Beyond Insulin: What Should You Know?

BeyondInsulin

When most people with type 1 diabetes (T1D) think about hormones, insulin is usually the first one that comes to mind—people with T1D use it daily to survive. But it takes more than just insulin to regulate blood-glucose levels. Hormones act as chemical messengers in the human body—they are released by a cell, organ, or gland into the bloodstream to control the activity of certain cells or organs. Those that aid in metabolism and digestion play a key role in blood-glucose maintenance. Insulin may be the popular hormone on the block, but there are several unsung heroes of blood-glucose control that are crucial to the human body—and especially in people with T1D.

Glucose control is a delicate (and often confusing) dance between hormones produced by the pancreas, small intestine (or “gut”), and even fat cells. Hence, a vital focus for JDRF is developing better treatments that “reset” the missing hormonal balance, and thus transform the way people with T1D treat the disease today to help them live healthier lives now and in the future. For instance, JDRF-funded scientists are in the beginning stages of development of a glucose-responsive insulin (GRI) that would work only when the body needs it. GRI would deliver the precise amount of insulin in response to circulating glucose levels to control and maintain normal blood-glucose levels throughout a daily routine with once-daily or less frequent dosing.

Here are a few important hormones you should be aware of, and how JDRF is funding research using  them to provide improvements in T1D treatment:

Amylin

Amylin is a hormone produced by the same cells in the pancreas that make insulin, the beta cells. And like insulin, amylin is absent in people with T1D. Amylin is made at the same time as insulin and complements its function to maintain blood-glucose levels—it controls the rate of glucose entering the bloodstream after a meal. Amylin also determines how fast nutrients are delivered from the stomach to the small intestine for absorption, which in turn influences the “feeling of fullness” and leads to reduction of appetite.

Pramlintide (Symlin)

Pramlintide is a synthetic hormone engineered to closely resemble amylin. Pramlintide is sold under the brand name Symlin and was approved for use in adults with both T1D and type 2 diabetes (T2D). Symlin is injected before a meal and works just like amylin in the bloodstream—it slows the movement of food through the gut to curb the sharp increase in blood glucose that occurs after a meal. It also allows people with T1D to use less insulin, lowers average blood-glucose levels, and reduces the risk of hyperglycemia after meals.

Glucagon

Most people with T1D are familiar with glucagon, which is important for maintaining optimal blood-glucose balance between meals. This naturally occurring hormone is made by the alpha cells in the pancreas and triggers the release of additional glucose into the bloodstream when needed. When people eat a meal, their glucagon levels are suppressed because the body will take up sugar from the meal that was just eaten. Conversely, glucagon levels rise during fasting to maintain normal blood sugar levels. Simply put, glucagon works oppositely to insulin—it increases blood glucose by stimulating its production by the liver. Unfortunately, glucagon function is dysregulated in people with T1D, thus exacerbating the surges in high and low blood glucoses regardless of the fed-fasted states.

People with T1D often carry a glucagon kit in case of severe hypoglycemia (low blood glucose) emergencies. Glucagon raises the body’s blood glucose when a person with T1D is unable to swallow liquid or food due to unconsciousness or seizure activity. A glucagon kit contains a vial of powdered glucagon and a syringe filled with liquid. The two are mixed and then injected.

Incretin hormones

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells after eating, even before blood-glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream and may directly reduce food intake. As expected, they also inhibit glucagon release from the pancreas. The two main candidate molecules that fulfill criteria for an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Both GLP-1 and GIP are rapidly inactivated in the bloodstream.

When food is consumed, the concentration of glucose rises and triggers incretin secretion. But in people with T1D, GLP-1 cannot work properly because insulin and amylin are missing. GLP-1 helps to lower blood glucose and contributes to blood-glucose control, limiting high blood-sugar levels without increasing the risk of hypoglycemia.

Leptin

Leptin is a hormone produced by fat cells that helps to regulate body weight. It is known as the “hunger hormone” because it signals to the brain that the body has had enough to eat, producing that post-meal “full” feeling. Leptin also controls the levels of several lipids in the blood stream, such as fatty acids, triglycerides, and cholesterol. In recent animal studies in models of T1D, leptin has been shown to influence glucose metabolism beneficially.

How they work together

Obtaining ideal blood-glucose control is a highly orchestrated process involving many hormones produced by the pancreas, fat cells, and the gut. Insulin therapy has been an important step toward restoring blood-glucose regulation, but it is only part of the ultimate solution. Here are just a few examples of how JDRF is working to optimize blood-glucose control by researching and developing drugs and hormones that will partner with insulin to provide even better treatments for people with T1D:

  • A research collaboration between JDRF and Amylin Pharmaceuticals (now acquired by Bristol-Myers Squibb) is testing the feasibility of mixing insulin with pramlintide to treat T1D. Successfully combining the two hormones mimics the natural co-secretion of these hormones by the beta cells, and thus may allow people to better regulate blood-glucose levels compared to insulin alone. Some T1D individuals currently administer insulin and pramlintide separately, so combining the two into a single dose offers a more convenient treatment option.
  • Adding a synthetic version of leptin known as metreleptin to T1D treatment might allow a reduction in insulin dose and lower the risk of high and low blood-glucose levels. A small, pilot clinical trial funded by JDRF and Amylin Pharmaceuticals aims to test whether a combination of insulin and metreleptin can improve blood-glucose control and regulate blood-lipid (including cholesterol) levels in people with T1D, as was seen in animal studies.
  • Several animal and a few human studies have shown that GLP-1-like hormonal drugs can elicit better blood-glucose control when added to insulin treatment. There are several approved incretin drugs used to treat T2D. JDRF is supporting clinical studies in various academic hospitals to test whether the addition of an incretin to insulin therapy has any advantages, as well as identify the group of T1D individuals that are most likely to benefit from such novel treatment options.
  • The current synthetic version of glucagon that is a staple of many emergency kits is packaged as a dry, powdered form to ensure stability and shelf life. It also cannot be kept for long periods of time in a pump, making the need for a liquid form of glucagon a top priority for researchers. Now, JDRF-funded scientists at Oregon Health & Science University and Legacy Health, a nonprofit hospital system in Portland, OR, are exploring such a formulation. Their work may not only make glucagon usable in standard diabetes pumps, but may also enable the operation of next-generation pumps that deliver both insulin and glucagon.

Bottom line is that JDRF is exploring possibilities to improve the treatment and lives of people with T1D, and reduce the burden of managing this challenging disease and its complications. It can seem like “information overload” when learning that there is more to blood-glucose control than insulin. We hope that this article, and its companion piece, All About Insulin, will help expand your knowledge about T1D management and ongoing research supported by JDRF.