The purpose of this project is to gather preliminary data on cholinergic control of insulin release in our population of women with a history of gestational diabetes (GDM) [and the attendant predisposition to develop NIDDM]. We have previously shown that the first phase insulin release in these women is not enhanced by alpha adrenergic blockade (using Dibenzyline). Older literature, however, has documented a significant enhancement of first phase release using phentolamine for alpha adrenergic blockade. We suggest that phentolamine has cholinergic effects [as well as alpha adrenergic antagonism] and that these effects may be the over-riding influence in those studies. We plan to replicate the reported effect of phentolamine (enhanced early insulin response to IV glucose) in these women, and then demonstrate that this effect is, contrary to previous thought, cholinergic in nature. The primary outcome variable is first phase insulin release. METHODS: We will use a with-in subjects, repeated measures design, studying 6-8 women with a history of gestational diabetes. Each will undergo a one-hour IVGTT on each of 3 consecutive days--baseline control, phentolamine IVGTT, phentolamine/atropine IVGTT. Studies will be conducted in the first 14 days of the menstrual cycle to control for hormonal effects on glucose regulation and subjects will be those previously completing the alpha adrenergic blockade study. IVGTT with drug combination will be conducted in the Clinical Electrophysiology Lab at Duke Hospital North, in collaboration with J. Marcus Wharton, M.D. During each IVGTT, women will receive an IV infusion. For baseline testing, this will consist of normal saline. For the phentolamine IVGTT, subjects will receive phentolamine, 5.0 mg bolus IV followed by 0.5 mg/minute. For the combined drug IVGTT, subjects will receive the identical phentolamine dosing, but with the addition of atropine, .035mg/kg body weight IV bolus given 10 minutes prior to glucose injection. PLANS: This project has been on hold since spring of 1996 due to the unavailability of phentolamine. The manufacturer has estimated that it will again become available early this year (1997). We intend to complete at least one more gestational [history] subject and 4-5 parous controls. With the first data (on 5 gestationals), it has become clear that data on normals is essential to interpret these preliminary findings. This project data set will presumably be used to develop a proposal to more fully study cholinergic influence on glucose regulation. SIGNIFICANCE: Any proven difference in the autonomic regulation of glucose metabolism in high risk individuals is potentially significant in that it may lead to interventions to cancel or delay the onset of NIDDM.
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| Barroso, Julie; Leserman, Jane; Harmon, James L et al. (2015) Fatigue in HIV-Infected People: A Three-Year Observational Study. J Pain Symptom Manage 50:69-79 |
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