| City: |
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Bronx |
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State:
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NY |
| Zip Code: |
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10461 |
| Conditions: |
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Diabetes Mellitus - Hypoglycemia - Autonomic Failure |
| Purpose: |
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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.
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| Study summary: |
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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. |
| Criteria: |
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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 |
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| Study is available at: |
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Albert Einstein College of Medicine / General Clinical Research Center
Bronx, NY 10461
United States
Primary Contact:
Cynthia Rivera
Email: carivera@aecom.yu.edu
Phone: 718-430-8670 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 22, 2011 |
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