Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: Prevalence and risk factors

Beregszàszi, Màrta; Tubiana‐Rufi, N.; Bénali, Karim; Noël, Michèle; Bloch, Juliette; Czernichow, P

doi:10.1016/s0022-3476(97)70121-5

Cited by 111 publications

(86 citation statements)

References 18 publications

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“…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).…”

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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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confidence: 99%

“…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).…”

mentioning

confidence: 99%

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

et al. 2006

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“…These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR. glucokinase; counterregulatory response; hypoglycemia-associated autonomic failure; calcium imaging; arcuate nucleus; ventromedial nucleus; ventromedial hypothalamus RECURRENT BOUTS of insulin-induced hypoglycemia (IIH) are common in patients with type 1 diabetes mellitus, especially children (3,4,23,43). Such recurrent bouts lead to severe dampening of the hormonal counterregulatory and adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia, a component of the clinical syndrome known as hypoglycemiaassociated autonomic failure (2, 13, 53).…”

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confidence: 99%

“…Our work (15,21,22), as well as that of others (60), strongly supports a role for GK as a key regulator of glucosensing in some neurons, similar to glucosensing in pancreatic ␤-cells (19, 31). Because a blunted AMR and increased VMH GK mRNA expression occur simultaneously 48 h, but not 24 h, after a single bout of IIH in adult, nondiabetic rats (15, 53), we postulated that increased GK activity in hypothalamic glucosensing neurons might make them more responsive to low glucose levels and underlie the reduced AMR in response to subsequent bouts of IIH.Since type 1 diabetes mellitus is common in children and tight regulation of blood glucose levels in these children is associated with a reduced AMR to IIH (3,4,20), we developed a model of an attenuated AMR following recurrent IIH in juvenile rats to investigate potential mechanisms underlying this phenomenon. We used 4-to 5-wk-old rats to assess the timing of the blunted AMR, as well as changes in VMH expression of GK mRNA and the responsiveness of VMN and ARC glucosensing neurons to glucose, which might accomAddress for reprint requests and other correspondence: B. E. Levin, Neurology Service (127C),…”

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Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Lee¹,

Sanders²,

Dunn-Meynell³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Kang L, Sanders NM, Dunn-Meynell AA, Gaspers LD, Routh VH, Thomas AP, Levin BE. Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. Am J Physiol Regul Integr Comp Physiol 294: R784-R792, 2008. First published December 19, 2007 doi:10.1152/ajpregu.00645.2007.-Antecedent insulin-induced hypoglycemia (IIH) reduces adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia. The ventromedial hypothalamus [VMH: arcuate (ARC) ϩ ventromedial nuclei] contains glucosensing neurons, which are thought to be mediators of these AMR. Since type 1 diabetes mellitus often begins in childhood, we used juvenile (4-to 5-wk-old) rats to demonstrate that a single bout of IIH (5 U/kg sc) reduced plasma glucose by 24% and peak epinephrine by 59% 1 day later. This dampened AMR was associated with 46% higher mRNA for VMH glucokinase, a key mediator of neuronal glucosensing. Compared with neurons from saline-injected rats, ventromedial nucleus glucose-excited neurons from insulin-injected rats demonstrated a leftward shift in their glucose responsiveness (EC50 ϭ 0.45 and 0.10 mmol/l for saline and insulin, respectively, P ϭ 0.05) and a 31% higher maximal activation by glucose (P ϭ 0.05), although this maximum occurred at a higher glucose concentration (saline, 0.7 vs. insulin, 1.5 mmol/l). Although EC50 values did not differ, ARC glucose-excited neurons had 19% higher maximal activation, which occurred at a lower glucose concentration in insulin-than salineinjected rats (saline, 2.5 vs. insulin, 1.5 mmol/l). In addition, ARC glucose-inhibited neurons from insulin-injected rats were maximally inhibited at a fivefold lower glucose concentration (saline, 2.5 vs. insulin, 0.5 mmol/l), although this inhibition declined at Ͼ0.5 mmol/l glucose. These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR. glucokinase; counterregulatory response; hypoglycemia-associated autonomic failure; calcium imaging; arcuate nucleus; ventromedial nucleus; ventromedial hypothalamus RECURRENT BOUTS of insulin-induced hypoglycemia (IIH) are common in patients with type 1 diabetes mellitus, especially children (3,4,23,43). Such recurrent bouts lead to severe dampening of the hormonal counterregulatory and adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia, a component of the clinical syndrome known as hypoglycemiaassociated autonomic failure (2, 13, 53). In nondiabetic adult rats, we showed that a single bout of hypoglycemia results in impairment of AMR, in association with upregulation of glucokinase (GK) mRNA expression in the ventromedial hypothalamus (VMH) (15, 53). This hypothalamic area, which includes the arcuate (ARC) and ventromedial nuclei (VMN), contains glucosensing neurons, which we postulate to be critical elements in the detection of and response to hypoglycemia (8,22,25,38,48,60). In contrast to most neurons in the brain, which utilize glu...

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“…Regular insulin given premeal has a slower onset and more prolonged action than endogenous insulin secretion. Consequently, the combination of conventional human insulins results in high postprandial blood glucose excursions and risk of hypoglycemia between meals and overnight (10,11).…”

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Randomized Cross-Over Trial of Insulin Glargine Plus Lispro or NPH Insulin Plus Regular Human Insulin in Adolescents With Type 1 Diabetes on Intensive Insulin Regimens

et al. 2003

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OBJECTIVE—To compare blood glucose control and incidence of nocturnal hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens managed with either an insulin analog combination or NPH insulin plus regular human insulin. RESEARCH DESIGN AND METHODS—In a randomized cross-over study, 28 adolescents with type 1 diabetes on multiple injection therapy received either insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week treatment arm, subjects completed home blood glucose profiles, and at the end of each treatment arm, they were admitted for an overnight metabolic profile. A total of 25 subjects completed the study. RESULTS—Compared with R/NPH therapy, LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus R/NPH): fasting (8.0 vs. 9.2 mmol/l, P < 0.0001), 2 h postbreakfast (8.1 vs. 10.7 mmol/l, P < 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P < 0.01), and 2 h postlunch (8.0 vs. 9.5 mmol/l, P < 0.002). However, there was no difference in mean blood glucose levels before or after the evening meal. Incidence of nocturnal hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH therapy; however, there was no difference in rates of self-reported symptomatic hypoglycemia. Total insulin dose required to achieve target blood glucose control was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P < 0.005), but there was no significant difference in HbA1c levels (LIS/GLAR versus R/NPH: 8.7 vs. 9.1%, P = 0.13). CONCLUSIONS—Combination therapy with insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and was at least as effective as R/NPH insulin therapy in maintaining glycemic control in adolescents on multiple injection regimens.

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Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: Prevalence and risk factors

Cited by 111 publications

References 18 publications

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

Glucokinase Is a Critical Regulator of Ventromedial Hypothalamic Neuronal Glucosensing

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons

Randomized Cross-Over Trial of Insulin Glargine Plus Lispro or NPH Insulin Plus Regular Human Insulin in Adolescents With Type 1 Diabetes on Intensive Insulin Regimens

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