Reduction of Pressure Pain Sensitivity as Novel Non-pharmacological Therapeutic Approach to Type 2 Diabetes: A Randomized Trial

Jens Faber, Ebbe Eldrup, Christian Selmer, Caroline Pichat, Sofie Korsgaard Hecquet, Torquil Watt, Svend Kreiner, Benny Karpatschof, Finn Gyntelberg, Søren Ballegaard, Albert Gjedde, Jens Faber, Ebbe Eldrup, Christian Selmer, Caroline Pichat, Sofie Korsgaard Hecquet, Torquil Watt, Svend Kreiner, Benny Karpatschof, Finn Gyntelberg, Søren Ballegaard, Albert Gjedde

Abstract

Background: Autonomic nervous system dysfunction (ANSD) is known to affect glucose metabolism in the mammalian body. Tradition holds that glucose homeostasis is regulated by the peripheral nervous system, and contemporary therapeutic intervention reflects this convention.

Objectives: The present study tested the role of cerebral regulation of ANSD as consequence of novel understanding of glucose metabolism and treatment target in type 2 diabetes (T2D), suggested by the claim that the pressure pain sensitivity (PPS) of the chest bone periosteum may be a measure of cerebral ANSD.

Design: In a randomized controlled trial of 144 patients with T2D, we tested the claim that 6 months of this treatment would reduce PPS and improve peripheral glucose metabolism.

Results: In the active treatment group, mean glycated hemoglobin A1c (HbA1c) declined from 53.8 to 50.5 mmol/mol (intragroup p = 0.001), compared with the change from 53.8 to 53.4 mmol/mol in the control group, with the same level of diabetes treatment but not receiving the active treatment (between group p = 0.036). Mean PPS declined from 76.6 to 56.1 units (p < 0.001) in the active treatment group and from 77.5 to 72.8 units (p = 0.02; between group p < 0.001) in the control group. Changes of PPS and HbA1c were correlated (r = 0.37; p < 0.001).

Conclusion: We conclude that the proposed approach to treatment of T2D is a potential supplement to conventional therapy.

Clinical trial registration: www.clinicaltrials.gov (NCT03576430).

Keywords: HbA1c; autonomic dysfunction; glucose control; glucose homeostasis; lateral hypothalamus; non-pharmacological intervention; pressure pain sensitivity; type 2 diabetes.

Conflict of interest statement

SB is a shareholder in the company UllCare A/S that holds the patent for the PPS-measurement device. He did not participate in patient selection, examinations, or evaluation of the examinations. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Faber, Eldrup, Selmer, Pichat, Hecquet, Watt, Kreiner, Karpatschof, Gyntelberg, Ballegaard and Gjedde.

Figures

FIGURE 1
FIGURE 1
Consort diagram.
FIGURE 2
FIGURE 2
Reduction in HbA1c (mmol/mol) over 6 months in the active and control groups; mean ± SE; p = 0.035 (n = 52 active group, n = 60 control group). HbA1c, glycated hemoglobin.
FIGURE 3
FIGURE 3
Reduction in HbA1c (mmol/mol) over 6 months among responders (a decrease in PPS ≥ 15 arbitrary units) versus non-responders (a decrease in PPS less than 15 arbitrary units); (active and control group together) mean ± SE; p < 0.001 (n = 52 in responder group and n = 60 in non-responder group). HbA1c, glycated hemoglobin; PPS, pressure pain sensitivity.
FIGURE 4
FIGURE 4
Correlation between reduction in PPS (arbitrary units) and reduction in HbA1c (mmol/mol) over the 6-month study period, including both the active and control groups; n = 112; r = 0.37; p < 0.001. PPS, pressure pain sensitivity; HbA1c, glycated hemoglobin A1c.
FIGURE 5
FIGURE 5
Overview of the neurophysiological pathways of the PPS concept. (A) Measurement site: pressure pain sensitivity is measured at the periosteum of the chest bone, rather than that of the skin. (B) Distinction between the polymodal receptor (periosteum) and the mechano receptor (skin): the dual function of the polymodal sensor cell in contrast to the other local sensory cells. Pressure pain threshold changes by the level of sympathetic activity. (C) Reactions of the polymodal sensor cell: the reactions of the polymodal sensor cell in response to the degree of applied pressure. (D) Two kinds for signals from periosteum to the brain: noxious (red, lateral spinothalamic tract) and non-noxious signal (blue, anterior spinothalamic tract) from A-delta and C-fibers use different pathways to the brain. (E) Signal pathways to the brain: transmission pathways of noxious and non-noxious sensory nerve stimulation to thalamus and somatosensoric areas of the cerebral cortex. (F) Sagittal view of brain with thalamus and hypothalamus: thalamus and hypothalamus. Both kinds of signals from the A-delta and C-fibers reach the thalamus and from there transmit to the lateral hypothalamus. (G) Frontal view of lateral hypothalamus: the lateral hypothalamus with the close association between homeostatic regulation of metabolism, wakefulness and Warning and Alarm system by the Orexin system, GABA (gamma aminobutyric acid) and MCH (melanin concentrating hormone).

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