situation. To improve hypoglycemia treatment, many companies are developing more efficient glucagon delivery solutions. Xeris Pharmaceuticals, Inc. is developing the Glucagon Rescue Pen or G-Pen using a patented non-aqueous formulation of glucagon that is room-temperature stable, low-volume, and pre-mixed in an auto-injectable device (similar to an EpiPen) that takes the injection process down to two steps (as opposed to nine steps with glucagon emergency kits currently on the market). Similarly, GlucaPen, an autoinjector in development by Enject, Inc. promises to simplify the delivery of glucagon. Unawareness Although one expects hypoglycemic episodes to be accompanied by the typical symptoms (e.g., tremor, sweating, palpitations, etc.), this is not always the case. When hypoglycemia occurs in the absence of such symptoms it is called hypoglycemic unawareness. Especially in people with long-standing type 1 diabetes and those who attempt to maintain glucose levels which are closer to normal, hypoglycemic unawareness is common. In patients with type 1 diabetes mellitus, as plasma glucose levels fall, insulin levels do not decrease – they are simply a passive reflection of the absorption of exogenous insulin. Also, glucagon levels do not increase. Therefore, the first and second defenses against hypoglycemia are already lost in established type 1 diabetes mellitus. Further, the epinephrine response is typically attenuated, i.e., the glycemic threshold for the epinephrine response is shifted to lower plasma glucose concentrations, which can be aggravated by previous incidents of hypoglycemia. The following factors contribute to hypoglycemic unawareness: There may be autonomic neuropathy The brain may have become desensitized to hypoglycemia The person may be using medicines which mask the hypoglycemic symptoms Autonomic neuropathy During hypoglycemia, the body normally releases epinephrine [more commonly known as adrenalin] and related substances. This serves two purposes: The β-effect of epinephrine is responsible for the palpitations and tremors, giving the patient warning that hypoglycemia is present. The β-effect of epinephrine also stimulates the liver to release glucose (gluconeogenesis and glycogenolysis). In other words, the epinephrine warns the patient that hypoglycemia is present and signals the liver to release glucose to reverse it. In the absence of epinephrine release, or when it is attenuated (reduced) during hypoglycemia, the patient may not be aware that his/her glucose level is low. This is termed 'hypoglycemic unawareness'. The problem is compounded since, in the absence of an appropriate epinephrine response, the usual responses of glycogenolysis and gluconeogenesis may also be lost or blunted. Since epinephrine release is