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Diabetes Gene That Causes Low and High Blood Sugar Levels

The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals. One of the effects of a sugar-rich vs a starch-rich meal is highlighted.

Graphic credit: Jakob Suckale, Michele Solimena – Solimena Lab and Review Suckale Solimena 2008 Frontiers in Bioscience PMID 18508724, preprint PDF from Nature Precedings, original data: Daly et al. 1998 PMID 9625092, CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=24016521

 

 

Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high 1) ___ sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes. Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. There are three main types of diabetes mellitus:

 

Type 1 DM results from the pancreas’s failure to produce enough 2) ___. This form was previously referred to as “insulin-dependent diabetes mellitus“ (IDDM) or “juvenile diabetes“. The cause is unknown.

 

Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses a lack of insulin may also develop. This form was previously referred to as “non insulin-dependent diabetes mellitus“ (NIDDM) or “adult-onset diabetes“. The most common cause is excessive body 3) ___ and insufficient exercise.

 

Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.

 

Prevention and treatment involve maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. Control of blood pressure and maintaining proper foot care are important for people with the disease. Type 1 DM must be managed with insulin injections. Type 2 DM may be treated with medications with or without insulin. Insulin and some oral medications can cause low blood sugar. Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 DM. Gestational diabetes usually resolves after the birth of the 4) ___. As of 2015, an estimated 415 million people had diabetes worldwide, with type 2 DM making up about 90% of the cases. This represents 8.3% of the world’s 5) ___ population. As of 2014, trends suggested the rate would continue to rise. Diabetes at least doubles a person’s risk of early 6) ___. From 2012 to 2015, approximately 1.5 to 5.0 million deaths each year resulted from diabetes. The global economic cost of diabetes in 2014 was estimated to be US$612 billion. In the United States, diabetes cost $245 billion in 2012.

 

A recent, perhaps hopeful, study of families with rare blood sugar conditions has revealed a new gene thought to be critical in the regulation of insulin, the key 7) ___ in diabetes. The research carried out at two British universities: Queen Mary University of London, University of Exeter and in the U.S.. Vanderbilt University, and published in the journal PNAS, could lead to the development of novel treatments for both rare and common forms of diabetes. In addition to the more common forms of diabetes (type 1 or type 2), in about 1-2 per cent of cases diabetes is due to a genetic disorder. A defective gene typically affects the function of insulin-producing cells in the pancreas, known as beta cells. The research team studied the unique case of a family where several individuals suffer from diabetes, while other family members had developed insulin-producing tumors in their pancreas. These tumors, known as insulinomas, typically cause low blood sugar levels, in contrast to diabetes which leads to high blood sugar levels. The authors were initially surprised about the association of two apparently contrasting conditions within the same families — diabetes which is associated with high blood sugar and insulinomas associated with low blood sugar. The research shows that, surprisingly, the same 8) ___ defect can impact the insulin-producing beta cells of the pancreas to lead to these two opposing medical conditions. The team also observed that males were more prone to developing diabetes, while insulinomas were more commonly found in females, but the reasons behind this difference are still unknown.

 

The researcher team identified a genetic disorder in a gene called MAFA, which controls the production of insulin in beta 9) ___. Unexpectedly, this gene defect was present in both the family members with diabetes and those with insulinomas, and was also identified in a second, unrelated family with the same unusual dual picture. This is the first time a defect in this gene has been linked with a disease. The resultant mutant protein was found to be abnormally stable, having a longer life in the cell, and therefore significantly more abundant in the beta cells than its normal version. The authors commented that they believe that this gene defect is critical in the development of the disease and that they are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas. The team stated that they are committed to understanding more about the causes of all types of 10) ___ and that this research provides important insights into the impact a change in this particular gene has on insulin-producing beta cells and how this relates to the development of a rare genetic form of diabetes. It’s also a great example of how studying rarer conditions could help us learn more about more common types of diabetes.“

 

The study was funded by Diabetes UK, while co-authors also got support from the UK National Institute of Health Research (NIHR), and the US National Institutes of Health, Wellcome Trust and Royal Society. Story Sources: Queen Mary University of London: researchers: Donato Iacovazzo, Sarah E. Flanagan, Emily Walker, Rosana Quezado, Fernando Antonio de Sousa Barros, Richard Caswell, Matthew B. Johnson, Matthew Wakeling, Michael Brandle, Min Guo, Mary N. Dang, Plamena Gabrovska, Bruno Niederle, Emanuel Christ, Stefan Jenni, Bence Sipos, Maike Nieser, Andrea Frilling, Ketan Dhatariya, Philippe Chanson, Wouter W. de Herder, Bjorn Konukiewitz, Gunter Kloppel, Roland Stein, Marta Korbonits, Sian Ellard. MAFAmissense mutation causes familial insulinomatosis and diabetes mellitus. Proceedings of the National Academy of Sciences, 2018; 201712262 DOI: 10.1073/pnas.1712262115

Queen Mary University of London. “Diabetes gene found that causes low and high blood sugar levels in the same family.“ ScienceDaily.com (15 January 2018); Wikipedia)

 

ANSWERS: 1) blood; 2) insulin; 3) weight; 4) baby; 5) adult; 6) death; 7) hormone; 8) gene; 9) cells; 10) diabetes

 

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