Reversibility of Unawareness of Hypoglycemia in Patients with Insulinomas

Mitrakou, Asimina; Fanelli, Carmine G.; Veneman, Th.F.; Perriello, G.; Calderone, S.; Platanisiotis, D.; Rambotti, A. M.; Raptis, S.; Brunetti, P; Cryer, Philip E.; Gerich, John E.; Bolli, Geremia B.

doi:10.1056/nejm199309163291203

Cited by 216 publications

(140 citation statements)

References 24 publications

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“…This implies that neuroprotective mechanisms, such as the presence of the ATP-sensitive potassium channel, prevent large-scale neuron death during hypoglycemia (Mobbs et al, 2001). However, recurrent hypoglycemia can result in long-term reductions in hypoglycemia awareness and compensatory autonomic responses that are not always fully reversible with avoidance of hypoglycemia (Mitrakou et al, 1993). Our results using a sensitive marker of cell death show that there are vulnerable cells, which may be neurons, in the medial prefrontal, orbital, and piriform cortex, that die after a single episode of moderate hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Tkacs

Pan

Raghupathi

et al. 2005

J Cereb Blood Flow Metab

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Intensive insulin therapy in patients with type 1 diabetes mellitus reduces long-term complications; however, intensive therapy is also associated with a three-fold increase in hypoglycemic episodes. The present study in conscious rats characterizes the physiologic and neuropathologic consequences of a single episode of moderate hypoglycemia. In this model, intravenous insulin is used to reduce plasma glucose to 30 to 35 mg/dL for 75 mins. This single hypoglycemic insult acutely induces hypoglycemia-associated autonomic failure (HAAF), with epinephrine responses to hypoglycemia reduced more than 36% from control. Neuropathology after this insult includes the appearance of dying cells, assessed with the marker Fluoro-jade B (FJ). After hypoglycemic insult, FJ þ cells were consistently seen in subdivisions of the medial prefrontal cortex, the orbital cortex, and the piriform cortex. There was a significant correlation between depth of hypoglycemia and number of FJ þ cells, suggesting that there is a critical threshold below which vulnerable cells begin to die. These data suggest that there is a population of cells that are vulnerable to moderate levels of hypoglycemia commonly experienced by patients with insulin-treated diabetes. These cells, which may be neurons, are primarily found in cortical regions implicated in visceral perception and autonomic control, raising the possibility that their loss contributes to clinically reported deficits in autonomic and perceptual responses to hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Tkacs

Pan

Raghupathi

et al. 2005

J Cereb Blood Flow Metab

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“…Evidence has accumulated to show that recurrent exposure to hypoglycaemia in people with type 1 diabetes results in cerebral adaptation, such that cognitive performance is relatively preserved during hypoglycaemia [22][23][24][25][26][27]. Repeated exposure to hypoglycaemia can also result in impaired hypoglycaemia awareness, and a shared mechanism for the two phenomena has been proposed [28].…”

Section: Introductionmentioning

confidence: 99%

The effects of acute hypoglycaemia on memory acquisition and recall and prospective memory in type 1 diabetes

et al. 2006

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Aims/hypothesis Global memory performance is impaired during acute hypoglycaemia. This study assessed whether moderate hypoglycaemia disrupts learning and recall in isolation, and utilised a novel test of prospective memory which may better reflect the role of memory in daily life than conventional tests. Subjects and methods Thirty-six subjects with type 1 diabetes participated, 20 with normal hypoglycaemia awareness (NHA) and 16 with impaired hypoglycaemia awareness (IHA). Each underwent a hypoglycaemic clamp with target blood glucose 2.5 mmol/l. Prior to hypoglycaemia, subjects attempted to memorise instructions for a prospective memory task, and recall was assessed during hypoglycaemia. Subjects then completed the learning and immediate recall stages of three conventional memory tasks (word recall, story recall, visual recall) during hypoglycaemia. Euglycaemia was restored and delayed memory for the conventional tasks was tested. The same procedures were completed in euglycaemic control studies (blood glucose 4.5 mmol/l). Results Hypoglycaemia impaired performance significantly on the prospective memory task (p=0.004). Hypoglycaemia also significantly impaired both immediate and delayed recall for the word and story recall tasks (p<0.01 in each case). There was no significant deterioration of performance on the visual memory task. The effect of hypoglycaemia did not differ significantly between subjects with NHA and IHA. Conclusions/interpretation Impaired performance on the prospective memory task during hypoglycaemia demonstrates that recall is disrupted by hypoglycaemia. Impaired performance on the conventional memory tasks demonstrates that learning is also disrupted by hypoglycaemia. Results of the prospective memory task support the relevance of these findings to the everyday lives of people with diabetes.

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“…Choice reaction times (3,8) and performance of Stroop interference tests become slower at ϳ3 mmol/l; short-term memory deteriorates at 2.5 mmol/l (9); and finger tapping, a simple motor task, slows at ϳ2.3 mmol/l (10). The glucose level at which some brain functions alter, such as the activation of autonomic counterregulatory responses (3,8,(11)(12)(13)) (a hypothalamic action [14]) or deterioration of the performance of the Stroop and memory tests (10,11,13), may change according to prior experience of hyper-or hypoglycemia, with higher or lower plasma glucose associated with the onset of change, respectively. Such changes may leave those diabetic patients with prior experience of hypoglycemia at high risk for severe hypoglycemia with no warning hypoglycemia unawareness (15).…”

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confidence: 99%

The Effect of Acute Hypoglycemia on Brain Function and Activation

et al. 2001

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The authors' aim was to examine the regional anatomy of brain activation by cognitive tasks commonly used in hypoglycemia research and to assess the effect of acute hypoglycemia on these in healthy volunteers. Eight right-handed volunteers performed a set of cognitive tasks-finger tapping (FT), simple reaction time (SRT), and four-choice reaction time (4CRT)-twice during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging of the brain on two occasions. In study 1 (n ‫؍‬ 6), plasma glucose was maintained at euglycemia (5 mmol/l) throughout. In study 2 (n ‫؍‬ 6), plasma glucose was reduced to 2.5 mmol/l for the second set. Performance of the tasks resulted in specific group brain activation maps. During hypoglycemia, FT slowed (P ‫؍‬ 0.026), with decreased BOLD activation in right premotor cortex and supplementary motor area and left hippocampus and with increased BOLD activation in left cerebellum and right frontal pole. Although there was no significant change in SRT, BOLD activation was reduced in right cerebellum and visual cortex. The 4CRT deteriorated (P ‫؍‬ 0.020), with reduction in BOLD activation in motor and visual systems but increased BOLD signal in a large area of the left parietal association cortex, a region involved in planning. Hypoglycemia impairs simple brain functions and is associated with task-specific localized reductions in brain activation. For a task with greater cognitive load, the increased BOLD signal in planning areas is compatible with recruitment of brain regions in an attempt to limit dysfunction. Further investigation of these mechanisms may help devise rational treatment strategies to limit cortical dysfunction during acute iatrogenic hypoglycemia. Diabetes 50:1618 -1626, 2001

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Reversibility of Unawareness of Hypoglycemia in Patients with Insulinomas

Abstract: Hypoglycemia itself can induce unawareness of the autonomic and neuroglycopenic symptoms of hypoglycemia and decrease the counterregulatory hormonal responses to hypoglycemia.

Cited by 216 publications

References 24 publications

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

The effects of acute hypoglycaemia on memory acquisition and recall and prospective memory in type 1 diabetes

The Effect of Acute Hypoglycemia on Brain Function and Activation

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