with one or two daily doses of long-acting insulin, or by steady infusion of low insulin levels by an insulin pump. the exact dose of insulin appropriate for each injection depends on the content of the meal/snack, and the individual person's sensitivity to insulin, and is therefore typically calculated by the individual with diabetes or a family member by hand or assistive device (calculator, chart, mobile app, etc.). people unable to manage these intensive insulin regimens are sometimes prescribed alternate plans relying on mixtures of rapid- or short-acting and intermediate-acting insulin, which are administered at fixed times along with meals of pre-planned times and carbohydrate composition. a non-insulin medication approved by the u.s. food and drug administration for treating type 1 diabetes is the amylin analog pramlintide, which replaces the beta-cell hormone amylin. addition of pramlintide to mealtime insulin injections reduces the boost in blood sugar after a meal, improving blood sugar control. occasionally, metformin, glp-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, or sglt2 inhibitor are prescribed off-label to people with type 1 diabetes, although fewer than 5% of type 1 diabetics use these drugs. lifestyle besides insulin, the major way type 1 diabetics control their blood sugar is by learning how various foods impact their blood sugar levels. this is primarily done by tracking their intake of carbohydrates – the type of food with the greatest impact on blood sugar. in general, people with type 1 diabetes are advised to follow an individualized eating plan rather than a pre-decided one. there are camps for children to teach them how and when to use or monitor their insulin without parental help. as psychological stress may have a negative effect on diabetes, a number of measures have been recommended including: exercising, taking up a new hobby, or joining a charity, among others. regular exercise is important for maintaining general health, though the effect of exercise on blood sugar can be challenging to predict. exogenous insulin can drive down blood sugar, leaving those with diabetes at risk of hypoglycemia during and immediately after exercise, then again seven to eleven hours after exercise (called the "lag effect"). conversely, high-intensity exercise can result in a shortage of insulin, and consequent hyperglycemia. the risk of hypoglycemia can be managed by beginning exercise when blood sugar is relatively high (above 100 mg/dl), ingesting carbohydrates during or shortly after exercise, and reducing the amount of injected insulin within two hours of the planned exercise. similarly, the risk of exercise-induced hyperglycemia can be managed by avoiding exercise when insulin levels are very low, when blood sugar is extremely high (above 350 mg/dl), or when one feels unwell. transplant in some cases, people can receive transplants of the pancreas or isolated islet cells to restore insulin production and alleviate diabetic symptoms. transplantation of the whole pancreas is rare, due in part to the few available donor organs, and to the need for lifelong immunosuppressive therapy to prevent transplant rejection. the american diabetes association recommends pancreas transplant only in people who also require a kidney transplant, or who struggle to perform regular insulin therapy and experience repeated severe side effects of poor blood sugar control. most pancreas transplants are done simultaneously with a kidney transplant, with both organs from the same donor. the transplanted pancreas continues to function for at least five years in around three quarters of recipients, allowing them to stop taking insulin. transplantations of islets alone have become increasingly common. pancreatic islets are isolated from a donor pancreas, then injected into the recipient's portal vein from which they implant onto the recipient's liver. in nearly half of recipients, the islet transplant continues to work well enough that they still don't need exogenous insulin five years after transplantation. if a transplant fails, recipients can receive subsequent injections of islets from additional donors into the portal vein. like with whole pancreas transplantation, islet transplantation requires lifelong immunosuppression and depends on the limited supply of donor organs; it is therefore similarly limited to people with severe poorly controlled diabetes and those who have had or are scheduled for a kidney transplant. pathogenesis type 1 diabetes is a result of the destruction of pancreatic beta cells, although what triggers that destruction remains unclear. 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. pancreases from people with type 1 diabetes also have signs of beta cell apoptosis, linked to activation of the janus kinase and tyk2 pathways. partial ablation of beta-cell function is enough to cause diabetes; at diagnosis, people with type 1 diabetes often still have detectable beta-cell function. once insulin therapy is started, many people experience a resurgence in beta-cell function, and can go some time with little-to-no insulin treatment – called the "honeymoon phase". this eventually fades as beta-cells continue to be destroyed, and insulin treatment is required again. beta-cell destruction is not always complete, as 30–80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis. alpha cell dysfunction onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon, which acts in antagonism with insulin to regulate blood sugar and metabolism. progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon hypoglycemia prevents a glucagon-mediated rescue of glucose levels. hyperglucagonemia onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%. insulin production will continue to fall as the immune system destroys beta cells, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early stage of the disease, leading to expanded alpha cell mass. this, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia. some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia. leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion. under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies. hypoglycemic glucagon impairment glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted in type 1 diabetics. beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release. autonomic inputs to alpha cells are much more important for glucagon stimulation in the moderate to severe ranges of hypoglycemia, yet the autonomic response is blunted in a number of ways. recurrent hypoglycemia leads to metabolic adjustments in the glucose sensing areas of the brain, shifting the threshold for counter regulatory activation of the sympathetic nervous system to lower glucose concentration. this is known as hypoglycemic unawareness. subsequent hypoglycemia is met with impairment in sending of counter regulatory signals to the islets and adrenal cortex. this accounts for the lack of glucagon stimulation and epinephrine release that would normally stimulate and enhance glucose release and production from the liver, rescuing the diabetic from severe hypoglycemia, coma, and death. numerous hypotheses have been produced in the search for a cellular mechanism of hypoglycemic unawareness, and a consensus has yet to be reached. the major hypotheses are summarized in the following table: mechanisms of hypoglycemic unawareness glycogen supercompensation increased glycogen stores in astrocytes might contribute supplementary glycosyl units for metabolism, counteracting the central nervous system perception of hypoglycemia. enhanced glucose metabolism altered glucose transport and enhanced metabolic efficiency upon recurring hypoglycemia relieves oxidative stress that would activate sympathetic response. alternative fuel hypothesis decreased reliance on glucose, supplementation of lactate from astrocytes, or ketones meet metabolic demands and reduce stress to brain. brain neuronal communication hypothalamic inhibitory gaba normally decreases during hypoglycemia, disinhibiting signals for sympathetic tone. recurrent episodes of hypoglycemia result in increased basal gaba which fails to decrease normally during subsequent hypoglycemia. inhibitory tone remains and sympathetic tone is not increased. in addition, autoimmune diabetes is characterized by a loss of islet specific sympathetic innervation. this loss constitutes an 80–90% reduction of islet sympathetic nerve endings, happens early in the progression of the disease, and is persistent though the life of the patient. it is linked to the autoimmune aspect of type 1 diabetics and fails to occur in type 2 diabetics. early in the autoimmune event, the axon pruning is activated in islet sympathetic nerves. increased bdnf and ros that result from insulitis and beta cell death stimulate the p75 neurotrophin receptor (p75ntr), which acts to prune off axons. axons are normally protected from pruning by activation of tropomyosin receptor kinase a (trk a) receptors by ngf, which in islets is primarily produced by beta cells. progressive autoimmune beta cell destruction, therefore, causes both the activation of pruning factors and the loss of protective factors to the islet sympathetic nerves. this unique form of neuropathy is a hallmark of type 1 diabetes, and plays a part in the loss of glucagon rescue of severe hypoglycemia. complications further information: complications of diabetes the most pressing complication of type 1 diabetes are the always present risks of poor blood sugar control: severe hypoglycemia and diabetic ketoacidosis. hypoglycemia – typically blood sugar below 70 mg/dl – triggers the release of epinephrine, and can cause people to feel shaky, anxious, or irritable. people with hypoglycemia may also experience hunger, nausea, sweats, chills, dizziness, and a fast heartbeat. some feel lightheaded, sleepy, or weak. severe hypoglycemia can develop rapidly, causing confusion, coordination problems, loss of consciousness, and seizure. on average, people with type 1 diabetes experience a hypoglycemia event that requires assistance of another 16–20 times in 100 person-years, and an event leading to unconsciousness or seizure 2–8 times per 100 person-years. the american diabetes association recommends treating hypoglycemia by the "15-15 rule": eat 15 grams of carbohydrates, then wait 15 minutes before checking blood sugar; repeat until blood sugar is at least 70 mg/dl. severe hypoglycemia that impairs someone's ability to eat is typically treated with injectable glucagon, which triggers glucose release from the liver into the bloodstream. people with repeated bouts of hypoglycemia can develop hypoglycemia unawareness, where the blood sugar threshold at which they experience symptoms of hypoglycemia decreases, increasing their risk of severe hypoglycemic events. 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