Abstract
Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic–pituitary–adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.
Highlights
The American Diabetes Association estimates that there are more than 30 million people in the U.S currently living with diabetes
Several studies have examined the effects of central leptin gene therapy using recombinant adenoviral vectors in obese [25,28,29,30,34,35] and normal rodents [26,27,29,36]
One study has used a lentiviral vector for leptin gene transfer, but this was administered centrally to study the effects on Alzheimer’s-like symptoms in presenilin mice [37]
Summary
The American Diabetes Association estimates that there are more than 30 million people in the U.S currently living with diabetes. 1.25 million of these are Type I, or insulin-dependent diabetes mellitus (IDDM) patients. Type I diabetes (T1D) is thought to result from either an autoimmune disorder that results in the destruction of pancreatic beta cells that secrete the hormone insulin or from unknown causes resulting in loss of pancreatic beta cell function [1,2,3]. A number of central changes such as hyperphagia, polydipsia, hyperglycemia and activation of the hypothalamic–pituitary–adrenal (HPA) axis occur in uncontrolled T1D [8,9,10]. Leptin is likely to be involved in the central dysregulation observed in T1D, since leptin levels are markedly reduced in T1D [11,12,13] and leptin regulates neuronal systems that control feeding and HPA function [10,14,15]
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