Developmental expression of glucokinase in rat hypothalamus

Sutherland, Vicki; McReynolds, Matthew R.; Tompkins, Linda S.; Brooks, Heddwen L.; Lynch, Ronald M.

doi:10.1016/j.devbrainres.2004.11.001

Cited by 12 publications

(16 citation statements)

References 27 publications

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“…GK and GKRP have been found in foetal pancreas and liver (Vandercammen & Van Schaftingen 1993;Garcia-Flores et al, 2002). Also in foetal hypothalamus GK mRNA was present in day 18 of development (Sutherland et al, 2005). Our result concluded that GK and GKRP were functionally active before birth in the rat brain.…”

Section: Expression Activity and Localization Of Hypothalamic Gk Andsupporting

confidence: 51%

Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides

Sanz¹,

Roncero²,

Álvarez³

et al. 2011

Update on Mechanisms of Hormone Action - Focus on Metabolism, Growth and Reproduction

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Section: Expression Activity and Localization Of Hypothalamic Gk Andsupporting

confidence: 51%

Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides

Sanz¹,

Roncero²,

Álvarez³

et al. 2011

Update on Mechanisms of Hormone Action - Focus on Metabolism, Growth and Reproduction

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“…Prior studies demonstrated the presence of glucokinase activity (37,38), mRNA (6 -8,39,40), and immunoreactive protein (41) in selective brain areas and in specific glucosensing neurons. Furthermore, pharmacological inhibition of glucokinase activity reduces [Ca 2ϩ ] i oscillations in glucose-excited neurons and increases them in glucose-inhibited neurons (6,7,42), and it decreases the firing rate of glucose-excited neurons (43).…”

Section: Discussionmentioning

confidence: 99%

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

et al. 2006

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To test the hypothesis that glucokinase is a critical regulator of neuronal glucosensing, glucokinase activity was increased, using a glucokinase activator drug, or decreased, using RNA interference combined with calcium imaging in freshly dissociated ventromedial hypothalamic nucleus (VMN) neurons or primary ventromedial hypothalamus (VMH; VMN plus arcuate nucleus) cultures. To assess the validity of our approach, we first showed that glucoseinduced (0.5-2.5 mmol/l) changes in intracellular Ca U nlike most neurons in the brain that utilize glucose to fuel their metabolic needs (1), a select group of neurons use glucose as a signaling molecule to alter their firing rate as a means of glucosensing (2,3). Glucose-excited neurons increase, whereas glucose-inhibited neurons decrease, their firing rate as ambient glucose levels rise (2-7). During situations of low glucose availability, glucose-inhibited neurons are activated and glucose-excited neurons inactivated (4 -8).The ventromedial hypothalamus (VMH) area contains both the ventromedial hypothalamic nucleus (VMN) and arcuate nucleus. Both contain glucosensing neurons that respond to differing levels of glucose and are linked to pathways involved in the regulation of glucose homeostasis (3-11) and the counterregulatory responses to hypoglycemia (12-19). Our work (6,7) and that of others (8) strongly support a role for glucokinase (hexokinase IV) as a key regulator of neuronal glucosensing, which is similar to its purported role in pancreatic ␤-cell glucosensing (20,21). We previously demonstrated that inhibition of glucokinase activity reduced glucose-excited and increased glucose-inhibited neuronal activity at 2.5 mmol/l glucose, the concentration at which they are normally active and inactive, respectively (6,7).Recurrent hypoglycemia is common in patients with type 1 diabetes, especially in children (22)(23)(24)(25). This leads to hypoglycemia-associated autonomic failure, in which counterregulatory responses to subsequent bouts of hypoglycemia are severely blunted (26 -28). Our previous studies suggested that the development of hypoglycemiaassociated autonomic failure might be associated with changes in the ability of VMH neurons to sense and respond to glucose (6,28). Furthermore, its development is associated with upregulation of glucokinase mRNA in the VMH (6,28,29). This upregulation might be a compensatory response that makes glucosensing neurons more sensitive to glucose by shifting their concentration-response to the left. If so, this could underlie the development of hypoglycemia-associated autonomic failure because it would require lower levels of glucose to be reached before counterregulatory responses were initiated. This would predict that increasing glucokinase activity would produce a leftward shift in glucose sensitivity in VMH glucosensing neurons such as it does in pancreatic ␤-cells, using a drug that increases glucokinase activity (30). It would also predict that reducing glucokinase activity would inhibit the response to glucose. Here, we ...

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“…It is worth noting that our inability to reliably measure decreased GK activity, even in the face of 75% reductions in GK mRNA over several days, is likely because the threshold sensitivity of virtually all GK assays is just below the normally low amounts of GK found in the VMH by either mRNA or protein expression (7,9,(23)(24)(25)(26). It is unlikely that the failure to document a decrease in GK activity in the face of large reductions in GK mRNA was due to prolonged stability of GK protein.…”

Section: Discussionmentioning

confidence: 99%

Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia

et al. 2008

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OBJECTIVE-The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS-The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after bilateral VMH injections of 1) a GK activator drug (compound A) to increase VMH GK activity, 2) low-dose alloxan (4 g) to acutely inhibit GK activity, 3) highdose alloxan (24 g), or 4) an adenovirus expressing GK short hairpin RNA (shRNA) to chronically reduce GK expression and activity. RESULTS-CompoundA increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia by 40 -62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to insulin-induced hypoglycemia by 23-50%.CONCLUSIONS-These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulininduced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects. Diabetes 57:1371-1379, 2008 H ypoglycemia is a major complication of insulin therapy for diabetes, and the incidence of hypoglycemia has increased as clinicians have attempted to maintain tighter control of blood glucose levels in diabetic subjects (1). During hypoglycemia, declining glucose levels are detected by peripheral glucosensors and by specialized glucosensing neurons within select areas of the brain (2). A subset of these glucosensing neurons reside in the ventromedial hypothalamus (VMH), a brain area that includes the arcuate hypothalamic nucleus (ARC) and ventromedial hypothalamic nucleus (VMN). Many previous studies have confirmed the importance of the VMH in mediating the counterregulatory response to hypoglycemia (3,4) and suggest that the glucosensing neurons in this area might be critical regulators of these responses.Glucokinase (GK) (hexokinase IV) is a likely candidate as a regulator of glucosensing in VMH neurons (5-10). In vitro, inhibiting GK activity with either RNA interference (RNAi) or with a variety of drugs reduces the sensitivity of VMN glucosensing neurons. On the other hand, pharmacological activation with Compound A increases their sensitivity to glucose (5-8,10). Also, pharmacological inhibition of GK activity with alloxan i...

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Developmental expression of glucokinase in rat hypothalamus

Cited by 12 publications

References 27 publications

Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides

Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

Ventromedial Hypothalamic Glucokinase Is an Important Mediator of the Counterregulatory Response to Insulin-Induced Hypoglycemia

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