Multifactorial Origin of Hypoglycemic Symptom Unawareness in IDDM: Association With Defective Glucose Counterregulation and Better Glycemic Control

Clarke, William L.; Gönder-Frederick, Linda; Richards, Fredrick E.; Cryer, Philip E.

doi:10.2337/diab.40.6.680

Cited by 55 publications

(37 citation statements)

References 21 publications

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“…The underlying mechanism is a threshold shift for the activation of glucose counterregulation toward lower BG levels due to (recurrent) exposure to decreased BG levels (19). Impaired glucose counterregulation has also been shown to be related to tight glycemic control (20,21). Pregestational SH comprised a markedly higher risk (OR [95% CI]: 9.2 [3.9 -21.7]) of subsequent first-trimester SH.…”

Section: Sequelae Of Shmentioning

confidence: 99%

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

et al. 2002

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OBJECTIVES -To investigate the frequency of severe hypoglycemia (SH) and hypoglycemic coma during the first trimester of type 1 diabetic pregnancy and in the 4 months before gestation and to identify risk indicators predicting first trimester SH in a nonselected nationwide cohort of pregnant women with type 1 diabetes.RESEARCH DESIGN AND METHODS -We conducted a longitudinal cohort survey in 278 pregnant type 1 diabetic women using questionnaires at inclusion and at 17 weeks of gestation, addressing the frequencies of SH (i.e., external help required) and hypoglycemic coma, general characteristics, hypoglycemia awareness, blood glucose symptom threshold, and the Hypoglycemia Fear Survey.RESULTS -The occurrence of SH (including hypoglycemic coma) rose from 0.9 Ϯ 2.4 episodes per 4 months before gestation to 2.6 Ϯ 6.3 episodes during the first trimester (P Ͻ 0.001), including an increase in episodes of coma from 0.3 Ϯ 1.3 to 0.7 Ϯ 3.7 (P ϭ 0.03). The proportion of women affected by SH rose from 25 to 41% (P Ͻ 0.001). First-trimester SH was independently related to a history of SH before gestation (odds ratio CONCLUSIONS -In type 1 diabetic pregnancy, the risk of SH is increased already before pregnancy and rises further during the first trimester. A history of SH before gestation, longer duration of diabetes, an HbA 1c level Յ6.5%, and a higher total daily insulin dose were risk indicators predictive for SH during the first trimester. Further research should aim to elucidate how the benefits of strict glycemic control balance with the markedly increased risk of SH early in pregnancy.[ Diabetes Care 25:554 -559, 2002

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Section: Sequelae Of Shmentioning

confidence: 99%

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

et al. 2002

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“…Hypoglycemia unawareness has been associated with a number of clinical factors, including tight glucose control (i.e., intensive insulin regimens), extended disease duration, and recent episodes of antecedent hypoglycemia (5)(6)(7)(8). It is also closely tied to blunted sympathoadrenal (i.e., epinephrine) responses to hypoglycemia, known as hypoglycemia-associated autonomic failure (HAAF).…”

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confidence: 99%

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

et al. 2006

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Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 ؎ 53 vs. 337 ؎ 57 pg/ml, P ‫؍‬ 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 ؎ 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 ؎ 28 vs. 192 ؎ 28 pg/ml, P ‫؍‬ NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemiainduced hypercortisolemia is not primarily responsible for the generation of HAAF. Diabetes 55

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“…of hypoglycaemia in these patients [3], thus leading into a vicious cycle [4]. Although glucose represents the main fuel for the brain, it is also possible that under conditions of glucose shortage, brain function is maintained by the uptake of other energetic substrates.…”

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confidence: 99%

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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Multifactorial Origin of Hypoglycemic Symptom Unawareness in IDDM: Association With Defective Glucose Counterregulation and Better Glycemic Control

Cited by 55 publications

References 21 publications

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

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

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