Effect of Fasting on Insulin-induced Hypoglycemia Counterregulation in Healthy Humans
Condition: Hypoglycemia
MeSH terms: Hypoglycemia
Study type: Interventional

Summary: 
      Iatrogenic hypoglycemia is still considered to be the number one barrier to effective
      glycemic control in patients with type 1 diabetes (T1D). In a previous study, we observed in
      dogs that liver glycogen content can be a determinant of hormonal and hepatic responses to
      insulin-induced hypoglycemia. In the experiments described herein, we will determine if
      nutritionally-manipulated changes in liver glycogen concentrations have an impact on
      hypoglycemic counterregulation in non-T1D control subjects.
    

Detailed description: 
      Because patients with type 1 diabetes (T1D) are required to estimate and administer their own
      insulin requirements, they frequently overestimate their needs. This often leads to
      debilitating insulin-induced hypoglycemia, which is the number one barrier to the safe,
      effective management of glycemia in this population. In addition to the difficulty estimating
      one's own insulin requirements after a meal, counterregulatory hormone responses to
      hypoglycemia are impaired in patients with T1D, thereby reducing hepatic glucose production
      (HGP) and increasing the depth and duration of the hypoglycemic episode.

      The discovery of ways by which counterregulatory responses to hypoglycemia can be improved is
      a priority. In previous experiments in the dog, we observed that experimentally decreasing
      liver glycogen content (using a 4-hour infusion of glucagon into the hepatic portal vein)
      reduces counterregulatory hormone secretion during insulin-induced hypoglycemia, thereby
      reducing hepatic glucose production (HGP). Interestingly, people with T1D have low fasting
      hepatic glycogen concentrations and the accretion of the sugar in the liver throughout the
      day is also diminished. Therefore, it is of great interest to understand the relationship
      between fasting, which would lower liver glycogen levels compared to normal caloric intake,
      and the counterregulatory responses to insulin-induced hypoglycemia. Furthermore, the
      translational significance of the investigator's previous findings is also of great
      importance. To these ends, the studies proposed herein will determine the effect of fasting
      on hypoglycemic counterregulation in healthy, non-T1D subjects. We hypothesize that fasting
      will diminish the hormonal and hepatic responses to insulin-induced hypoglycemia.

      Each subject will undergo two trials; one where they eat an isocaloric breakfast and lunch
      prior to an insulin-induced hypoglycemic challenge and a second one during which they remain
      fasted prior to the hypoglycemic challenge. This study design will allow us to assess the
      relationship between fasting and the counterregulatory responses to insulin-induced
      hypoglycemia. For these preliminary studies, only healthy subjects will be studied, thereby
      reducing their complexity (e.g., no overnight inpatient visits or the need to adjust insulin
      doses during the feeding periods). Upon completion, we intend to study the more metabolically
      vulnerable T1D patients.
    

Intervention name(s): Fasting; Feeding
Intervention type(s): Other; Other
Intervention description(s): Subjects remain fasted prior to insulin-induced hypoglycemia.; Subjects eat a normal breakfast and lunch prior to insulin-induced hypoglycemia.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Two subjects will undergo two metabolic studies, one after having remained fasted and one after having eaten breakfast and lunch.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: glucagon; hepatic glucose production; liver glycogen