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Metabolic inflammation as a cause of insulin resistance

Important Points:

Metabolic inflammation as a cause of insulin resistance

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 bracket, have a silent blood sugar problem known as insulin resistance. It begins when cells in your muscles, body fat, and liver repel or ignore the signal sent out by the hormone insulin to take glucose from bloodstream into our cells for breakdown or storage. Glucose, commonly called blood sugar and is the body’s main source of fuel.

Insulin resistance increases the risk for prediabetes, Type 2 diabetes, and a host of other serious health problems, including heart attacks, strokes and cancer.

2. How does Insulin Resistance Develop?

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

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 began – your blood sugar may spike and you may manifest prediabetes or type 2 diabetes. You are also at risk of developing non-alcoholic fatty liver disease (NAFLD), a condition that increases your risk for liver damage and heart disease.

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

Insulin resistance does not always manifest to the naked eye but here are other possible signs that are visible:

  • 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) increases the odds of insulin resistance and metabolic syndrome, which is also linked to insulin resistance.
  • 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.
  • Dark skin patches. If insulin resistance is severe, you may have visible skin changes including patches of darkened skin on the back of your neck or on your elbows, knees, knuckles or armpits. This discoloration is called acanthosis nigricans.

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

As early as 1950’s, a connection between inflammation and insulin resistance seemed to present especially in the obese, but the mechanics of the link were unknown. Recently, this has become clearer. Research has shown an association between the body activating signal pathways for inflammation over and over and a decrease in insulin sensitivity which is a rise in insulin resistance. Elevated levels of many inflammation signaling molecules (cytokines) and the inflammatory marker C-reactive protein (CRP) were found in those with insulin resistance and its symptoms, especially those that were obese.

5. 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., and 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. 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.

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

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

6. Can understanding 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, so 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 and interferes with insulin signaling and action. This interference only adds to the cascade of errors (pathogenesis) that leads to insulin resistance. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both the accumulation and the interference mentioned should be studied further to fully understand the connection between inflammation and insulin resistance.

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What is the relationship between metabolic Inflammation and type 2 diabetes?

Important Points:

  • Inflammation
  • Diabetes
  • Obesity
  • Metabolic syndrome
  • Beta cells

What is the relationship between metabolic Inflammation and type 2 diabetes?

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 fat tissue and the higher their chances of developing Type 2 diabetes. In this article, we will highlight the emerging role of inflammation in the pathway that leads to 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 and is characterized by high blood pressure, a large waist circumference, elevated fasting glucose and triglycerides, and low HDL cholesterol.

Metabolic inflammation (MI) 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 hindered by obesity-related inflammation. Metabolically activated macrophages are key cells in the process believed to spike both pro- and anti-inflammatory pathways in reaction to excess fat.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. The main clinical diagnostic features are impaired glucose tolerance and hyperglycaemia which occur as the result of an absolute or relative insulin deficiency or resistance to its action. Chronic hyperglycaemia associated with diabetes can result in end organ dysfunction and failure and may 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 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.Effective novel therapeutic approaches are needed 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 Type 2. The increase in prevalence of the condition has been related to well-recognized risk factors, such as the adoption of a western lifestyle, lack of physical activity, and high sugar diet. 

Genetic predisposition, ethnicity, and aging are not modifiable risk factors for Type 2 diabetes, but 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 the 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 salt led to decreased blood sugar 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 an enzyme which is one component in the insulin response pathway.

A landmark study to correlate inflammation with diabetes, conducted in animal models by Hotamisiligil et al. in 1993, revealed that tumor necrosis factor-alpha (TNF-alpha) played a role in obesity and particularly in insulin resistance and diabetes.Causal connections between inflammation and obesity or Type 2 diabetes were made because of these findings. 

Over the next decades, many studies provided more supporting evidence for the role of inflammation in the initiation and progression of diabetes.Accumulative evidence suggests that chronic inflammation in target cells of insulin action may contribute to obesity, insulin resistance, and related metabolic disorders including Type 2 diabetes. 

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

In several studies, our understanding of insulin resistance and insulin secretion in the onset of Type 2 diabetes and its 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. As it progresses, this shift in pancreatic function 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 Type 2 diabetes, it is generally accepted that abnormal insulin sensitivity precedes the clinical diagnosis of diabetes by up to 15 years.Therefore, along with looking into the mechanism of insulin resistance, studies have investigated the pathways leading to beta cell failure.

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

The evidence is inconclusive whether the inflammatory state in Type 2 diabetes can spread to other organs such as the liver, the neural system, and possibly skeletal muscle. More research is needed to determine this.

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

Below are some of the approaches currently being investigated.

  1. Gauging anti-inflammatory diets in streamlining an individual’s microbiome through innovative approaches for Type 2 diabetes
  2. Examining the effects of vitamin D supplementation on serum levels of inflammatory markers through clinical trials; results so far are inconsistent
  3. investigating whether antagonists of leukotriene production enzymes or receptor binding BLT1 have benefits for metabolic and cardiovascular health; results have not been reported yet

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

Given the increasing prevalence of diabetes, it is crucial that research focuses on its prevention as well as its treatment. Heart disease, the metabolic syndrome and type 2 diabetes (T2D) all have a high level 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.

Type 1 diabetes 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 possible use of stem cells to regenerate pancreatic beta cells could potentially be the key to permanent treatment of Type 1 diabetes. Therefore, after a holistic review of the possible mechanisms that lead to Type 1 and Type 2 diabetes 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.