Mechanisms Responsible for Hypoglycemia Associated Autonomic Failure (HAAF)

Purpose
Many studies have demonstrated that when people with diabetes are intensively treated with insulin in order to maintain their glucose within the normal range, all the complications of diabetes can be prevented or delayed. However, such treatment carries a significant risk of severe hypoglycemia (excessively low blood glucose levels), which may be life-threatening. Thus, ideal treatment with insulin in patients with diabetes can be seen as a double-edged sword: intensive treatment will delay the complications but is also associated with an increased risk of disabling hypoglycemia. In normal conditions, when hypoglycemia occurs, the body responds by secreting a variety of hormones and by activating the autonomous nervous system which ultimately will result in increasing the blood glucose to normal levels. Patients with diabetes, lose this capacity to effectively respond to hypoglycemia and become more susceptible to a fall in plasma glucose. Paradoxically, repeated episodes of hypoglycemia—especially in the most vulnerable persons with type 1 who need insulin for life--induce a metabolic deterioration that further increases the risk of developing hypoglycemia.

Our proposal focuses on understanding the mechanisms the body uses in order to respond to hypoglycemia and on potential tools (medicines) that may be used in order to prevent this metabolic deterioration associated with repeated episodes of hypoglycemia.

Based on previous data generated in our laboratory (and others), we propose that repeated episodes of hypoglycemia are associated with a deterioration in the "body sensor" for hypoglycemia in diabetes. Moreover, since many studies have shown that such deterioration in the response to hypoglycemia can be induced also by exercise (patients with diabetes are at greater risk for hypoglycemia after exercise), we propose that exercise (and other stresses) affect the hypoglycemia response by endorphin release (endorphins are proteins responsible for inhibition of the neuroendocrine response system).

Developing a method that will decrease the incidence of severe hypoglycemia will result in safer control of blood glucose, a decrease in the complications of diabetes, and ultimately in a better quality and longer life for many patients with diabetes.

Study Type: Interventional
Study Design: Control: Placebo Control
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Mechanisms of Hypoglycemia Associated Autonomic Failure

Estimated Enrollment: 116
Study Start Date: March 2008
Estimated Study Completion Date: January 2013
Estimated Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)

Detailed Description:
Severe hypoglycemia (SH) is the major limitation of intensive insulin treatment in type 1 diabetes (T1DM), and the near-term prospects for perfected insulin therapy without this risk are dim. Intensively treated T1DM patients suffer from impaired counterregulation of hypoglycemia (HYPO)—ie, HYPO-Associated Autonomic Failure (HAAF) and HYPO unawareness (HU)—which enhance their susceptibility to SH. The precise mechanisms of HAAF and HU, however, have not been clarified, though multiple redundant control systems are implicated. Experimental HYPO and exercise in normal and T1DM subjects reproduce HAAF and HU, providing a robust experimental paradigm of these disorders. We have shown that fructose, infused in a catalytic dose for modulating glucokinase activity, results in augmentation of the counterregulatory responses to HYPO in nondiabetic and in T1DM individuals. We hypothesize that an equivalent infusion of fructose will prevent HAAF in nondiabetic and in T1DM persons. Furthermore, since both HYPO and exercise are associated with endogenous opioid (EO) release, and blocking EO improves HYPO counterregulation, we hypothesize that repeated HYPO episodes induce alterations in the modulatory effects of EO on hormonal and glucose counterregulation, ultimately leading to HAAF. We also propose that HYPO autoregulation, and hepatic glycogen metabolism play important roles in the development of HAAF and HU. The specific aims are: 1) to determine the effects of previous modulation of glucokinase activity on the counterregulatory hormonal and glucose recovery responses to subsequent HYPO in nondiabetic and T1DM subjects, 2) to examine the effects of blocking the inhibitory action of endorphins on the central neuroendocrine response system (with naloxone), during recurrent HYPO or exercise, on subsequent HYPO counterregulatory responses in nondiabetic and T1DM subjects, 3) to analyze the effects of recurrent mild HYPO (autoregulation), on subsequent HYPO counterregulation in nondiabetic and in T1DM subjects, and 4) to determine the effects of recurrent HYPO on hepatic glycogen content in nondiabetic and T1DM subjects, and the effects of normalization of liver glycogen content, by means of insulin and glucose administration, on experimental HAAF in T1DM subjects.

Eligibility
Ages Eligible for Study: 19 Years to 64 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: Yes

Criteria
Inclusion Criteria:

• Non-diabetic individuals
• Patients with type 1 diabetes mellitus

Exclusion Criteria:

• Pregnant or planning to get pregnant women
• Breast-feeding women
• Children
• Subjects taking pain killers or drug addicts