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Cited by 128Heart Rate Variability and Autonomic ControlDiabetes, Cardiovascular Risks, and LipoproteinsCardiovascular Function and Risk Factors

Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review

Open access
Williams, Scott M., Eleftheriadou, Aikaterini, Alam, Uazman, Cuthbertson, Daniel J., Wilding, John P. H.·2019·Diabetes Therapy
DOI 10.1007/s13300-019-00693-0PMC PMC6848658
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Abstract

Cardiac autonomic neuropathy (CAN) is a major complication of type 1 and type 2 diabetes mellitus (T1DM and T2DM). The increased morbidity, cardiovascular and all-cause mortality associated with CAN is established from numerous epidemiological studies. However, CAN is increasingly recognised in people with prediabetes (pre-DM) and the metabolic syndrome (MetS) with a reported prevalence up to 11% and 24% respectively. CAN is associated with components of MetS including hypertension and obesity, predating hyperglycaemia. The aetiology of CAN is multifactorial and there is a reciprocal relationship with insulin resistance and MetS. Obstructive sleep apnoea (OSA) is also associated with CAN possibly through MetS and an independent mechanism. An estimated global prevalence of the impaired glucose tolerance (IGT) form of pre-DM of 587 million people by 2045 means CAN will become a major clinical problem. CAN is independently associated with silent myocardial ischaemia, major cardiovascular events, myocardial dysfunction and cardiovascular mortality. Screening for CAN in pre-DM using risk scores with analysis of heart rate variability (HRV) or Sudoscan is important to allow earlier treatment at a reversible stage. The link between obesity and CAN highlights the therapeutic potential of lifestyle interventions including diet and physical activity to reverse MetS and prevent CAN. Weight loss achieved using these dietary and exercise lifestyle interventions improves the sympathetic and parasympathetic HRV indices of cardiac autonomic function. Further research is needed to identify high-risk populations of people with pre-DM or obesity that might benefit from targeted pharmacotherapy including metformin, sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) analogues. Bariatric surgery also improves HRV through weight loss which might also prevent CAN in severe obesity. This article reviews the literature on CAN in obesity, pre-DM and MetS, to help determine a rationale for screening, early intervention treatment and formulate future research questions in this highly prevalent condition.

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Crossref · 10.1007/s13300-019-00693-0

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  • Lifestyle interventions such as exercise and eating a healthy diet have been shown to be effective in reducing SNS activation, which in part may be mediated by improving cardiometabolic risk factors.

    “Furthermore, lifestyle interventions such as exercise and eating a healthy diet have been shown to be effective in reducing SNS activation, which in part may be mediated by improving these cardiometabolic risk factors92,94.”

    From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [92]

    The Exercise Interventions section reports improved HRV after exercise and suggests reduced autonomic activation; the Dietary Interventions section links improved HRV with weight loss and improved metabolic risk factors. The review does not establish that both exercise and diet reduce SNS activation specifically, or that improvements in cardiometabolic risk factors mediate that reduction. It describes lifestyle-related reversal of SNS predominance as a possibility for further study (Future Therapies and New Directions; page numbers unavailable). (LLM, conf=0.82)

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  • In diabetes, SNS predominance is speculated to be a downstream effect of hyperinsulinemia, hyperglycaemia and insulin resistance.

    “In the case of diabetes, this SNS predominance is speculated to be a downstream effect of hyperinsulinemia, hyperglycaemia and insulin resistance92, while obesity may trigger increased SNS activity as an adaptive mechanism to increase resting energy expenditure and compensate for the positive energy balance93.”

    From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [92]

    The Pathogenesis of CAN section (page unavailable) says SNS predominance can result from hyperinsulinaemia and parasympathetic denervation. It links hyperglycaemia to autonomic neuropathy, but not specifically to SNS predominance, and says SNS predominance may lead to further insulin resistance in prediabetes. The claim therefore attributes a broader causal account to the review than it gives. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In diabetes and obesity/metabolic syndrome, the balance between the two autonomic branches shifts towards SNS predominance.

    “In these disease states, it is believed that the balance between the two autonomic branches shifts towards SNS predominance.”

    From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [92]

    The Pathogenesis of CAN section describes a shift toward SNS predominance in early cardiac autonomic neuropathy, linked to metabolic syndrome and parasympathetic denervation. The Introduction also describes early parasympathetic denervation in diabetes and reduced parasympathetic activity in obesity. The claim extends that early-stage pattern to these disease states generally, whereas the review notes that sympathetic denervation occurs later in CAN. (LLM, conf=0.84)

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Research works printed but not linked: 7

  1. [42]Wu JS Yang YC Lin TS Epidemiological evidence of altered cardiac autonomic function in subjects with impaired glucose tolerance but not isolated impaired fasting glucose J Clin Endocrinol Metab 2007 92 10 3885 3889 17666483
  2. [50]Ge Xiaoli Pan Shu-Ming Zeng Fangfang Tang Zi-Hui Wang Ying-Wei A Simple Chinese Risk Score Model for Screening Cardiovascular Autonomic Neuropathy PLoS ONE 2014 9 3 e89623 24621478 PMC3951191
  3. [62]Fisher VL Tahrani AA Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives Diabetes Metab Syndr Obes 2017 10 419 434 29062239 PMC5638575
  4. [66]Wulsin LR Horn PS Perry JL Massaro JM D’Agostino RB Autonomic imbalance as a predictor of metabolic risks, cardiovascular disease, diabetes, and mortality J Clin Endocrinol Metab 2015 100 6 2443 2448 26047073
  5. [83]Greco C Spallone V Obstructive sleep apnoea syndrome and diabetes. Fortuitous association or interaction? Curr Diabetes Rev. 2016 12 2 129 155 25808418
  6. [152]Vinik AI, Casellini C, Parson HK, Colberg SR, Nevoret ML. Cardiac autonomic neuropathy in diabetes: a predictor of cardiometabolic events. Front Neurosci. 2018;12. PMC6119724 30210276
  7. [159]Pop-Busui R Boulton AJM Feldman EL Diabetic neuropathy: a position statement by the American Diabetes Association Diabetes Care 2017 40 1 136 154 27999003 PMC6977405

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Authors
Williams, S. M., Eleftheriadou, A., Alam, U., Cuthbertson, D. J., & Wilding, J. P. H.
Affiliations
  • Leighton Hospital (GB)
  • University of Liverpool (GB)
Corresponding author
Williams, Scott M.
ORCID
Venue
Diabetes Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-09-24
Volume
10
Issue
6
Pages
1995-2021
ISSN
  • 1869-6953 (ISSN-L)
  • 1869-6961
DOI
10.1007/s13300-019-00693-0
PMC
PMC6848658
OpenAlex
W2976953405
Cited by
128
References
166
Citations by year
2026: 14 · 2025: 16 · 2024: 22 · 2023: 15 · 2022: 19 · 2021: 21 · 2020: 19 · 2019: 2
FWCI
2.76
Type
journal article
Language
en
Update notices
correction (2019-10-04)
Open access
Licence
Locations
  • Diabetes Therapy (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
cardiac autonomic neuropathy, obesity, metabolic syndrome, prediabetes, heart rate variability, Sudoscan, obstructive sleep apnea, insulin resistance, impaired glucose tolerance, cardiovascular mortality, silent myocardial ischemia, bariatric surgery, SGLT2 inhibitors, GLP-1 receptor agonists, metformin, lifestyle intervention, weight loss, cardiovascular screening

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