Written by Jennifer Clark
March 20, 2011
Diabetes Mellitus is a groups of chronic diseases characterized by high levels of blood-glucose levels caused by the body’s inability to produce insulin or the body’s cells unresponsiveness to insulin (Grosvenor & Smolin 2006). According to the World Health Organization (2011), there are approximately 220 million people worldwide that have at least one type of diabetes. However, many people with the disease do not get diagnosed. In the US, approximately 18.8 million people have been diagnosed with diabetes, yet it is estimated that 7.0 million people have diabetes but have not been diagnosed (CDC, 2011). This is much more significant than the approximated 1.7 million people in Canada that were diagnosed with diabetes in 2009 (Statistics Canada, 2010).
There are three types of diabetes mellitus: Type 1, Type 2, and gestational diabetes. All three types are caused by different malfunctions in the insulin-regulation process in the body. Therefore, diabetics experience episodes of extremely high and low blood-glucose levels. High blood-glucose levels can result in glucosuria, a condition that results excretion of large amounts of glucose through urine (Nelson & Cox 2005). This can lead to frequent urination, known as polyuria, as well as polydipsia when large amounts of water is consumed to compensate for the amount lost from urination. Low blood-glucose levels can be lethal or cause serious health problems such as damage to the heart, blood vessels, kidneys, eyes, and nerves. In fact, diabetes is the leading cause of both kidney failure and blindness in adults (Grosvenor & Smolin 2006; American Diabetes Association 2011).
Although the pathology of diabetes is fairly understood by scientists, the etiologies of what caused the malfunctions in the insulin-regulation process to occur are not entirely understood. For each types, different theories involving genetics and environmental factors have been suggested to explain why each type of diabetes develops.
Type 1 Diabetes Mellitus
Type 1 diabetes (T1DM), also known as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, accounts for nearly 5-10% of all diabetes cases and is usually diagnosed before the age of 30. It occurs when insulin is no longer produced in the body because the insulin-producing β-cells located in the islets of Langerhans of the pancreas have been destroyed. In result, glucose molecules can no longer be absorbed by the cells of the body. This causes blood-glucose levels to elevate when glucose is consumed as well as prevents cells from storing glucose to produce energy when blood-glucose levels are low. Therefore, the only way to ensure proper glucose metabolism is to inject insulin into the body before consuming glucose.
The etiology of T1DM is not entirely understood, but theories involving genetics, environmental factors, and diet propose explanations to what exactly is causing the destruction of the insulin-producing β-cells.
Genetic links to T1DM have been studied since the late 1970s. Many genes have been associated with the onset of T1DM, all of which are found in two chromosome regions: the human leukocyte antigen (HLA) region on chromosome 6p21 and the insulin gene region on chromosome 11p15 (Morran, et al. 2008). The HLA loci contributes approximately 42% to familial inheritance wheres the insulin gene loci only contributes about 10%. The HLA region is associated with proper immune system functioning and is thought to be responsible for the development and activation of the autoimmune response that causes the onset of T2DM. However, recent studies have shown that over forty more loci might be linked to the onset of T1DM, making the genetics of diabetes more complexed previously believed (Barrett, et al. 2009).
The theory that is most accepted by health professionals is that a viral infection triggers diabetes-susceptible genes to cause an autoimmune response, which attacks and destroy its own insulin-producing β-cells in the islets. This idea evolved from studies in the 1970s involving the encephalomyocarditis (EMC) virus in male mice that produced diabetes-like symptoms and the Kilham rat virus (KRV) in rats that produced rapidly-occurring autoimmune diabetes (Boucher, et al. 1975; Jun & Yoon 2001). Since then, research has focused on whether viruses can influence the diabetes-susceptible genes in humans. According to Jun & Yoon (2001), 13 different viruses have been associated with the onset of T1DM. The most common of these viruses are thought to be Coxsackie B, Rubella, and mumps which can directly infect and destroy the β-cells, and Coxsackie B4 which has been shown to cause severe T1DM in children (von Herrath 2009).
Also, recent research suggests that vitamin D deficiency can contribute to the onset of T1DM. The vitamin D system in the body interacts with the VDR and CYP27B1 genes located on chromosome 12, many of which are located in the β-cells of the islets (Mathieu & Badenhoop 2005). Mutations on the CYP37B1 gene causes rickets and other vitamin D deficiencies in children, whereas mutations on the VDR gene have been associated with the increase risk of many types of cancer, reduced bone mineral density, and immune disorders. With the immune disorders, researchers believe that vitamin D may act as an immunosuppressive agent that can protect against the autoimmune response seen in T1DM. Scientist hypothesize that this occurs due to vitamin D’s essential role in insulin secretion. Norman, et al. (1980) found that the pancreas contains vitamin D-dependent calcium-binding proteins and cytosol receptors that contribute to the proper secretion of insulin. Without proper vitamin D intake, inadequate secretion of insulin occurs, triggering an autoimmune response (Giulietti, et al. 2004). Although research supports this theory, the pathology of vitamin D in diabetes has still yet to be fully identified.
Type 2 Diabetes Mellitus
Type 2 diabetes (T2DM), also known as non-insulin dependent mellitus (NIDDM), is the most common type of diabetes, accounting for 90-95% of all diabetes cases. It occurs when there is a defect in the regulation of insulin activity in the body (Nelson & Cox 2005). Unlike in T1DM, int T2DM the body still has the ability to produce insulin, but the cells become unresponsive to the insulin molecules. By doing so, it reduces the amount of insulin uptake in the cells, forcing glucose to remain in the bloodstream. Studies also show that T2DM may also be caused by a decrease in β-cell mass and an increase in β-cell apoptosis, which reduces the amount of insulin released from the islets (Butler, et al. 2003). T2DM usually occurs with a combination of many diseases which is referred to as metabolic syndrome (Grosvenor & Smolin 2006). These diseases can include obesity, hypertension, high levels of blood lipids, and insulin insensitivity.
Both genetic and environmental factors contribute to the onset of T2DM. Like T1DM, specific genes have been associated with the increased risk of developing T2DM. The gene that has been found to have the strongest association with T2DM is the TCF7L2 gene (Saxena, et al. 2006). It is involved with impaired insulin secretion and increased hepatic glucose production. The other two genes that have strong correlations to T2DM are PPARγ, which has a strong correlation with insulin resistance, and KCNJ11, which is thought to be associated with decreased insulin secretion (Rios & Gutierrez Fuentes 2010).
The major environmental factor associated with T2DM is excess weight, particularly in the abdominal region. With the drastic increase in obesity rates in the last few decades, excess fat is believed to be associated with the increase in T2DM (Tamasan, et al. 2010). Research suggests that adipose tissue can communicate with the brain and peripheral tissues by secreting hormones responsible for the regulation of appetite and metabolism (Lazar, 2005). In particular, adipose tissue secretes many proteins including leptin that maintain glucose metabolism and insulin production. Thus, adipose tissue can cause an imbalance in glucose-insulin modulation, which fluctuates the blood-glucose levels in the body. Therefore, unlike T1DM, T2DM can be prevented and sometimes cured with the elimination of unhealthy living habits.
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) occurs in 5-10% of women during pregnancy. It happens when the pancreatic β-cells are unable to produce excess amounts of insulin to compensate for the insulin-blocking hormones released during pregnancy (Metzger, 2007). Fortunately, 90-95% of all women with GDM regain normal insulin production after giving birth (CDC, 2011). However, GDM is usually an early sign of diabetes with 35-60% of women developing diabetes 10-20 years after being diagnosed with the disease.
Although the etiology of GDM is not entirely understood, evidence suggests that a combination of the increase maternal adiposity and the increase hormonal effects of pregnancy on insulin-insensitivity are the main factors that contribute to the development of the disease (Buchanan & Xiang 2005). Since insulin resistance usually begins during mid-pregnancy and progresses till the end of the third trimester, the increase adipose tissue around the abdomen is thought to contribute to the cells’ insulin insensitivity, similar to excess body fat in T2DM. Also, since both insulin resistance and hormones re-stabilizes after delivery, it is thought the the hormones may contribute to the reduction in insulin production in the β-cells. In addition, certain factors can increase the risk of developing GDM during pregnancy such as being overweight, pre-diagnosed or undiagnosed with a type of diabetes, and genetic predisposition (Metzger 2007).
Conclusion
Although the etiology of diabetes is not fully understood, research has distinguished the specific malfunctions each type cause in the insulin-regulation process of the human body. With further research in the causes of the malfunctions, understanding of how insulin regulation is effected by genetic and environment factors can be established and can be used to reduce and prevent the development of diabetes in the future.
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