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Type 1 Diabetes

Kai Estrada

Introduction

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What is Diabetes and What are the Differences Between Type 1 and Type 2?

Diabetes is a genetic disease in which the body’s ability to produce or respond to the hormone insulin is impaired, which leads to high blood sugar. Type 1 diabetes (T1D), previously referred to as juvenile onset diabetes or insulin-dependent diabetes, is a form of diabetes caused by an autoimmune response. Approximately 5%-10% of people with diabetes have type 1. This autoimmune response destroys the insulin producing beta cells of the islets of Langerhans located in the pancreas. This severely lowers or effectively eliminates the body’s ability to produce insulin. On the other hand, type 2 diabetes (T2D) is characterized by insulin resistance. This means that the beta cells are intact and secrete insulin, as they should, but the body’s cells have become resistant to its effects. It is estimated that 90%-95% of people with diabetes are type 2 diabetics (2,3). In T1D, cells have no insulin to respond to, where in T2D there is insulin present in the blood stream, but the cells are unable to respond to it.

 

What is Insulin and Why is it Important?

Insulin, a hormone, helps control blood glucose levels. When someone eats, insulin is released to signal muscle, fat, and liver cells to take up glucose from the bloodstream to be used for energy. When insulin isn’t produced, blood glucose levels become elevated, which can cause organ damage or lead to other dangerous conditions (1).

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t1d_1.jpg
t2d2.jpg

"Difference Between Type 1 Diabetes and Type 2 Diabetes.” Will's Way, www.diabeteswillsway.com/blog/five-differences-between-type-1-and-type-2-diabetes-in-children-201605/.

“Diabetes: Type 1 Diabetes v/s Type 2 Diabetes.” 

Visually, 14 Feb. 2014, visual.ly/community/infographic/health/diabetes-type-1-diabetes-vs-type-2-diabetes.

T1D_T2D_compare.PNG

Treatment and Symptoms

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Type 1 diabetics rely on insulin injections administered manually or via an insulin pump. Lifestyle changes, such as exercising regularly and forming healthy eating habits may help manage symptoms of T1D. Without treatment, a patient may develop retinopathy, kidney damage, poor blood circulation, and nerve damage. Destruction of the beta cells occurs over time and may take a period of weeks to years before symptoms are apparent. Symptoms of diabetes include frequent urination, dehydration, weight loss, and fatigue. T1D most frequently develops in people under the age of 20, but may occur in older individuals (1). There are alternative treatments with T1D having been cured by pancreas transplantation and by islet transplantation. While this may seem like the obvious choice of treatment for patients with T1D, there is a relative lack of donors for allogenic transplantation. Essentially, it is nearly impossible to find a perfect donor for this type of transplantation. Additionally, the body must be kept in a continuously immunosuppressed state to prevent autoantibodies from destroying the healthy beta cells in the transplant1. While transplantation may be promising in the future, the only true treatment for T1D is insulin injection.

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Basic Genetics of Type 1 Diabetes

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So far, we only know that an autoimmune disorder causes T1D, but generally occurs in genetically susceptible individuals. In general, T1D is considered a complex genetic trait. This is because multiple genetic loci contribute to susceptibility and environmental factors may serve as triggers for onset of the disease. There is familial clustering in the disease, with siblings having a 6% chance to develop T1D, while the general population has a 0.4% chance. Insulin or an insulin precursor may serve as an autoantigen, which causes the body’s immune system to destroy it and/or the beta cells of the pancreas (4,5).

Symptoms of T1D

 

Increased Thirst & Frequent Urination: Since glucose can't be absorbed by cells, there is an increased blood glucose level. The kidneys are forced to work harder to filter and excrete the excess glucose in urine. Since glucose is a polar molecule, its secretion also removes water from the system and can cause dehydration. Dehydration, due to glucose secretion, leads to increased thirst. This increased thirst and need for glucose secretion leads to frequent urination.

 

Extreme Hunger: In T1D, insulin resistance prevents glucose from being absorbed and broken down into energy. Since your body is unable to breakdown the food you eat into energy, you feel hungry even though you may have eaten. Excessive hunger is caused by the body’s need for energy.

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Unintended Weight Loss: If the body can't uptake glucose for later use as energy, your body will resort to using the body fat you already have. Breaking down fat for energy leads to this unintentional weight loss.

 

Fatigue/Weakness: Since diabetes prevents glucose uptake and storage, there is less glucose for the body to break down into energy. This lack of fuel leads to fatigue and weakness over time.

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Blurred Vision: When blood sugar is high, the blood thickens and draws more water from surrounding tissues. This thicker blood leads to swelling of the lens of the eye. The resultant swelling of the lens can cause temporarily blurred vision.

 

Ketoacidosis: Since glucose can’t be absorbed, the body must break down existing adipose tissue for energy. Breaking down adipose tissue releases ketone bodies into the blood stream. These ketone bodies make the blood more acidic.

t1d_signal_diagram1.png

The left depicts a Type 1 Diabetic, who has no insulin in their blood stream. The right depicts a healthy insulin signaling pathway. As insulin binds to the extracellular component of the insulin receptor, the intracellular portion of the receptor autophosphorylates. This autophosphorylation activates IRS1/2. Activation of IRS1/2 causes PI3K to bind using its p85 subunit. Once bound, PI3K will phosphorylate PIP2 to PIP3. PTEN is a negative regulator of IRS1/2 activation and can dephosphorylate PIP3. As PIP3 concentrations increase, PDK1 and AKT are recruited towards the plasma membrane and PDK1 is activated. Activated PDK1 phosphorylates AKT. Insulin sensitive cells typically have stores of vesicles that contain GLUT4, which is an insulin dependent glucose transporter. In a cell that isn’t stimulated by insulin, AS160 is continuously inhibiting the translocation of the GLUT4 vesicles to the plasma membrane. Phosphorylated AKT inhibits AS160, thus allowing translocation to occur. AKT also inhibits GSK3, which is a natural inhibitor of glycogen synthase. By inactivating an inhibitor, glycogen synthase is activated and glycogen synthesis can occur. AKT is not only allowing translocation of GLUT4 to the plasma membrane, but allowing glycogen syntheses to occur. As glucose concentrations rise, AKT activates a downstream mTORC1. mTORC1 phosphorylates p70S6K, which acts as a negative feedback inhibitor of IRS1/2.

t1d_signal_diagram2.png

Modified from

Coté, Mario, and Mario De Tullio. “G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes.” Nature News, Nature Publishing Group, www.nature.com/scitable/topicpage/g-protein-coupled-receptors-pancreatic-islets-and-14257267.

 

After a meal, blood glucose levels rise. Glucose is taken up into pancreatic beta cells through the GLUT2 transporter. As glucose enters the beta cell, it is metabolized, leading to increased production of ATP. This causes the ATP/ADP ratio to rise, which causes potassium channels to close. As potassium channels close, cell depolarization increases, causing calcium channels to open. The increasing calcium concentration causes insulin to be secreted.

t1d_signal_diagram3.png

The left depicts untreated type 1 diabetes. This is evident because there is no insulin in the bloodstream. The right depicts a type 1 diabetic who is being treated with insulin injections, as this is the only way to get insulin. As insulin binds to the extracellular component of the insulin receptor, the intracellular portion of the receptor autophosphorylates. This autophosphorylation activates IRS1/2. Activation of IRS1/2 causes PI3K to bind using its p85 subunit. Once bound, PI3K will phosphorylate PIP2 to PIP3. PTEN is a negative regulator of IRS1/2 activation and can dephosphorylate PIP3. As PIP3 concentrations increase, PDK1 and AKT are recruited towards the plasma membrane and PDK1 is activated. Activated PDK1 phosphorylates AKT. Insulin sensitive cells typically have stores of vesicles that contain GLUT4, which is an insulin dependent glucose transporter. In a cell that isn’t stimulated by insulin, AS160 is continuously inhibiting the translocation of the GLUT4 vesicles to the plasma membrane. Phosphorylated AKT inhibits AS160, thus allowing translocation to occur. AKT also inhibits GSK3, which is a natural inhibitor of glycogen synthase. By inactivating an inhibitor, glycogen synthase is activated and glycogen synthesis can occur. AKT is not only allowing translocation of GLUT4 to the plasma membrane, but allowing glycogen syntheses to occur. As glucose concentrations rise, AKT activates a downstream mTORC1. mTORC1 phosphorylates p70S6K, which acts as a negative feedback inhibitor of IRS1/2.

References

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  1. Atkinson, Mark A, and George S Eisenbarth. “Type 1 Diabetes: New Perspectives on Disease Pathogenesis and Treatment.” The Lancet, vol. 358, no. 9277, 2001, pp. 221–229., doi:10.1016/s0140-6736(01)05415-0.

  2. “Diabetes Home.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 Aug. 2018, www.cdc.gov/diabetes/basics/type1.html.

  3. “Diagnosis and Classification of Diabetes Mellitus.” Diabetes Care, vol. 33, no. Supplement_1, 2009, doi:10.2337/dc10-s062.

  4. Pociot, F, and M F McDermott. “Genetics of Type 1 Diabetes Mellitus.” Genes & Immunity, vol. 3, no. 5, 2002, pp. 235–249., doi:10.1038/sj.gene.6363875.

  5. “Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies.” Tom L. Van Belle, Ken T. Coppieters, and Matthias G. Von Herrath. Physiological Reviews 2011 91:1, 79-118

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