The Human Pancreatic Islet Methylome and Its Role in Type 2 Diabetes

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Abstract

Popular Abstract in English
Sugar is the main source of energy in our bodies. If your blood sugar drops below a certain level, it can cause serious damage to your brain. On the other hand, having a very high blood sugar level for a long time can cause diabetes. For this reason, blood sugar levels in our bodies are maintained within a certain range by a group of hormones that work together. These hormones are produced by the pancreatic islets that consist of five cell types. Each cell type produces a special hormone that plays a role in the fine-tuning of sugar levels in our bodies. When you have a meal, your blood sugar will rise, and the pancreatic beta-cells will sense this and release insulin. Insulin is a hormone that sends a signal to certain cells in your body to store excess sugar and remove it from blood. When you haven’t eaten for some time, your blood sugar goes down and pancreatic alpha-cells produce glucagon. Glucagon does the opposite of insulin and sends a signal to certain cells in your body to release some sugar from their stores. Patients with type 2 diabetes have problems producing enough insulin, and produce more glucagon than is needed. To make things worse, the cells that are supposed to receive signals from insulin to store sugar are not very responsive. As a result, sugar is not cleared from your blood. Having high blood sugar for a long time is one of the main reasons for heart attacks, kidney failure, blindness and lower limb amputation.
Why do certain people get type 2 diabetes? Many factors can increase your risk of getting type 2 diabetes. Some are genetic (determined by the genes you inherit from your parents), and others are environmental. People that have diabetes running in their family are more likely to become diabetic themselves. The main reasons why the number of people with type 2 diabetes is increasing worldwide are probably: being overweight, eating unhealthy food, and not exercising. Other factors include: smoking, ethnicity, aging, high blood pressure, and poor nutrition during pregnancy. One way in which these different environmental factors can affect the way your body works is via epigenetic modifications.
What are epigenetic modifications, and how do they work? Epigenetic modifications are molecules that are attached to your DNA and can change the way your genes behave without changing the gene itself. The DNA that you inherit from your parents is made up of a sequence of four letters (A, T, C and G); this sequence provides your cells with an instruction manual that tells them what to do. Although all the cells in your body carry exactly the same instruction manual (DNA), they look and behave very differently. This is because a group of proteins and small molecules that are attached to your DNA make every cell-type use different parts of the instruction manual (express different genes). In other words, each cell has a different epigenome on top of the DNA that tells it to express a group of genes, and prevents it from expressing others. The epigenome can help your genome remember certain experiences that it was exposed to. They could be good experiences (for example, healthy diet and exercise) that help your body adapt, or they could be bad experiences (for example, unhealthy diet, pollutants, starvation and poor nutrition as a fetus) that make you sick. There are different types of epigenetic modifications that give different signals, and can be located in different parts of the DNA sequence. DNA methylation is one of these epigenetic modifications; it is made by the attachment of a molecule, known as a methyl group, to the letter C in your DNA sequence (mainly those followed by the letter G). These methyl groups can block certain proteins from reaching the switch button that turns your genes on.
DNA methylation of pancreatic islets is different in patients with type 2 diabetes. Pancreatic islets from patients with type 2 diabetes have either more or fewer of these methyl groups in different parts of their DNA sequence than healthy people. In general, patients with type 2 diabetes have fewer methyl groups attached to their DNA, especially in certain parts of the DNA sequence. In some cases, the genes that are located in these regions behave differently in patients with type 2 diabetes, including genes that are important for the normal function of pancreatic islets and their ability to produce insulin and glucagon. For example, pancreatic islets from patients with type 2 diabetes have more methyl groups attached to the gene that produces insulin and another gene that regulates it. It is possible that these epigenetic changes are one of the reasons that make patients with type 2 diabetes produce less insulin.
The sequence of letters that makes up your DNA is predetermined by your parents. Because the methyl group is mainly added to the letter C, followed by a G, people that don’t have CG cannot have a methyl group attached to their DNA. That means that many of the changes caused by the addition or removal of these methyl groups will be different for different people based on the sequence of letters that make up their DNA. If this happens in a region that plays a role in diabetes, people with a certain sequence of letters will be more affected than others.
Almost 50 percent of people are unaware that they have diabetes. By the time they are diagnosed, a lot of the damage has already been done to their bodies. Researchers have been trying to find a ‘fingerprint’ that can help them identify individuals that are likely to get type 2 diabetes, so that they can get help, and control their blood sugar level before it gets worse. A number of DNA ‘fingerprints’ have been found, but researchers are still trying to find even more reliable ones. Epigenetic ‘fingerprints’ are an interesting tool that is already being used in cancer research. We and other researchers are trying to find an epigenetic ‘fingerprint’ in blood DNA that could predict if an individual will get diabetes in the future.
How can I avoid becoming diabetic? You can avoid getting type 2 diabetes by exercising, eating healthy food, and avoiding many of the other risk factors. Although you can’t change your genes, having a healthy lifestyle can protect you from getting diabetes, or at least delay its onset. We believe that sometimes an unhealthy lifestyle can make certain epigenetic changes to the pancreatic islets, and that these changes can cause diabetes. The good news is that some of these changes can be reversed by a healthy lifestyle, and thus protect you from getting diabetes.

Detaljer

Författare
  • Tasnim Dayeh
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes

Nyckelord

Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
Handledare/Biträdande handledare
Tilldelningsdatum2016 feb 3
Förlag
  • Epigenetics and Diabetes
Tryckta ISBN978-91-7619-234-4
StatusPublished - 2016
PublikationskategoriForskning

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