Counterregulatory Hormones

Hormones that work against the action of insulin, raising blood glucose levels in response to hypoglycemia (low blood sugar). The main counterregulatory hormones are glucagon, epinephrine (also known as adrenaline), cortisol, and growth hormone.

People who don’t have diabetes have a number of defense mechanisms against hypoglycemia. First, the pancreas decreases its insulin output, allowing blood glucose to rise. Second, the alpha cells of the pancreas secrete the counterregulatory hormone glucagon, which signals the liver to release more glucose. Third, the adrenal glands secrete epinephrine, which signals the liver and kidneys to produce more glucose; in addition, epinephrine keeps certain body tissues, such as muscle, from using as much glucose from the bloodstream, and it acts to reduce insulin secretion. Epinephrine is the same “fight or flight” hormone that revs the body up in response to danger, and it produces the symptoms that normally herald an episode of hypoglycemia, such as hunger, sweating, trembling, “butterflies,” and heart palpitations. In some cases, especially when glucagon and epinephrine fail to adequately raise blood glucose levels, the body releases cortisol and growth hormone, which can also increase blood glucose levels.


After years of having Type 1 diabetes, many individuals lose most of these defenses against hypoglycemia. To begin with, they are not able to benefit from reduced secretion of insulin by the pancreas; the reason why people with Type 1 diabetes must use injected or infused insulin is that the pancreas no longer makes insulin at all. Also, for reasons unknown, people with Type 1 diabetes usually lose their ability to secrete glucagon. In addition, after recurring episodes of even mild hypoglycemia, the epinephrine response gets blunted — in other words, blood sugar must drop lower before epinephrine gets secreted.

Individuals with such problems are said to have defective glucose counterregulation, and they are extremely prone to bouts of severe hypoglycemia. (Counterregulation problems may also develop in people with Type 2 diabetes, particularly those taking insulin, but they tend to be less common and less severe.) Besides contributing to the development of hypoglycemia, a deficient epinephrine response leads to hypoglycemia unawareness. Because the early warning signs usually triggered by epinephrine fail to appear, a person with such a deficiency who experiences hypoglycemia may not become aware of the marked drop in blood sugar levels in time to take corrective steps.

There is evidence that scrupulously avoiding even mild hypoglycemia for a few weeks may help to improve the epinephrine response. People experiencing frequent or severe episodes of hypoglycemia should contact their diabetes health-care team.