Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans

Veneman, T.; Mitrakou, A.; Mokan, M.; Cryer, Philip E.; Gerich, J.

doi:10.2337/diabetes.43.11.1311

Cited by 70 publications

(83 citation statements)

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“…From a qualitative point of view, results of this study resemble those observed with lactate infusion preceding insulin-induced hypoglycaemia [5,6] with the main effect exerted on plasma epinephrine concentrations. No effect was detected on plasma glucagon concentration and only a limited increase in the plasma norepinephrine concentrations occurred.…”

Section: Discussionsupporting

confidence: 68%

“…This issue has been addressed previ- ously by us and others [5,6], the results of those studies supporting a role for lactate as an alternative fuel for the brain under the condition of insulin-induced hypoglycaemia. The present study provides evidence that the complex mechanism responsible for the hormonal responses which might prevent severe neuroglycopenia can be rapidly reversed, even after its activation, by a non-glucose fuel such as lactate.…”

Section: Discussionmentioning

confidence: 88%

“…In the previous studies, indeed, lactate infusion preceded hypoglycaemia. In our previous study, for instance, lactate infusion was begun 60 min before induction of hypoglycaemia, whereas in the study by the other group [6] there was at least a 30-min gap between the beginning of the lactate treatment and the reduction of plasma glucose below 4.0 mmol/l. Under these conditions, an adaptation process cannot be ruled out to account for the increase observed in the glycaemic threshold, reduced magnitude of autonomic and neuroglycopenic symptoms, counterregulation hormone responses and cognitive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

et al. 2000

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Patients with Type I (insulin-dependent) diabetes mellitus receiving intensified insulin therapy and having strict metabolic control are exposed to the risk of recurrent episodes of hypoglycaemia [1]. Defective counterregulatory and symptomatic responses to hypoglycaemia are responsible for reduced awareness of hypoglycaemia [2] which can aggravate cerebral dysfunction by increasing the occurrence and severity Diabetologia (2000) 43: 733±741Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects Abstract Aims/hypothesis. We have previously shown that lactate protects brain function during insulin-induced hypoglycaemia. An adaptation process could, however, not be excluded because the blood lactate increase preceded hypoglycaemia. Methods. We studied seven healthy volunteers and seven patients with Type I (insulin-dependent) diabetes mellitus with a hyperinsulinaemic (1.5 mUḱ g ±1´m in ±1 ) stepwise hypoglycaemic clamp (4.8 to 3.6, 3.0 and 2.8 mmo/l) with and without Na-lactate infusion (30 mmol´kg ±1´m in ±1 ) given after initiation of hypoglycaemic symptoms. Results. The glucose threshold for epinephrine response was similar (control subjects 3.2 0.1 vs 3.2 0.1, diabetic patients = 3.5 0.1 vs 3.5 0.1 mmol/l) in both studies. The magnitude of the response was, however, blunted by lactate infusion (AUC; control subjects 65 28 vs 314 55 nmol/l/180 min, zenith = 2.6 0.5 vs 4.8 0.7 nmol/l, p < 0.05; diabetic patients = 102 14 vs 205 40 nmol/l/180 min, zenith = 1.4 0.4 vs 3.2 0.3 nmol/l, p < 0.01). The glucose threshold for symptoms was also similar (C = autonomic 3.0 0.1 vs 3.0 0.1, neuroglycopenic = 2.8 0.1 vs 2.9 0.1 mmol/l, D = autonomic 3.2 0.1 vs 3.2 0.1, neuroglycopenic 3.1 0.1 vs

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

et al. 2000

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“…Cognitive function was not measured in that study, but in a more recent but similar study, with a rather larger dose of beta-hydroxybutyrate, a delay in the onset of cognitive dysfunction was also demonstrable [31], thus confirming that some effect of the ketone bodies was cerebral, even if the detection of hypoglycaemia and onset of counterregulation were not. These studies provide an explanation for the clinical presentation of ketotic hypoglycaemic states in childhood [32]; however, except in the special circumstances of inborn errors of metabolism, ketones are unlikely to provide a useful therapeutic manoeuvre for protecting cerebral function during hypoglycaemia in pharmacological treatment of diabetes, although ketogenic diets have been used in the management of children with some forms of intractable epilepsy, perhaps ameliorating a problem of glucose uptake. However, in insulin-induced hypoglycaemia as encountered in the treatment of diabetes, circulating ketone levels are suppressed by insulin.…”

Section: Brain Metabolism and Hypoglycaemiamentioning

confidence: 99%

Hypoglycaemia in diabetes mellitus - protecting the brain

Amiel

1997

Diabetologia

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The principal danger of hypoglycaemia is the associated loss of brain function. Under normal circumstances, the brain is almost exclusively dependent on glucose to fuel its metabolism and function and, since its glucose stores are negligible, normal brain function relies upon an adequate supply of glucose from its blood supply.In animal models, prolonged very profound hypoglycaemia eventually results in neurone death (compared with ischaemia, which results in non-selective loss of all brain cell types) [1]. In clinical practice, apparent full recovery is the rule even from severe episodes of hypoglycaemia. Permanent impairment of brain function is seen only after the most severe episodes, usually associated with massive insulin overdose, often either deliberate or malicious [2]. In general, the loss of brain function due to hypoglycaemia presents in any degree from mild confusion or disinhibition to coma and full recovery apparently occurs within an hour of restoration of normoglycaemia [3]. There are concerns that recurrent episodes of hypoglycaemia-associated coma may result in permanent damage to cortical (intellectual) function although in adults the data are inconclusive, with some studies suggesting an acceleration of the age-related decline in performance on IQ testing [4], while others relate this to associated diabetic neuropathy [5]. Prospective studies of people who have been at particular risk for recurrent severe hypoglycaemia show no effect on long-term cognitive function [6,7]. There is evidence of permanent impairment of IQ after recurrent hypoglycaemic episodes occurring before the age of 5 years (i. e. affecting the developing brain) [8]. (For a review of the possible long-term effects of recurrent hypoglycaemia, see [9]). Protective mechanisms against severe hypoglycaemiaIn health, severe hypoglycaemia (now defined as the state in which the patient is unable to self-treat because of impaired function and has to be treated by someone else [10]), does not occur because of the efficient systems the body has to detect and deal with

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“…Associated with loss of subjective awareness of hypoglycaemia is a lowering of the glucose concentration required to initiate the counterregulatory response to hypoglycaemia, as well as a reduction in the magnitude and intensity of the counterregulatory response at any given blood glucose concentration [3,4,5]. The speculation that these defects are principally the result of defective glucose sensing gains support from data showing similar changes in the neuroendocrine rePerception of a minor decrease in plasma glucose concentration and initiation of a counterregulatory response are essential factors in the defence against sesponse to experimental hypoglycaemia when non-glucose metabolic fuels are available to replace the glucose [6,7].…”

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confidence: 99%

The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man

et al. 2002

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Aims/hypothesis. The role of glucose sensing cells in the human hepatic portal system in the initiation of the neuroendocrine responses to acute hypoglycaemia is not known. We investigated the effect of raising blood glucose concentrations in the hepatic-portal vein on neurohumoral responses during induction of systemic hypoglycaemia in nine healthy male volunteers. Methods. Each subject received an insulin infusion (3 mU·kg -1 ·min -1 ) on two occasions, in random order. Variable rate glucose infusion was used to maintain plasma glucose at 5 mmol/l for 60 min, then 3.2 mmol/l for 60 min. At 20 min prior to hypoglycaemia, subjects drank 20 g of glucose in water or water sweetened with saccharin. In five of the volunteers, the oral glucose was labelled with U-13C6 glucose, which showed peak systemic glucose absorption between 90 and 110 min. Five volunteers also repeated the study with a euglycaemic clamp.Results. Oral glucose was associated with a reduction in the early adrenaline response to hypoglycaemia, the area under the curve from 90 to 110 min falling from 24.02±20.84 (means ± SD) to 15. vere hypoglycaemia during the pharmacological treatment of diabetes mellitus. The inability to generate or detect the warning symptoms of early hypoglycaemia puts diabetic patients at high risk of episodes of severe hypoglycaemia [1] and often the fear of hypoglycaemia limits the optimisation of glycaemic control [2]. Associated with loss of subjective awareness of hypoglycaemia is a lowering of the glucose concentration required to initiate the counterregulatory response to hypoglycaemia, as well as a reduction in the magnitude and intensity of the counterregulatory response at any given blood glucose concentration [3,4,5]. The speculation that these defects are principally the result of defective glucose sensing gains support from data showing similar changes in the neuroendocrine rePerception of a minor decrease in plasma glucose concentration and initiation of a counterregulatory response are essential factors in the defence against se-

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Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans

Cited by 70 publications

References 0 publications

Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

Hypoglycaemia in diabetes mellitus - protecting the brain

The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man

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