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`Ventromedial Hypothalamus (VMH) Thioredoxin-1 Overexpression Preserves the Counterregulatory Response to Hypoglycemia and Normal Glucose Sensing by VMH Glucose-Inhibited (GI) Neurons in Rats with Type 1 Diabetes Mellitus (T1DM)"

by
Chunxue Zhou
Pharmacology, Physiology and Neuroscience Program
B.S. 2009, Fudan University, Shanghai, China


Thesis Advisor: Vanessa Routh, Ph.D.
Professor
Department of Pharmacology, Physiology and Neuroscience

Friday, June 16, 2017
11:00 A.M., MSB E609


Abstract

All patients with type 1 and many with advanced type 2 diabetes mellitus (T1DM and T2DM, respectively) require intensive insulin therapy to prevent long-term consequences of hyperglycemia. However, hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the ability of the brain to sense subsequent hypoglycemia and generate the autonomic and neuroendocrine counterregulatory responses (CRR) that normally restore euglycemia. This condition is known as hypoglycemia associated autonomic failure (HAAF). Within the brain the ventromedial hypothalamus (VMH) plays a key role in the detection of hypoglycemia and CRR initiation. Glucose sensing neurons within the VMH are likely candidates for sensing and responding to hypoglycemia. This project focused exclusively on glucose-inhibited (GI) neurons in the VMH and their role in the CRR and HAAF.

We have previously shown that RH impairs activation of VMH GI neurons in low glucose. This was associated with increased VMH oxidative stress and s-nitrosation of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC). S-nitrosation of sGC renders it insensitive to NO and impairs activation of VMH GI neurons by low glucose. In non-diabetic control rats HAAF, VMH sGC s-nitrosation and the blunted activation of VMH GI neurons in low glucose was prevented by systemic supplementation with the glutathione precursor n-acetylcysteine (NAC). Unfortunately, we found that NAC did not restore normal glucose sensing by VMH GI neurons when RH occurred during diabetes. We then tested the hypothesis that VMH overexpression of another antioxidant, thioredoxin 1 (Trx-1), preserves normal glucose sensing and the CRR in diabetic rats before and after RH. We found that inhibition of VMH Trx reductase, the enzyme which regenerates reduced Trx, decreased glycemia recovery in response to insulin induced hypoglycemia and the activation of VMH GI neurons in low glucose. In addition, VMH Trx activity was lower in rats with streptozotocin (STZ)-induced T1DM compared to that of non-diabetic controls. Interestingly, VMH Trx-1 overexpression slowed the induction of diabetes by STZ and lowered the insulin requirements to prevent severe hyperglycemia in STZ rats. More importantly, VMH Trx-1 overexpression completely restored the CRR and the activation of VMH GI neurons by low glucose in STZ rats. However, VMH Trx-1 overexpression was not effective when RH occurred during diabetes. Our data suggest that increasing both the GSH and Trx antioxidant defenses in VMH may be necessary to fully restore the CRR and activation of VMH GI neurons by low glucose when RH occurs during diabetes. Thus, VMH antioxidant defense is a promising therapeutic target for preventing HAAF in diabetic patients undergoing intensive insulin therapy.


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