CN119113399A

CN119113399A - Portal Plexus Nerve Stimulator for Blood Glucose Regulation

Info

Publication number: CN119113399A
Application number: CN202411629766.6A
Authority: CN
Inventors: 王守东; 赵闻
Original assignee: Hangzhou Shenluo Medical Technology Co ltd
Current assignee: Hangzhou Shenluo Medical Technology Co ltd
Priority date: 2024-11-14
Filing date: 2024-11-14
Publication date: 2024-12-13

Abstract

The application discloses a hepatic portal nerve stimulator for regulating blood sugar, which comprises a pulse generator and an electrode, wherein the pulse generator is programmed to guide pulse electric signals at a frequency of 1kHz to 10kHz, an amplitude of 0.1mA to 10mA and a pulse width of 10 microseconds to 50 microseconds and guide pulse electric signals at a frequency of 1Hz to 100Hz, an amplitude of 0.1mA to 10mA and a pulse width of 100 microseconds to 500 microseconds, one end of the electrode is capable of being implanted at a hepatic portal nerve plexus part of a subject, and the other end of the electrode is connected with one end of the pulse generator and used for receiving pulse signals and electrically stimulating at the electrode based on the received pulse signals. The stimulation of the hepatic portal nerve plexus by the hepatic portal nerve stimulator of the application can regulate the blood glucose level of a subject.

Description

Hepatic portal nerve stimulator for regulating blood sugar

Technical Field

The invention relates to the technical field of medical appliances, in particular to a hepatic portal nerve plexus stimulator for regulating blood sugar.

Background

The nerve regulation technique is a method for regulating body functions by using a nervous system, and realizes the regulation of physiological processes by intervening nerve signal transduction or activity. Such techniques include a variety of methods such as electrical stimulation, optogenetics, sonic stimulation, and the like. Neuromodulation techniques have been widely studied and applied in a variety of fields, such as pain management, neurological disease treatment, metabolic regulation, and the like. However, the mechanism of neuromodulation in human blood glucose regulation has not been studied and applied.

Disclosure of Invention

The invention aims to provide a hepatic portal nerve stimulator for regulating blood sugar.

The invention provides a hepatic portal nerve stimulator for regulating blood sugar, which comprises a pulse generator and an electrode;

The pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1kHz to 10kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds, and to direct the pulsed electrical signal at a frequency of 1Hz to 100Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds;

one end of the electrode can be implanted into the hepatic portal plexus part of the subject, and the other end of the electrode is connected with one end of the pulse generator and is used for receiving pulse signals and electrically stimulating the electrode based on the received pulse signals.

In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1kHz to 5kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds.

In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 5kHz to 10kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds.

In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1Hz to 30Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 30Hz to 70Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 70Hz to 100Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

In some embodiments, the pulse generator is programmed to perform a single electrical stimulation of the subject's hepatic portal plexus by at least 1-5 min.

In some embodiments, the pulse generator is programmed to periodically sustain stimulation of the subject's hepatic portal plexus.

In some embodiments, the pulse generator is programmed to stop electrical stimulation for 48 hours as a cycle of electrical stimulation of the hepatic portal plexus of the subject for 24 hours.

In some embodiments, the neurostimulator further comprises a programmable logic device for sending instructions to the pulse generator, the pulse generator for determining the frequency and duration to be output based on the instructions.

The stimulation of the hepatic portal nerve plexus by the hepatic portal nerve stimulator of the application can regulate the blood glucose level of a subject.

Drawings

Fig. 1a and 1b show the results of intravenous glucose tolerance test of SD rats.

FIG. 2 shows the 24-hour blood glucose monitoring results of 1Hz-100Hz electrically stimulated chinamarry pigs.

FIG. 3 shows the results of 24-hour blood glucose monitoring of 1kHz-10kHz electrically stimulated chinamarry pigs.

FIG. 4 shows the results of c-fos detection for SD rats.

FIG. 5 shows the results of the peak blood glucose elevation rate of 1kHz-10kHz electrically stimulated chinamarry pigs.

FIG. 6 shows the results of the peak blood glucose reduction rate of 10Hz-100Hz electrically stimulated chinamarry pigs.

Figure 7 shows a graph of blood glucose at 24 hours after a patient receives 24 hours of high band continuous stimulation.

Figure 8 shows a graph of blood glucose at 24 hours after a patient receives 24 hours of low frequency band continuous stimulation.

FIG. 9 shows the results of the peak blood glucose rise rate of patients receiving 1kHz-10kHz electrical stimulation.

FIG. 10 shows the results of the peak blood glucose reduction rate of patients receiving 1HZ-100Hz electrical stimulation.

Fig. 11 is a photograph showing a procedure for surgically operating an implanted neurostimulator.

Fig. 12 shows a schematic diagram of a neural stimulator in one embodiment.

Fig. 13 shows a schematic diagram of a neural stimulator in yet another embodiment.

Fig. 14 shows a schematic diagram of a neural stimulator in another embodiment.

Fig. 15 shows a schematic diagram of a neural stimulator in yet another embodiment.

Detailed Description

For a better understanding of the invention, its full technical route, and its advantages, reference should be made to the following detailed description of the invention taken in conjunction with the accompanying drawings. The embodiments described below are only some of the embodiments of the present invention and do not include all of the embodiments. Based on the embodiments of the present invention, other embodiments that can be obtained by a person skilled in the art without any inventive effort are within the scope of the present invention.

In the examples described below, unless otherwise indicated, conventional methods used are recognized or commonly employed by those skilled in the art, and instruments, reagents, consumables, etc. used in the examples of the present invention are available through normal commercial routes.

The health problem caused by too high or too low blood sugar is focused on reducing the blood sugar in the medical community at present, the main way is to rely on medicines, and no other mature regulation means exists clinically.

In order to overcome the above problems, the medical community has been largely explored. The medical community finds that the blood sugar can be reduced by performing medical therapy on the hepatic portal nerve plexus, the celiac vagus nerve, the pancreatic sympathetic nerve and other parts.

For example, in the medical search most relevant to the present application, one of them was carried out by Cotero et al in the article "Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine" in journal Nature Biomedical Engineering, 2022, which carried out a peripheral focused ultrasound stimulation (PERIPHERAL FOCUSED ULTRASOUND STIMULATION, pFUS) test on the hepatic plexus. Cotero et al found that the hepatic plexus was ultrasonically stimulated under a parametric selection of 1.1Mhz carrier, 135mV peak signal generation amplitude, 150us pulse duration, 5Hz pulse repetition frequency, and the test experiment showed repeatable blood glucose lowering.

Secondly Waataja et al, in the paper "Use of a bio-electronic device comprising of targeted dual neuromodulation of the hepatic and celiac vagal branches demonstrated enhanced glycemic control in a type 2 diabetic rat model as well as in an Alloxan treated swine model" of journal Frontiers in Neuroscience of 2022, found that the glucose tolerance of the test subjects was significantly improved, i.e. showed a decrease in blood glucose, by simultaneously electrically stimulating the celiac vagus nerve with an amplitude of 8 mA, a pulse width of 4 ms, a frequency of 1 Hz, and electrically stimulating the hepatic vagus nerve with an amplitude of 8 mA, a pulse width of 90 μs, a frequency of 5000 Hz, i.e. by electrically stimulating the vagal branches of the liver and the celiac, etc.

In conclusion, the medical community currently only finds the electric stimulation regulation mechanism of the vagus nerve of the liver and the pFUS regulation mechanism of the hepatic portal nerve plexus, and only finds the regulation mechanism of the hepatic portal nerve plexus on lowering blood sugar, and the medical community does not conduct nerve regulation research on the hepatic portal nerve Cong Zheyi based on electric stimulation, and does not find the regulation mechanism of the hepatic portal nerve on raising blood sugar by stimulation in all other stimulation fields including electric stimulation and pFUS.

On the basis of the above-mentioned studies in the medical community, the applicant conducted a great deal of experimental investigation and applied the mechanism through a medical device, a nerve electric stimulator, on the basis of the new mechanism discovered. The applicant emphasizes that the present state of the art of medical science is expressed with the aim of explaining that the current researchers do not conduct research in the field of electrical stimulation for the hepatic portal nerve plexus, i.e. there is no motivation to conduct conventional parameter selection in this field to achieve, let alone to choose certain parameters to achieve, an increase in blood glucose.

The medical device product provided by the applicant is explained below:

the application provides a hepatic portal nerve stimulator for regulating blood sugar, which comprises a pulse generator and electrodes;

In one embodiment, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1kHz to 5kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds. At a frequency of 1kHz to 5kHz, the blood sugar peak value is obviously increased, and the blood sugar increase amplitude is gentle for a subject, so that the blood sugar is prevented from being sharply increased, and the blood sugar is safer.

In one embodiment, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 5kHz to 10kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds. At a frequency of 5kHz to 10kHz, the blood glucose peak elevation rate is rapidly increased, and the blood glucose elevation efficiency is high.

In one embodiment, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1Hz to 30Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds. At frequencies of 1Hz to 30Hz, the blood glucose peak decrease is relatively pronounced, with rapid increases in blood glucose peak decrease rate as the frequency increases, at which the blood glucose lowering efficiency is higher for the subject.

In one embodiment, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 30Hz to 70Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds. At frequencies of 30Hz to 70Hz, the blood glucose peak reduction is more pronounced, with increasing frequency, the blood glucose peak reduction rate steadily increases, and for subjects, at this frequency, the blood glucose reduction efficiency is higher and the blood glucose reduction amplitude is smoother, and safer.

In one embodiment, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 70Hz to 100Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds. At frequencies from 70Hz to 100Hz, the blood glucose peak decrease is more pronounced for the subject, and as the frequency increases, the blood glucose peak decrease rate decreases, but at this frequency the blood glucose lowering effect is still more pronounced.

The connection relationship between the pulse generator and the electrode as the device itself and between the pulse generator and the electrode is consistent with the prior art, and is not the focus of the application, which is described only generally.

The pulse generator can be subcutaneously implanted in a patient or hung outside the patient, and the electric stimulation excited by the pulse generator can be smoothly transmitted to the hepatic portal nerve of the patient through the electrode.

Generally, the pulse generator may include machine readable data containing instructions for generating and transmitting suitable therapeutic signals. Other elements of the pulse generator may include one or more processors, memory, and/or input-output devices. Accordingly, processes for providing adjustment signals and performing other related functions may be performed by computer-executable instructions contained on a computer-readable medium. The pulse generator may include a plurality of portions, elements and/or subsystems (e.g., for directing signals according to multiple signal delivery parameters). The pulse generator may also receive and respond to input signals derived from one or more sources. The input signal may direct or affect the manner in which the treatment instructions may be selected, executed, updated and/or otherwise executed.

The pulse generator may obtain energy from an external power source to generate the therapeutic signal. In another embodiment, the pulse generator may obtain energy from an internal power source in addition to, or alternatively to, an external power source to generate the therapeutic signal. For example, the implanted pulse generator may include a non-rechargeable battery or a rechargeable battery to provide such energy. When the internal power source comprises a rechargeable battery, an external power source may be used to recharge the battery. The external power source may be charged accordingly from a suitable power source.

Specifically, as shown in FIG. 12, in one embodiment, the neurostimulator includes a pulse generator, an electrode lead removably and electrically connected to the pulse generator, and an electrode disposed at an end of the electrode lead. In this embodiment, the electrode lead is implanted in the patient, and the electrode is positioned in close proximity to the neural target to stimulate the neural target by outputting the electrical stimulation signal via a pulse generator attached to the skin of the human body. The advantages of the embodiment are that the wound is small for patients, the short-term implantation can be performed, the corresponding diseases can be treated in a short period, and the method can also be used for testing the effectiveness of treatment before the long-term stimulator is implanted.

In one embodiment, as shown in fig. 13, the neurostimulator is a fully implanted neurostimulator. The pulse generator is provided with a battery and a receiving coil, and is implanted into a human body together with the nerve stimulating electrode to work, and the external power supply supplies power by using the transmitting coil after the electricity consumption in the pulse generator is finished so as to keep the nerve stimulator to work. The advantage of the embodiment is that the pulse generator can be implanted in the body for a long time, so that the daily influence on a patient is reduced, and the power can be supplied by using a charger (not shown) after the electric quantity is consumed.

In one embodiment, as shown in fig. 14, the neurostimulator is a fully implanted neurostimulator. The pulse generator does not use a battery to store energy, the energy storage unit is a capacitor, and the operation of the pulse generator can be realized by continuously carrying out wireless power supply with a wireless power supply device which is matched with the pulse generator and is arranged outside a human body. The pulse generator has the advantages that the pulse generator is not provided with a battery inside, the volume of the pulse generator implanted in a human body is greatly reduced, the implantation wound is smaller, the safety is higher, the problem of the battery cycle life is solved, and the battery of the external power supply device is replaced after the battery cycle life is exhausted, so that the pulse generator does not need to be taken out by a surgical operation.

In one embodiment, as shown in fig. 15, the neurostimulator is a fully implanted neurostimulator. Compared to the embodiment shown in fig. 14, the electrode leads are reduced, and the electrodes are directly arranged on the pulse generator, and the pulse generator is directly arranged near the nerve target point during implantation to stimulate the target nerve.

The applicant has carried out an electrical stimulation test on the animal body with the above-mentioned parameter selection. The applicant needs to explain that in the research field of the detail of nerve regulation, animal experiments and human experiments show extremely sufficient anastomosis, and parameters of animal experiments are generally accepted to be directly used in clinic.

For example, in "Yuan, H., lin, J.K. & Wang, W.D. (2016). Effect of

transcutaneous vagus nerve stimulation in a chronic feline epilepsy model study. Brain Stimulation, 9(6), 796-803"、"Campbell, J. N.,&Meyer, R. A. (2006). Mechanisms of neuropathic pain. Neuron, 52(1), 77-92"、"Fregni, F., Boggio, P. S., Lima, M. C., Ferreira, M. J., Wagner, T.,Rigonatti, S. P., ...&Pascual-Leone, A. (2006). A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of depression. Neurology, 66(6), 448-450"、"Song, Z., Ultenius, C., Meyerson, B. A., Linderoth, B. (2009). Pain relief by spinal cord stimulation involves serotonergic mechanisms: An experimental study in a rat model of mononeuropathy. Pain, 147(1-3), 241-248" In a large number of documents, the method is well verified.

For this, the applicant conducted the following animal experiments multiple and repeatedly:

SD rat experiment

1. Rat surgical procedure

After the rats were anesthetized, the abdominal cavities of the rats were opened, the hepatic portal sites were exposed, and the stimulating electrodes were fixed at the hepatic portal sites, as shown in fig. 11 (left panel).

2. Intravenous glucose tolerance test (Intravenous Glucose Tolerance Test IVGTT)

The experiment was used to test the glucose metabolism of rats and was specifically performed by intravenous injection of 500mg/Kg glucose into rats under anesthesia and then testing the rats for blood glucose excursion over two hours, each IVGTT test lasting 2 hours.

3. Hepatic plexus stimulation

Rats were subjected to an IVGTT test prior to initiation of stimulation to obtain a baseline value for glucose tolerance, and then to a 5 minute start of hepatic plexus stimulation (high frequency/low frequency, uninterrupted stimulation) and to a second IVGTT test, and after termination of the test, the stimulation was turned off.

C-fos detection

Immediately after the stimulation, the SD rats were fixed by 4% paraformaldehyde injection, and then the liver tissues were collected and c-fos was detected by ELISA.

Bama miniature pig experiment

1. Surgical operation

After general anesthesia of the experimental pigs, a stimulating electrode was implanted in the portal part of the liver, and an adjustable current pulse generator was implanted subcutaneously in the abdomen, as shown in fig. 11 (right panel), and a 24-hour blood glucose monitor (CGM) was installed in the left back of the pigs.

2. Blood glucose monitoring

The whole-course diet and time of the experimental pigs are fixed. The experimental pigs were subjected to a 3-day cycle mode, "no stimulation was started for 2 days, then stimulation was started for 24 hours (uninterrupted stimulation)", and the blood glucose change values were recorded.

Experimental results

As shown in FIG. 1a and FIG. 1b, from the results of the intravenous glucose tolerance test of SD rats, it can be seen that the electrical stimulation of 1Hz-10Hz can significantly lower the blood glucose peak value below the baseline level, while the electrical stimulation of 1kHz-10kHz greatly increases the blood glucose peak value beyond the baseline level.

C-fos is a protein marker commonly used in neuroscience research to detect neuronal activity. As shown in FIG. 4, the c-fos detection result of the rat shows that the hepatic portal plexus can activate the neuron activity of the hepatic portal plexus by receiving the current stimulation in the frequency range of 1Hz-100Hz, and can inhibit the neuron activity of the hepatic portal plexus by receiving the current stimulation of 1kHz-10kHz (the data are mean value plus or minus standard deviation).

The same phenomenon was further verified in live pigs. As shown in FIG. 2, the 24-hour blood glucose monitor of live pigs showed that the 24-hour blood glucose of experimental pigs was significantly reduced from baseline under 10Hz-100Hz electrical stimulation. As shown in FIG. 3, blood glucose was significantly increased in experimental pigs at an electrical stimulation frequency of 1kHz-10kHz for 24 hours.

Since high frequencies are inhibitory to neurotransmission, the electrical stimulation is more inhibitory as the frequencies increase. As shown in fig. 5, the blood glucose increasing effect appears from 1kHz, and the blood glucose peak increasing rate increases with increasing frequency. At 7kHz the blood glucose peak rise rate has reached about 70% and at 10kHz the blood glucose rise rate has exceeded 120%. The rise rate in fig. 5 = (highest blood glucose value measured in test frequency band-highest blood glucose value of baseline)/last blood glucose value of baseline is 100%.

As shown in FIG. 6, the blood glucose peak lowering rate gradually increased under the electric stimulation of 1Hz-50Hz, and the blood glucose peak lowering rate exceeded 20% at 1 Hz. The effect of reducing blood sugar is better at 30Hz-70Hz, and the peak reduction rate of blood sugar is more than 40% at 30Hz and 70 Hz. Under the electric stimulation of 50Hz-100Hz, the blood sugar peak value reduction rate gradually decreases, and the blood sugar peak value reduction rate still reaches about 20% under 100 Hz. The decrease rate in fig. 6 = (baseline blood glucose maximum value) - (blood glucose maximum value measured in test frequency band)/baseline blood glucose final value is 100%.

To further verify the accuracy of animal experiments, the applicant has also conducted the following human clinical experiments with careful attitudes.

Clinical trials

Blood sugar increasing experiment for frequent hypoglycemia patients

1. Surgical operation

After general anesthesia of the patient, a stimulating electrode is implanted in the portal area of the liver, and an adjustable current pulse generator is implanted subcutaneously in the abdomen, and a 24-hour blood glucose monitoring instrument (CGM) is installed in the buttocks of the patient.

2. Blood glucose monitoring

The whole course diet and time of the patient are fixed. Firstly, a program control instrument is turned off for one week, the basic blood sugar value (base line) of a patient is recorded, then the patient is turned on for 2 weeks, high frequency band is used for continuous stimulation during program control, parameter adjustment is carried out, after ideal blood sugar is obtained during test, the constant stimulation of parameters of fixed degree is carried out, and one week of blood sugar value (1 kHZ-10 kHZ) is recorded.

As shown in FIG. 7, the baseline is a graph of blood glucose at 24 hours at ordinary times for patients with frequent hypoglycemia, and 1kHz, 5kHz, and 10kHz are graphs of blood glucose 24 hours after receiving 24 hours of high-frequency continuous stimulation, respectively. At an electrical stimulation frequency of 1kHZ-10kHZ, the patient had a significant rise in blood glucose over 24 hours.

As shown in fig. 9, the blood glucose increasing effect appears from 1kHz, and the blood glucose peak increasing rate increases with increasing frequency. The blood glucose peak elevation rate at 3kHz exceeded 20%, the blood glucose peak elevation rate at 7kHz had reached about 60%, and the blood glucose elevation rate at 10kHz exceeded 100%.

Blood sugar reducing experiment for diabetics

1. Surgical operation

After general anesthesia of the patient, a stimulating electrode is implanted in the portal area of the liver, and an adjustable current pulse generator is implanted subcutaneously in the abdomen, and a 24-hour blood glucose monitor (CGM) is installed on the patient's upper buttocks.

2. Blood glucose monitoring

The whole course diet and time of the patient are fixed. Firstly, a program control instrument is turned off for one week, the basic blood sugar value (base line) of a patient is recorded, then the patient is turned on for 2 weeks, continuous stimulation is carried out by using a low frequency band during program control, parameter adjustment is carried out, the continuous stimulation of a fixed program parameter is carried out after ideal blood sugar is obtained during test, and the blood sugar value (1 Hz-100 Hz) of one week is recorded.

As shown in FIG. 8, the baseline is a graph of blood glucose for 24 hours at ordinary times for diabetics, and 1Hz, 30Hz, 70Hz, and 100Hz are graphs of blood glucose for 24 hours after receiving the low-frequency continuous stimulation, respectively. At an electrical stimulation frequency of 1-100Hz, the blood glucose of the patient is significantly reduced in 24 hours.

As shown in FIG. 10, the blood glucose peak reduction rate gradually increased under the electrical stimulation of 1Hz-50 Hz. The effect of reducing blood sugar by the electric stimulation at 30Hz-70Hz is better, and the peak reduction rate of blood sugar at 30Hz and 70Hz is more than 50 percent. Under the electric stimulation of 50Hz-100Hz, the blood sugar peak value reduction rate gradually decreases, the blood sugar peak value reduction rate exceeds 10% under 1Hz, and the blood sugar peak value reduction rate still exceeds about 20% under 100 Hz.

The applicant believes that this may be explained by the mechanism by which the portal plexus can acquire blood glucose level signals from blood monitored by surrounding hepatocytes and pass up into the hypothalamus. Whereas portal neurons receive different means of neuromodulation (activation/inhibition) of neuronal activity. The activated hepatic plexus has an increased discharge frequency and thus transmits up to the hypothalamus a blood glucose signal higher than the hepatocyte-monitor blood glucose signal (basal value), whereas in the inhibited hepatic plexus, neuronal excitability is inhibited at the site and its discharge frequency is decreased and thus transmits up to the hypothalamus a blood glucose signal lower than the hepatocyte-monitor blood glucose signal (basal value). The arciform nuclear neurons (ARCs) in the hypothalamus are able to recognize this glycemic signal, and the POMC neurons and AgPR neurons in ARCs can regulate appetite to affect feeding behavior to regulate blood glucose. And ARC neurons are able to further transmit blood glucose signals to paraventricular nuclear neurons (PVN), which are the regulatory centers of the neuroendocrine system, in the hypothalamus.

PVN can regulate the relevant regulated glucose metabolic pathway by secreting multiple neuroendocrine hormones (1) hypothalamic-pituitary-adrenocortical alcohol axis (HPA axis) PVN can secrete Corticotropin Releasing Hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn affects the secretion of cortisol by the adrenal cortex. Cortisol is an important stress hormone that promotes glucose production and release, thereby increasing blood glucose levels. (2) Hypothalamic-pituitary-thyroxine (HPT) axis PVN can secrete Thyrotropin Releasing Hormone (TRH) which stimulates the anterior pituitary to release Thyrotropin (TSH), which in turn stimulates thyroxine secretion, thyroxine can increase insulin sensitivity and promote glucose utilization, thereby regulating blood glucose levels.

In summary, the applicant provides that the 1kHz-10kHz current stimulates the hepatic portal nerve plexus to obviously raise the blood sugar level so as to solve the problem of lower blood sugar, and the 1Hz-100Hz current stimulates the hepatic portal nerve plexus to obviously lower the peak value of blood sugar so as to solve the problem of higher blood sugar.

Claims

1. A neural stimulator for regulating blood glucose, comprising a pulse generator and an electrode;

2. The neurostimulator of claim 1, wherein the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1kHz to 5kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds.

3. The neurostimulator of claim 1, wherein the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 5kHz to 10kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds.

4. The neurostimulator of claim 1, wherein the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1Hz to 30Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

5. The neurostimulator of claim 1, wherein the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 30Hz to 70Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

6. The neurostimulator of claim 1, wherein the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 70Hz to 100Hz, an amplitude of 0.1mA to 10mA, and a pulse width of 100 microseconds to 500 microseconds.

7. The neurostimulator of any one of claims 1 to 6, wherein the pulse generator is programmed to perform a single electrical stimulation of the subject's hepatic plexus by at least 1-5 min.

8. The neurostimulator of any of claims 1 to 6, wherein the pulse generator is programmed to periodically sustain stimulation of the subject's hepatic plexus.

9. The neurostimulator of claim 8, wherein the pulse generator is programmed to stop electrical stimulation for 24 hours as a cycle of electrical stimulation of the subject's hepatic portal plexus.

10. The neurostimulator of any of claims 1 to 6 further comprising a programmable controller for sending instructions to the pulse generator for determining the frequency and duration to be output based on the instructions.