Categories
Uncategorized

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.

Categories
Uncategorized

Beta Cells

Table of Contents:

  • Diabetes
  • Insulin resistance
  • Type 1 Diabetes
  • Type 2 Diabetes

Basics of Beta Cells

The pancreas is an exocrine gland that produces two key hormones involved in the regulation of blood sugar: Insulin and Glucagon. Beta cells are distinctive cells within the pancreas that are responsible for the production of insulin. They’re one of a minimum of 5 different types of islet cells, located within the section of the pancreas called the islets of Langerhans, that secrete hormones directly into the blood.

The Role of Beta Cells
The main role of beta cells is to provide and secrete insulin into the bloodstream when needed. When blood sugar levels begin to rise, such as when you are eating, beta cells quickly respond by secreting insulin into the bloodstream to take up the glucose being produced and store it in fat cells. Insulin should be considered primarily a fat storage hormone clearing the blood stream of excessive glucose and converting it to fat. Diabetes is a disease of insulin resistance in which these beta cells are either attacked or destroyed by the immune system (type 1 diabetes), or become resistant to the effects of insulin (type 2 diabetes).

The Role of Amylin and C-peptide
As a byproduct of insulin production, beta cells also produce two other products: Amylin and C-peptide.

  • Amylin slows the speed of glucose coming into the blood in acting as a short-term regulator of blood sugar levels.
  • C-peptide is secreted into the blood in equal quantities to insulin, but its role remains uncertain. It may prevent damage of arteries and diminished blood flow to the extremities as many people suffering from severe diabetes will have these symptoms. It is possible that when beta cells are destroyed, C-peptide is lost, but often patients experience early small vessel disease and neuropathy symptoms prior to Beta cell depletion. 

The Role of Beta Cells in Diabetes

Type 1 Diabetes
In Type 1 diabetes, beta cells die from an immune attack. Immune cells which normally fight harmful bacteria and viruses mistakenly destroy beta cells in the pancreas. The cause and avenue of destruction isn’t clear; however, the results of a study published in early 2011 show that these beta cells become stressed at the earliest stages of the illness.

In studies using mice, cells respond to this stress by triggering a death pathway leading to the loss of beta-cell function and ultimately loss of cell mass. As a result, stress on beta cells resulting from an immune attack may be responsible for type 1 diabetes. Type 1 diabetes has strong genetic links and mostly occurs in children.

Type 2 Diabetes
In Type 2 diabetes, the body loses sensitivity to insulin over time until it becomes immune to the effects of insulin. Consequently, it tries to compensate by producing more insulin. Research has shown that elevated blood sugar levels (chronic hyperglycemia) over a protracted amount of time will result in beta cell burn out or cell turnover. Although the exact cause is unclear, certain factors could contribute significantly such as chronic low-grade inflammation, the accumulation of high levels of glucose (glucotoxicity), or simply the effects of lipoproteins, leptin, and cytokines which play a role in glucose regulation.

Insulin Resistance in Type 2 Diabetes
The beta cells of the pancreas work as extremely connected clusters called islets, and their response to rising blood sugar levels are coordinated by little groups of “leader cells”, which initiate their coordination once blood sugar levels peak in the blood. It is possible that the leader cells are more metabolically active and more glucose-sensitive than the rest making them the primary target for insulin resistance.

Insulin resistance in type 2 diabetes starts out, as described above, with decreasing peripheral sensitivity to insulin leading to an overproduction of insulin by the beta cells.  This peripheral insulin resistance is primarily triggered by chronic over storage of fat as a result of excessive carbohydrate consumption and inadequate glycogen depletion.

Due to the increasing levels of insulin resistance, patients continue to suffer from elevated blood glucose levels with sweeping consequences. After a period of time, internal insulin production decreases, likely from excessive fat accumulation in the pancreas and localized changes in blood flow, resulting in the patient needing an external source of insulin.

New Drug To Stimulate Growth of Beta Cells
Researchers from Mount Sinai Hospital have discovered a unique combination of medication that induces the growth of beta cells. The lead author of the study Andrew Stewart, MD had this to say:

“We have discovered a drug combination that makes beta cells regenerate at rates that are suitable for treatment. The next big hurdle is figuring out how to deliver them directly to the pancreas.”

If beta cells can be stimulated to regenerate, then insulin resistance will no longer be an insurmountable obstacle for diabetics, and it will provide the much-needed breakthrough in the treatment of diabetes.

Keywords

  • Beta cells
  • Insulin resistance
  • Type1 diabetes
  • Type 2 diabetes

References

1.   Mayo Clinic: Type 2 diabetes. Retrieved from https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/symptoms-causes/syc-20351193

2.   Mayo Clinic: Type 1 diabetes. Retrieved from https://www.mayoclinic.org/diseases-conditions/type-1-diabetes-in-children/symptoms-causes/syc-20355306

3.   NCBI (2008): Insulin signaling in the pancreatic beta-cell. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18481923

4.   Science Daily (2018): Diabetes: New drug cocktail increases human beta cell proliferation at rapid rates. Retrieved from https://www.sciencedaily.com/releases/2018/12/181220111759.htm