Rates of severe hypoglycemia have generally declined due to the advent of rapid-acting and long-acting insulin products in the 1990s and early 2000s; however, acute hypoglycemic still causes 4–10% of type 1 diabetes-related deaths.The other persistent risk is diabetic ketoacidosis – a state where lack of insulin results in cells burning fat rather than sugar, producing toxic ketones as a byproduct. Ketoacidosis symptoms can develop rapidly, with frequent urination, excessive thirst, nausea, vomiting, and severe abdominal pain all common. More severe ketoacidosis can result in labored breathing, and loss of consciousness due to cerebral edema. People with type 1 diabetes experience diabetic ketoacidosis 1–5 times per 100 person-years, the majority of which result in hospitalization. 13–19% of type 1 diabetes-related deaths are caused by ketoacidosis, making ketoacidosis the leading cause of death in people with type 1 diabetes less than 58 years old. Long-term complications
In addition to the acute complications of diabetes, long-term hyperglycemia results in damage to the small blood vessels throughout the body. This damage tends to manifest particularly in the eyes, nerves, and kidneys causing diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy respectively. In the eyes, prolonged high blood sugar causes the blood vessels in the retina to become fragile.People with type 1 diabetes also have increased risk of cardiovascular disease, which is estimated to shorten the life of the average type 1 diabetic by 8–13 years. Cardiovascular disease as well as neuropathy may have an autoimmune basis, as well.
People with type 1 diabetes tend to have more CD8+ T-cells and B-cells that specifically target islet antigens than those without type 1 diabetes, suggesting a role for the adaptive immune system in beta cell destruction. Type 1 diabetics also tend to have reduced regulatory T cell function, which may exacerbate autoimmunity. Destruction of beta cells results in inflammation of the islet of Langerhans, called insulitis. These inflamed islets tend to contain CD8+ T-cells and – to a lesser extent – CD4+ T cells. Abnormalities in the pancreas or the beta cells themselves may also contribute to beta-cell destruction. The pancreases of people with type 1 diabetes tend to be smaller, lighter, and have abnormal blood vessels, nerve innervations, and extracellular matrix organization. In addition, beta cells from people with type 1 diabetes sometimes overexpress HLA class I molecules (responsible for signaling to the immune system) and have increased endoplasmic reticulum stress and issues with synthesizing and folding new proteins, any of which could contribute to their demise.The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis induced or exacerbated by CD8+ T-cells and macrophages. Necroptosis can be triggered by activated T cells – which secrete toxic granzymes and perforin – or indirectly as a result of reduced blood flow or the generation of reactive oxygen species. As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death.