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"Recurrent Hypoglycemia and Type 1 Diabetes Mellitus Independently Blunt Adrenal Epinephrine Release"

by
Branly O. Orban
Pharmacology & Physiology Program
M.S., Stevens Institute of Technology, New Jersey
B.S., Montclair State University, New Jersey


Thesis Advisors: Joshua R. Berlin, Ph.D. & Vanessa H. Routh, Ph.D.
Professors
Department of Pharmacology & Physiology

Friday, December 21, 2012
1:00 P.M., MSB Room H-609


Abstract

With the loss of glucose-dependent regulation of insulin and glucagon release in type 1 diabetes mellitus (T1DM), other hormones, such as the catecholamine, epinephrine (EPI), become more important in controlling plasma glucose levels. EPI is released during insulin-induced hypoglycemia in T1DM patients. Under these conditions, EPI produces tremors, anxiety, increased heart rate and blood pressure in the midst of hypoglycemia, resulting in hypoglycemia awareness. However, the EPI response to hypoglycemia is blunted in T1DM and even more so in patients under aggressive insulin therapy who experience recurrent hypoglycemia (RH). This blunted response makes T1DM patients prone to hypoglycemia unawareness and at risk of progressing to convulsions, coma and even death when treated with insulin. The mechanisms underlying the blunting of the EPI response in T1DM are not fully understood.
Since circulating EPI is synthesized in and released from the adrenal medulla (AM), we asked whether T1DM and RH directly affect adrenomedullary regulation of catecholamine release. Using a perfused gland preparation in the rat, we found that both adrenal EPI levels and release evoked by acetylcholine (Ach) were unchanged in non-diabetic rats that had depressed in vivo responses to insulin-induced hypoglycemia following RH. However, RH reduced in vivo adrenal EPI release evoked by electrical stimulation of the adrenal nerve. These findings are consistent with decreased synaptic activation of adrenal EPI release.
We also found that adrenal EPI content and release produced by Ach were unchanged in rats made diabetic with streptozocin (STZ) after eight weeks of uncontrolled hyperglycemia. On the other hand, adrenal EPI content and release evoked by Ach were reduced in spontaneously diabetic rats after eight weeks of poorly controlled hyperglycemia. Hypoinsulinemia and hyperglycemia were common to both STZ and spontaneously diabetic rats. Therefore, our conclusion is that neither of these conditions directly affects adrenomedullary function. Since the principal difference between these two models of T1DM is that spontaneous diabetes develops in an autoimmune-dependent manner, we infer that the observed reduction in adrenal EPI content and release are due to an autoimmune mechanism.
Together, these results suggest that T1DM and RH may alter adrenal EPI release by different mechanisms. Compromised adrenomedullary function resulting from T1DM and/or RH may contribute to the blunted EPI response to hypoglycemia observed in T1DM patients under aggressive insulin therapy


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