Coefficient of variation of R–R intervals in electrocardiogram is a sensitive marker of anemia induced by autonomic neuropathy in type 1 diabetes

Saito, Takatoshi; Tojo, Katsuyoshi; Nishimura, Rimei; Kageyama, Shigeru; Tajima, Naoko

doi:10.1016/j.diabres.2007.03.015

Cited by 6 publications

(5 citation statements)

References 22 publications

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“…Serum EPO levels are decreased in type 1 diabetic patients with postural hypotension in comparison to age-and duration-matched type 1 diabetics free of complications as well as non-anemic, non-diabetic controls and patients with iron deficiency anemia (Winkler et al, 1999). A blunted EPO response to severe anemia has also been described as a result of autonomic neuropathy in studies of patients with both types 1 and 2 diabetes (Cotroneo et al, 2000;Ricerca et al, 1999;Saito et al, 2007;Spallone et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

“…One potential cause of anemia in diabetes is EPO deficiency or ineffectiveness (Bosman et al, 2001(Bosman et al, , 2002. A number of investigators have described the association of autonomic neuropathy in diabetic patients with anemia (Cotroneo et al, 2000;McGill and Bell, 2006;Ricerca et al, 1999;Saito et al, 2007;Spallone et al, 2004;Winkler et al, 1999). Since denervation of the kidney or use of beta adrenergic blocking agents are known to decrease kidney EPO production in experimental animals (Beynon, 1977;Fink and Fisher, 1976, it has been thought that loss of autonomic innervation of the kidney secondarily resulted in decreased EPO production.…”

Section: Discussionmentioning

confidence: 99%

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Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice

Schmidt

Green

Feng

et al. 2008

Experimental Neurology

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Autonomic neuropathy is a significant diabetic complication resulting in increased morbidity and mortality. Studies of autopsied diabetic patients and several rodent models demonstrate that the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in prevertebral ganglia is the occurrence of synaptic pathology resulting in distinctive dystrophic neurites ("neuritic dystrophy"). Our prior studies show that neuritic dystrophy is reversed by exogenous IGF-I administration without altering the metabolic severity of diabetes, i.e. functioning as a neurotrophic substance. The description of erythropoietin (EPO) synergy with IGF-I function and the recent discovery of EPO's multifaceted neuroprotective role suggested it might substitute for IGF-I in treatment of diabetic autonomic neuropathy. Our current studies demonstrate EPO receptor (EPO-R) mRNA in a cDNA set prepared from NGF-maintained rat sympathetic neuron cultures which decreased with NGF deprivation, a result which demonstrates clearly that sympathetic neurons express EPO-R, a result confirmed by immunohistochemistry. Treatment of STZ-diabetic NOD-SCID mice have demonstrated a dramatic preventative effect of EPO and carbamylated EPO (CEPO, which is neuroprotective but not hematopoietic) on the development of neuritic dystrophy. Neither EPO nor CEPO had a demonstrable effect on the metabolic severity of diabetes. Our results coupled with reported salutary effects of EPO on postural hypotension in a few clinical studies of EPO-treated anemic diabetic and non-diabetic patients may reflect a primary neurotrophic effect of EPO on the sympathetic autonomic nervous system, rather than a primary hematopoietic effect. These findings may represent a major clinical advance since EPO has been widely and safely used in anemic patients due to a variety of clinical conditions.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice

Schmidt

Green

Feng

et al. 2008

Experimental Neurology

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show abstract

“…Serum EPO levels were decreased in type 1 diabetic patients with postural hypotension in comparison to age- and duration-matched type 1 diabetics free of complications as well as non-anemic, non-diabetic controls and patients with iron deficiency anemia (Winkler et al, 1999). A blunted EPO response to severe anemia has also been described as a result of autonomic neuropathy in studies of patients with both types 1 and 2 diabetes (Ricerca et al, 1999; Cotroneo et al, 2000; Spallone et al, 2004; Saito et al, 2007). …”

Section: Discussionmentioning

confidence: 92%

Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2Akita) diabetic mouse sympathetic ganglia

Schmidt¹,

Feng²,

Wang³

et al. 2011

Experimental Neurology

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The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3-4 weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4 weeks of insulin therapy beginning at 2 months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3 month diabetic or insulin treated Akita mice. Treatment with ARA290 for 7 weeks beginning at 4 months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55-74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4 month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy.

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“…acclimation time, ECG sampling rate, and duration of recording), and has been shown to be incompatible with a high-throughput data collection setup such as that used by the IMPC (Electrophysiology 1996 ; Sammito and Böckelmann 2016 ). Next, CV provides an indication of the function of the parasympathetic nerve and the autonomic nervous system through the physiological phenomenon of RR variation (Saito et al 2007 ). Such measurements, however, require stable and prolonged measurement times to be meaningful, which, as stated above for HRV, we do not have in the context of the high-throughput testing paradigm used herein.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

Oestereicher,

Wotton,

Ayabe

et al. 2023

Mamm Genome

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Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.

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Coefficient of variation of R–R intervals in electrocardiogram is a sensitive marker of anemia induced by autonomic neuropathy in type 1 diabetes

Cited by 6 publications

References 22 publications

Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice

Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice

Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2Akita) diabetic mouse sympathetic ganglia

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice

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