Type 2 Diabetes mellitus

Type 2 Diabetes mellitus

Observed genes

Polygenic score

Influential genes: TCF7L2,CDKAL1,IGF2BP2

TCF7L2 stands out as the most potent gene when it comes to the risk of developing type 2 diabetes.

Studies have found that the CDKAL1 gene is linked with both the development of diabetes and the complications that can arise from the disease.

The IGF2BP2 gene produces a protein involved in the stimulation of insulin action, a vital process in glucose metabolism​.

Overview

Diabetes mellitus (DM) is a chronic disease caused by many different mechanisms, with one thing in common – a higher blood sugar level – a condition known as Hyperglycemia. Type 2 is one of the four main group types of diabetes, making up 90-95% of all the cases (the other groups being Type 1 diabetes, Gestational diabetes mellitus, and specific types of diabetes due to other causes).

The body tissues aren’t able to utilize glucose as intended due to a buildup of “insulin resistance” (mainly caused by constantly higher glucose levels triggered by stress or its excessive intake in diet). Additionally, the pancreas can’t cover the increased demand for insulin anymore, causing “pancreatic insufficiency” – a relative lack of insulin. Together these 2 processes are the basis for developing Type 2 Diabetes. 

If left untreated, hyperglycemia can damage the kidneys, nerves, vessels, and  eyes, leading to several complications, like, for example, full blindness. Healing processes are impaired, leading to chronic wounds and putting diabetic patients at risk of infections, severely endangering their health. In extreme cases, the defects on limbs can lead to amputations of extremities. Besides the direct effects of diabetes, it’s also an established risk factor for coronary heart disease and ischemic stroke, especially in combination with other health conditions (such as impaired blood lipid levels, obesity, and hypertension).

 

Prevalence and risk factors

Over the last 30 years there has been a huge growth of cases globally, developed regions having even faster growth rate, mainly caused by the lifestyle of modern society. Nowadays, we face a prevalence rate of 9.3 % in adults (equivalent to 463 million people) [5], which is projected to continue rising. Between 2000 and 2016, the premature mortality rates from diabetes (meaning before the age of 70) increased by 5%.  

The main risk factors, such as an unhealthy diet full of fats and prefabricated sugars, combined with smoking and little physical activity, are often seen even in younger generations. 

 

Genetics 

Type 2 diabetes (T2D) is a complex disease influenced by both genetic and environmental factors, making it a multifactorial disease. While lifestyle choices play an important role in its development, certain genetic variations can also increase the risk of developing T2D. However, the presence of these genetic variations does not guarantee the development of T2D. 

Genome-wide association studies have contributed to the discovery of genetic variants associated with susceptibility to T2D. Key genes involved in β-cell function, insulin secretion, insulin resistance, and glucose homeostasis have emerged as critical contributors to the development of T2D. The discovery of the underlying biological pathways involved in the development of the condition opens up opportunities for targeted therapeutic intervention.[6,7]

T2D is heterogeneous in nature, as both common single nucleotide polymorphisms (SNPs) with small effects and rare variants with large effects have been identified. In addition, research is now extending to non-coding elements (e.g. enhancers) that may potentially contribute to the development of T2D.[8,9] 

Understanding the genetic basis of T2D is essential for the development of personalized treatment and prevention strategies. Genetic testing allows us to detect whether you have the predisposition to develop this condition. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

 

Symptoms 

Diabetes evolves very slowly; it can take many years for the patient to notice that something is wrong. First symptoms are usually nonspecific, such as fatigue or higher susceptibility to infections (parodontitis, urinary tract infections…). Typical patients complain of increased thirst (polydipsia) and frequent urination (polyuria), extreme hunger, and frequent infections. Chronic complications can be already present by the time of diagnosis with years of uncontrolled diabetes.  

                                                                                                                              

Disease detection / screening / diagnosis 

Blood glucose monitoring is crucial for the diagnosis of Type 2 Diabetes mellitus. Diagnostic blood screening should be a part of every preventive checkup – diabetes is often detected unexpectedly as a part of other examinations. Venous blood should be analyzed for diagnostic purposes, but capillary blood obtained superficially also plays an important role in monitoring glycemia (concentration of glucose in the blood). The main diagnostic tests consist of fasting plasma glucose, glycated hemoglobin, and OGTT.

  • Fasting plasma glucose - normal blood glucose levels are in a range of 3,9 – 5,6 mmol/l. Fasting glucose levels over 7 mmol/l are considered diabetes. The state between 5,6-7 mmol/l is named prediabetes. Glycemia over 11 mmol/l in any state is always considered diabetes.  
  • OGTT (oral glucose tolerance test) - if the diagnosis can’t be made based on fasting glucose levels, an oral glucose tolerance test is performed. 
  • Glycated hemoglobin (A1C) indicates average blood sugar level for the past two or three months and is therefore very useful in monitoring the effectiveness of the treatment. 

 

Therapy  

Having diabetes doesn’t necessarily mean that the patient must inject insulin, as often thought by many people. The first step is reviewing the patient's lifestyle, including diet and physical activity. If you can’t maintain the desired blood sugar level only with lifestyle changes, it may be necessary to prescribe peroral antidiabetics. Overall, Metformin is used the most (based on lowered glucose production by the liver and increased sensitivity of tissues), but there are many groups based on different principles that can help lower glycemia. If all those steps fail, insulin may be prescribed. The insulin type, dosage, and usage scheme vary for each patient and should be determined by a specialist. 

 

Prevention  

Healthy lifestyle is important in both the prevention and treatment of Type 2 Diabetes. As already mentioned above – eliminating prefabricated sugar, simple carbs, and unhealthy fats (mainly trans-fat and saturated fat), weight loss, regular physical activity among many other factors – all these lifestyle changes can prevent the disease. 

 

Prognosis 

Diabetes is a complex disease with many variables and possible complications; it is almost impossible to estimate the exact risk for a specific patient. Prognosis is based on the succession of the treatment – it is believed that people with sufficient treatment and lifestyle changes may live as long as healthy patients.

Recommendations

  • Follow a regular, balanced & healthy diet
  • Eliminate prefabricated sugars and unhealthy fats (mainly trans-fat and saturated fat)
  • Manage you weight
  • Maintain a regular physical activity
  • Visit your GP for routine check-ups regulary

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Recommendations

  • Follow a regular, balanced & healthy diet
  • Eliminate prefabricated sugars and unhealthy fats (mainly trans-fat and saturated fat)
  • Manage you weight
  • Maintain a regular physical activity
  • Visit your GP for routine check-ups regulary

Sources

  1. World Health Organization. (2021, November 10). Diabetes. World Health Organization. Retrieved December 10, 2021, from https://www.who.int/news-room/fact-sheets/detail/diabetes. 
  2. Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med. 2017 Jul 19;15(1):131. doi: 10.1186/s12916-017-0901-x. PMID: 28720102; PMCID: PMC5516328.
  3. Diabetes - Symptoms and causes. (2021). Retrieved 10 December 2021, from https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444
  4. American Diabetes Association. (2021, January 1). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021. Diabetes Care. Retrieved December 10, 2021, from https://care.diabetesjournals.org/content/44/Supplement_1/S15
  5. Rodney A Hayward, Mde. S. P. M. (2021). Screening for type 2 diabetes mellitus - UpToDate. https://www-uptodate-com.ezproxy.is.cuni.cz/contents/screening-for-type-2-diabetes-mellitus?search=prevalence%20diabetes%20mellitus%20typ%202&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=4
  6. Ali O. Genetics of type 2 diabetes. WJD. 2013;4(4):114. doi:10.4239/wjd.v4.i4.114
  7. Khetan S, Kursawe R, Youn A, et al. Type 2 Diabetes–Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets. Diabetes. 2018;67(11):2466-2477. doi:10.2337/db18-0393
  8. Leung A, Natarajan R. Long Noncoding RNAs in Diabetes and Diabetic Complications. Antioxidants & Redox Signaling. 2018;29(11):1064-1073. doi:10.1089/ars.2017.7315
  9. Chi T, Lin J, Wang M, Zhao Y, Liao Z, Wei P. Non-Coding RNA as Biomarkers for Type 2 Diabetes Development and Clinical Management. Front Endocrinol. 2021;12. doi:10.3389/fendo.2021.630032

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