Involvement of neuropeptide Y in glucose sensing in the dorsal hypothalamus of streptozotocin diabetic rats – in vitro and in vivo studies of transmitter release

Diabetologia, Sep 2002

Aims. Within the brain, subgroups of neurons respond differently to altered glucose concentrations. Identification of neuropeptide Y in hypothalamic neurons that sense glucose suggests a role for neuropeptide Y in glucose sensing. Using in vitro and in vivo techniques to monitor transmitter release, we investigated whether lowering glucose concentration affects the release of neuropeptide Y from the brain, and whether this process is altered in Type I (insulin-dependent) diabetes mellitus. Methods. Male Sprague-Dawley rats were treated with 48 mg/kg streptozotocin or vehicle intravenously. The effect of reduced glucose on endogenous neuropeptide Y overflow from slices of hypothalamus and medulla incubated in Krebs solution was examined 4 weeks later. The hypothalamus was separated into a dorsal region containing the paraventricular nucleus and a ventral region containing the arcuate nucleus. Results.Streptozotocin-induced diabetes increased basal neuropeptide Y overflow in the dorsal and ventral hypothalamus (ppp Conclusion. These region-specific effects of low glucose on neuropeptide Y overflow in diabetic rats support a part for neuropeptide Y in altered glucose sensing in Type I diabetes.

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Involvement of neuropeptide Y in glucose sensing in the dorsal hypothalamus of streptozotocin diabetic rats – in vitro and in vivo studies of transmitter release

M. Gozali 0 J. M. Pavia 0 M. J. Morris 0 0 Neuroendocrine Laboratory, Department of Pharmacology, University of Melbourne , Victoria, Australia Aims. Within the brain, subgroups of neurons respond differently to altered glucose concentrations. Identification of neuropeptide Y in hypothalamic neurons that sense glucose suggests a role for neuropeptide Y in glucose sensing. Using in vitro and in vivo techniques to monitor transmitter release, we investigated whether lowering glucose concentration affects the release of neuropeptide Y from the brain, and whether this process is altered in Type I (insulin-dependent) diabetes mellitus. Methods. Male Sprague-Dawley rats were treated with 48 mg/kg streptozotocin or vehicle intravenously. The effect of reduced glucose on endogenous neuropeptide Y overflow from slices of hypothalamus and medulla incubated in Krebs solution was examined 4 weeks later. The hypothalamus was separated into a dorsal region containing the paraventricular nucleus and a ventral region containing the arcuate nucleus. Results. Streptozotocin-induced diabetes increased basal neuropeptide Y overflow in the dorsal and ventral hypothalamus (p<0.05) but not the medulla. In vitro neuropeptide Y overflow was reduced by low glucose in the dorsal hypothalamus in diabetic, but not in control rats. No effect of reduced glucose was observed in the ventral hypothalamus or medulla. In vivo push-pull studies in the paraventricular nucleus also showed greater neuropeptide Y overflow in diabetic rats relative to control rats (p<0.05). Insulininduced hypoglycaemia induced a decrease in neuropeptide Y overflow in diabetic rats, while an increase was observed in control rats (p<0.05). Conclusion. These region-specific effects of low glucose on neuropeptide Y overflow in diabetic rats support a part for neuropeptide Y in altered glucose sensing in Type I diabetes. [Diabetologia (2002) 45:1332-1339] - Long-term maintenance of tight glycaemic control through multiple daily injections or an insulin pump has been shown to be protective against the onset and progression of the long-term complications of Type I (insulin-dependent) diabetes mellitus [1, 2]. However, recurrent hypoglycaemia becomes an inevitable problem in intensive insulin treatment, contributing to diabetes morbidity and mortality [3]. Acute hypoglycaemia causes cognitive dysfunction, without impairing the function of the peripheral nervous system [4], while untreated hypoglycaemia can progressively lead to coma, convulsions and eventually death. The response to insulin-induced hypoglycaemia involves increased plasma concentrations of the counter-regulatory hormones, namely glucagon, adrenaline, cortisol and growth hormones [5]. Hypoglycaemic patients generally have neurogenic and neuroglycopenic symptoms [6]. These symptoms tend to occur at a higher plasma glucose concentration in chronically hyperglycaemic Type I diabetic patients [7]. However, during intensive insulin therapy, specifically after recurrent episodes of hypoglycaemia, a glycaemic threshold shift occurs, and lower plasma glucose concentrations are required to activate the same defence mechanisms [6, 8]. This can result in a clinical syndrome known as hypoglycaemia unawareness, with a loss of warning symptoms. Hypoglycaemia unawareness has been proposed to produce a 25-fold increase in the frequency of severe hypoglycaemia in Type I diabetic patients [9, 10], resulting in initiation of a vicious cycle of hypoglycaemia. Although the distinct mechanisms underlying hypoglycaemia unawareness are still not clear, several hypotheses have been suggested [11, 12]. Various mechanisms could contribute to the loss of warning symptoms, and brain glucose sensing is likely to play a major role in regulating the simultaneous responses to hypoglycaemia and the activation of counter-regulatory responses. Glucose sensing in the central nervous system (CNS) has been associated with the glucose sensing neurons [13]. Clear evidence of abnormalities in central glucose sensing and transport have been shown in Type I diabetes, involving a resetting of the normal homeostatic mechanisms [14], and more recently in diet-induced obesity [15]. Select groups of neurons in the brain respond to moderate changes in blood glucose by altering their firing rate. Glucose-sensitive (GS) neurons decrease their firing rate upon increased glucose concentrations, while glucose-responsive (GR) neurons are those that increase their firing in response to increased glucose concentrations. Since the proposal of glucose sensing neurons in the hypothalamus [16], many studies have investigated this question. Effects of systemic glucose on neurons of the lateral hypothalamus (LH), ventromedial nucleus (VMN), paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus, as well as the nucleus tractus solitarius (NTS) of the brainstem have been reported in several mammalian species, including the cat, rat and mouse [17 (...truncated)


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M. Gozali, J. Pavia, M. Morris. Involvement of neuropeptide Y in glucose sensing in the dorsal hypothalamus of streptozotocin diabetic rats – in vitro and in vivo studies of transmitter release, Diabetologia, 2002, pp. 1332-1339, Volume 45, Issue 9, DOI: 10.1007/s00125-002-0890-x