Combining Celiac and Hepatic Vagus Nerve Neuromodulation Reverses Glucose Intolerance and Improves Glycemic Control in Pre- and Overt-Type 2 Diabetes Mellitus

Figures

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  Figure 1. Two Viking neuroregulators were used to generate high and low frequency signals. The high frequency consisted of a 5000 Hz HFAC charge-balanced waveform (a). The low-frequency signal consisted of a 1 Hz charge-balanced waveform (b).

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  Figure 2. Experimental timeline highlights the long duration of time between alloxan treatment and the initiation of experiments. This gave ample time for a static glycemic state in swine following alloxan treatment prior to OGTT experiments. Blue arrows indicate IVGTTs, orange arrowhead indicates alloxan treatment and orange arrows indicates OGTTs.

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  Figure 3. HFAC was delivered to the hepatic branches (red arrow) and stimulation was applied to the celiac branch (green). Modulation of both branches has demonstrated modified liver and pancreatic function leading to changes in PG. Figure adapted from Waataja et al. 2022 [64] and originally created using biorender.com (accessed on 29 June 2022).

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  Figure 4. Intravenous glucose tolerance tests demonstrated glucose intolerance in Pre-Diabetic (a,b) and Diabetic (c,d) swine. This was demonstrated through higher FPG and greater area under the curve (AUC) following alloxan in both groups. * p < 0.01, ** p = 0.012.

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  Figure 5. Application of HFAC + stimulation increased performance on OGTTs in Pre-Diabetic (a,b) and Diabetic (c,d) swine. HFAC+ stimulation were applied concurrently starting at 5 min following glucose ingestion and for the entire duration (4 h) of the OGTT experiment. Note: A baseline decrease during HFAC + stimulation experiments was due to lasting attenuation of FPG with HFAC + stimulation applications * p = 0.004, ** p = 0.003.

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  Figure 6. HFAC + stimulation may have a large therapy window. Diabetic neuropathy initiates at the distal ends of nerves and moves centrally during T2DM progression (neuropathy progression shown in red on the depiction of the vagus nerve). Coinciding with vagus nerve degeneration is decreased vagal tone, HRV and heart rate recovery (HRR). Current pharmaceutical therapies typically start at the onset of T2DM (i.e., FPG ≥ 126 mg/dL). Created with biorender.com (accessed on 9 August 2023).

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  Figure 7. Autonomic neuropathy proceeds development of T2DM and progression of T2DM further promotes autonomic neuropathy. In parallel with autonomic dysregulation, other factors such as excess weight, little exercise, poor diet and genetics contribute to T2DM development. Methods to treat glycemic dysregulation associated with T2DM reverse autonomic dysfunction which promotes euglycemia. HRF: heart rate frequency, HRR: heart rate recovery Created with biorender.com (accessed on 29 July 2023).