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
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J. M. Pavia
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M. J. Morris
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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]
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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)