Editor’s Note: This is the eighth post in our miniseries about diabetes drugs. Tune in on October 2 for the next installment.
Many people do not think of the brain when considering the causes of or treatments for diabetes. So it may be surprising to learn that the drug we are discussing today works by activating brain cells.
The pancreas creates many hormones besides insulin, including a hormone called amylin. Amylin is a protein that is secreted along with insulin from pancreatic beta cells in response to a meal. In people without diabetes, the blood levels of amylin rise and fall along with insulin levels, but in people with Type 2 diabetes, amylin levels are reduced, and in people with Type 1 diabetes, amylin levels are almost undetectable.
Amylin acts in a very different manner from insulin to reduce blood glucose, activating a certain area in the brain called the area postrema. The brain normally is protected from chemicals or hormones in the blood by a barrier in the blood vessels called the “blood–brain” barrier. However, the area postrema is outside the “blood-brain” barrier and therefore is exposed to any hormones that are present in the blood.
The result of amylin activating this area of the brain is the slowing of stomach emptying, the suppression of glucagon (a hormone that raises blood glucose levels) secretion, and the suppression of appetite. When rats are given a chemical that interferes with amylin’s activation of the area postrema, they have higher after-meal blood glucose levels, their stomachs empty more quickly, they eat more, and they gain fat. This strongly suggests that amylin works to suppress the introduction of glucose into the blood by reducing stomach emptying and appetite, and indicates that the relative absence of this hormone in people with diabetes may contribute to altered glucose levels and, potentially, obesity.
While giving amylin directly to people with diabetes would seem like an ideal solution, the problem is that the hormone is difficult to make in a stable formulation for injection. Researchers have solved this problem by modifying the amino acid structure of the hormone, producing a synthetic version of amylin that works as well as amylin itself. This modified amylin protein is called pramlintide (brand name Symlin) and is approved for use in combination with insulin therapy for people with either Type 1 or Type 2 diabetes.
Pramlintide is administered via a pen-injector device. The drug has been studied in clinical trials lasting from roughly four months to one year in both those with Type 1 and with Type 2 diabetes in combination with insulin and, in certain studies, sulfonylureas or metformin. The reduction in HbA1c (an indicator of blood glucose control over the previous 2–3 months) seen with this drug is roughly 0.3% to 0.4%. People taking pramlintide in clinical studies have also experienced a weight loss of approximately 4 pounds, as well as small reductions in their insulin doses.
Side effects do occur with the use of pramlintide, with the most potentially serious being hypoglycemia (low blood glucose). Pramlintide by itself does not cause hypoglycemia, but when given with insulin, it can cause severe hypoglycemia. In clinical studies, this often occurs when pramlintide is first started. The risk of hypoglycemia appears to be reduced over time and by reducing the dose of insulin when a person is first starting pramlintide. Other side effects that commonly occur with the use of this medicine are nausea, headache, vomiting, loss of appetite, and abdominal pain.
In people with Type 2 diabetes, the initial dose of pramlintide is typically 60 micrograms administered immediately before meals. (The usual insulin dose should be decreased by a doctor when a person is first starting pramlintide.) The pramlintide dose can be raised to 120 micrograms if a person has tolerated the 60-microgram dose for a week. In people with Type 1 diabetes, the initial dose is generally 15 micrograms, which is usually raised in 15-microgram increments to a maintenance dose of 30 or 60 micrograms.
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