Cardiovascular Reflex Abnormalities in Children and Adolescents With Diabetes Mellitus

Ringel, Richard; Chalew, Stuart A.; Armour, Karen A.; McLaughlin, Judith V; McCarter, Robert; Kramer, Wendy E.

doi:10.2337/diacare.16.5.734

Cited by 25 publications

(21 citation statements)

References 26 publications

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“…Subtle changes of autonomic function can, however, be shown many years earlier [2]. There are two reports of a reduced heart rate response to postural change and deep breathing in 30 % of children with diabetes of less than 10 years duration [9,38]. Although structural changes of the autonomic nerve have been shown in diabetic rats, there has not been any suitable animal model for studying autonomic dysfunction [21].…”

Section: Discussionmentioning

confidence: 99%

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Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

et al. 2000

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Diabetic neuropathy is a serious complication affecting as many as 60 % of diabetic patients [1]. Its clinical manifestations can vary from reduced nerve conduction velocity and sensory deficits to autonomic disturbances associated with increased mortality [2,3]. Despite numerous research efforts, the pathogenesis of diabetic neuropathy remains incompletely understood. Proposed mechanisms include microvascular abnormalities, altered Schwann cell or neuronal metabolism, deficiencies of neurotrophic substances and slowing of axonal transport [4±7]. In diabetic patients, changes in function of peripheral and autonomic nerves can be detected very early in the dis- Abstract Aims/hypothesis. To improve understanding of the pathophysiology of diabetic neuropathy and to establish a primate model for experimental studies, we examined nerve changes in baboons with Type I (insulin-dependent) diabetes mellitus. We also examined the effect of aminoguanidine (an inhibitor of the formation of advanced glycation end products) on nerve function. Methods. Male baboons (Papio hamadryas) were assigned to four groups; control, diabetic, control and diabetic treated with aminoguanidine. Diabetes was induced with streptozotocin (60 mg/kg, intravenous). Insulin and aminoguanidine (10 mg/kg) were injected subcutaneously daily. Motor and sensory nerve conduction velocity was measured using standard techniques. Autonomic function was examined by measuring heart rate response to positional change. Sural nerve morphometry was analysed in the diabetic group (mean duration 5.5 years) along with their age-matched controls. Results. The diabetic groups were smaller in size with a mean HbA 1 c of 8.9 ± 1.2 %. The nerve conduction velocity and heart rate response was reduced in the diabetic groups. Morphometric analysis of the diabetic sural nerve showed smaller axon diameter (2.99 ± 0.06 mm vs 3.29 ± 0.06 mm; p < 0.01) accompanied by thinner myelin (1.02 ± 0.02 mm vs 1.15 ± 0.02 mm, p < 0.01) with no change in the axon density. Treatment with aminoguanidine for 3 years had no effect on glycaemic control and did not restore conduction velocity or autonomic dysfunction in the diabetic animals, contrary to the studies in rats. Conclusions/interpretation. These results show that the primate is a good model to study diabetic neuropathy and suggest that the accumulation of advanced glycation end products are not an early mechanism of nerve damage in this disorder. [Diabetologia (2000) 43: 110±116]

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Section: Discussionmentioning

confidence: 99%

“…There is a characteristic slowing of both motor and sensory nerve conduction velocity which improves with better metabolic control [6,8]. Abnormalities of heart rate variation have also been reported [2,9]. These functional abnormalities precede overt symptoms by many years.…”

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confidence: 99%

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

et al. 2000

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“…Both cardiac reflex tests have been reported to be reliable indications of diabetic cardiac autonomic dysfunction. [17][18][19] Applying singlephoton emission computed tomography (SPECT) using the tracer 123-I-MIBG to etablished Type 1 DM patients, we have previously observed a significant association of CF-SG autoantibodies and cardiac sympathetic denervation. 7 This scintigraphic technique is a direct and very sensitive approach for assessment of cardiac sympathetic innervation.…”

Section: Discussionmentioning

confidence: 99%

Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction

et al. 1998

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There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23%) and CF-PSG autoantibodies in 21 (10%) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5%) and 1 (2%) of patients with non-diabetic neurological diseases and 3 (2%) and 4 (3%) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; > or =2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29% vs 17%, p = 0.06). However, 4 (80%) of 5 newly diagnosed and 23 (32%) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25%) of 58 newly diagnosed (p < 0.05) and 7 (11%) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM.

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“…In adolescents with diabetes, evidence for cardiovascular autonomic nerve involvement has come from an increase in test abnormalities (29–31%) [2, 3] and from differences between diabetic and control groups [3, 4, 5]. However, there is less evidence for persisting dysfunction or declining function in longitudinal studies.…”

Section: Studies Of Cardiovascular Reflexesmentioning

confidence: 99%

Autonomic Neuropathy: Diagnosis and Impact on Health in Adolescents with Diabetes

Donaghue¹

1998

Horm Res Paediatr

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Symptomatic autonomic neuropathy and abnormal cardiovascular autonomic tests are associated with increased mortality due to vascular disease and increased risk of sudden deaths. Intensive therapy in the DCCT caused a significant risk reduction of developing autonomic nerve abnormalities at five years only in the Primary Prevention Group (4 vs. 9%). At the Royal Alexandra Hospital for Children, the prevalence of cardiovascular reflex abnormalities is 28%. Over 5 years, we have found no increase in the rate of single cardiovascular abnormalities and a low rate of persistence. Two or more abnormalities developed in 5%. Repeated measures of pupillary function showed a significant increase in abnormalities and a higher level of persistently abnormal tests. Spectral analysis and 24-hour BP monitoring may detect autonomic dysfunction at earlier stages but longitudinal studies are not yet available.

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Cardiovascular Reflex Abnormalities in Children and Adolescents With Diabetes Mellitus

Cited by 25 publications

References 26 publications

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction

Autonomic Neuropathy: Diagnosis and Impact on Health in Adolescents with Diabetes

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