteria influence the chronic low grade inflammation that culminates in insulin resistance and the increase in fat deposits and body weight gain, characteristic of obese individuals.

With the acknowledgement of these obesity and inflammation induction mechanisms, several strategies to block or attenuate them are being developed and tested, in order to benefit obese and type 2 diabetic patients. We will look at these mechanisms and the effect they have:

3.1. Antibiotic Therapy

The use of broad spectrum antibiotic therapy greatly modifies the gut microbiota profile although the prevalence of surviving bacteria and the benefits for the host have not been determined, as the concept of a “healthy” gut microbiota is still under investigation.

The main mechanism suggested by antibiotic administration is a reduction in circulating LPS levels, which lessens inflammation and improves the insulin resistance induced by obesity in the liver, muscle, and adipose tissue. Improved intestinal function has also been noted as a benefit of the administration of antibiotics.

However, even with this striking metabolic improvement in antibiotic therapy experiments, it seems that translating this strategy to humans is not the best option, as there are complex issues such as antibiotic resistance in chronic administration panels and evidence that indicates a relationship between chronic low-dose antibiotic therapy and body weight gain.

3.2. Probiotics

Probiotics are live microorganisms that can be consumed through fermented foods or supplements. More and more studies show that the balance or imbalance of bacteria in your digestive system is linked to overall health and disease. Probiotics promote a healthy balance of gut bacteria and have been linked to a wide range of health benefits.

As obesity is a key cause of diabetes, probiotics can help with weight loss through a number of different mechanisms. An example is that some probiotics prevent the absorption of dietary fat in the intestine.The fat is then excreted through feces rather than stored in the body. Probiotics may also help you feel fuller for longer, burn more calories and store less fat. This is partly caused by increasing levels of certain hormones, such as GLP-1.

Probiotics may also help with weight loss directly. In one study, dieting women who took Lactobacillus rhamnosus for 3 months lost 50% more weight than women who didn’t take a probiotic. Another study of 210 people found that taking even low doses of Lactobacillus gasseri for 12 weeks resulted in an 8.5%.

It is however important to note that not all probiotics aid in weight loss. Some studies have found certain probiotics, such as Lactobacillus acidophilus, can even lead to weight gain.

3.3. Prebiotics

Prebiotics are classified as the non-digestible food ingredients that probiotics can feed off. They are used in the gut to increase populations of healthy bacteria, aid digestion and enhance the production of valuable vitamins. Galactooligosaccharides (GOS) are the most advanced form of prebiotics which belong to a group of particular nutrient fibers that feed and encourage the growth of good bacteria in the gut.

The major source of prebiotics is dietary fibre. They occur naturally in fruits and vegetables, but you can also take them in the form of nutritional supplements.

3.4. Bariatric Surgery

Bariatric surgery is an important method in the treatment of obesity. It is quite effective in achieving and protecting weight loss. This effectiveness of obesity treatment after bariatric surgery is not only related to food consumption. The altered microbiota after bariatric surgery has an impact on its effectiveness. Malabsorption status after bariatric surgery, changes in the metabolism of bile acids, changes in gastric pH, and changes in the metabolism of hormones lead to gut microbiota changes. Changes in microbiota also affect energy homeostasis. Because of these reasons, body weight loss is achieved after bariatric surgery.

4. What role will gut microbiota play in the treatment of T2DM in the future?

It is becoming increasingly clear that gut microbiota has profound impact on general health and well-being. Notably, it is now well-established that imbalanced gut microbiota is linked to host glycemic control impairment and T2DM development. Although the precise role of gut microbiota remains incompletely understood, further investigation is likely to be very helpful in the treatment and control of obesity, and resultant Type 2 Diabetes.

Current treatments of this complex chronic disease are far from being ideal since in a majority of patients, T2DM remains poorly controlled in the long run. Using pre/probiotics to control blood glucose has been considered for a long time, and the discovery of the key roles of gut bacteria in T2DM has boosted research efforts in this field.

A better understanding of how gut microbiota impacts general health will help in outlining new treatment strategies. These strategies will help in identifying probiotic strains with antidiabetic activities, or nutritional interventions that can increase helpful microbiota in the gut.

References:

1. Hindawi (2013): Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance. Retrieved from https://www.hindawi.com/journals/mi/2013/986734/2. Frontiers in Endrocrinology (2019): Impact of Gut Microbiota on Host Glycemic Control. Retrieved from https://www.frontiersin.org/articles/10.3389/fendo.2019.00029/full

3. NCBI (2019): The effects of bariatric surgery on gut microbiota in patients with obesity: a review of the literature. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343052/

4. Bimuno(2018) : Prebiotics. Retrieved from https://www.bimuno.com/prebiotics

5. Healthline (2016): 8 Health Benefits of Probiotics. Retrieved from https://www.healthline.com/nutrition/8-health-benefits-of-probiotics

To reverse diabetes, weight loss and a low-carbohydrate diet must be combined. These are independent factors for reversing diabetes.

Weight loss can achieve diabetes reversal through decompressing (decongesting) the liver and pancreas, improving blood flow, and reducing adipocyte hormonal responses.

As the worldwide epidemic of obesity continues to worsen, the epidemic of type 2 diabetes follows, and 1 out of every 2 Americans born today is predicted to get type 2 diabetes. Clinically, we observe a progression of obesity to eventual type 2 diabetes through the lens of insulin resistance and metabolic syndrome.

In a recent study at Ohio State University, obese patients with metabolic syndrome ate a low-carbohydrate diet but maintained their weight. A four-week low-carb diet resulted in the reversal of the metabolic syndrome, even though there was no weight loss. Reversal of metabolic syndrome is key to reversing prediabetes and type 2 diabetes.

Parker N. Hyde, et al. Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI Insight, 2019; 4 (12)

A low-carbohydrate diet can achieve diabetes reversal through reduced insulin requirements (reduced insulin production), a reduction in glycated lipids, proteins, and receptors, reduced lipid storage, and increased lipid mobilization

The clinical relevance of this is that patients can become rapidly insulin sensitive again, well before they have returned to normal weight. Explaining this to patients provides the encouragement they need to continue a long path to ultimate success. The only way we will know a patient’s insulin sensitivity is to actually check the insulin level.

Have you had your insulin level checked?