Vagus nerve modulation for the treatment of hypoglycemic conditions

Abstract

Neuromodulation systems and methods for the treatment or control of hypoglycemia are provided. In one example, a method of treating hypoglycemia in a subject includes applying a first electrical signal to a first nerve or organ of the subject using a neuromodulation system, where the first electrical signal initiates nerve stimulation or a nerve block on the first nerve or organ of the subject, and optionally applying a second electrical signal to a second nerve or organ of the subject, where the second electrical signal initiates nerve stimulation or a nerve block on the second nerve or organ of the subject.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed as a PCT international application on November 23, 2022, and claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 282,397, filed on November 23, 2021, which is incorporated by reference in its entirety herein.

[0002] Introduction The annual incidence of severe hypoglycemia (requiring third party assistance) is 1.0-1.7 episodes per patient per year. Hypoglycemia can cause loss of consciousness, stroke, coma or death. Repeated hypoglycemic episodes are associated with cardiovascular disease. Insulin therapy-induced hypoglycemia (low plasma glucose (PG) typically below 70 mg / Dl) is problematic for diabetic patients. Repeated hypoglycemic episodes are associated with cardiovascular disease, and severe hypoglycemia (PG below approximately 54 mg / Dl and requiring third party assistance) can cause loss of consciousness, stroke, coma and death.

[0003] There are approximately 235,000 emergency department visits per year for the treatment of diabetic hypoglycemia, costing the health care system approximately $120 million per year. Severe nocturnal hypoglycemia is suspected to contribute to an estimated 6% of all deaths in diabetic patients under the age of 40 and can cause high levels of anxiety. Recent reports have shown that 10% of deaths in type 1 diabetes patients were caused by hypoglycemia. Hypoglycemia in diabetic patients is primarily attributed to diabetic medications such as sulfonylureas and more commonly insulin therapy. Insulin therapy-induced hypoglycemia occurs in both type 1 and type 2 diabetes patients.

[0004] As the percentage of the population suffering from type 2 diabetes mellitus (T2DM) increases, hypoglycemia has become a problem in this diabetic segment. Insulin therapy for type 2 diabetes is prescribed primarily in the later stages of the disease (HbA1c approximately 9% or higher). This segment of the T2DM population is large and growing with a total of 80 million patients worldwide. Henderson et al. reported that 73% of insulin-dependent T2DM subjects experience hypoglycemic episodes annually, with 15% having severe episodes (Henderson, 2003).

[0005] Treatment of hypoglycemia typically involves injections of dextrose or glucagon, and / or ingestion of fast-acting carbohydrates. However, these treatments are not ideal for nocturnal hypoglycemia and / or are contraindicated for severe hypoglycemic episodes. Insulin pump therapy in conjunction with glucose sensor technology reduces the risk of hypoglycemia, but it remains a significant issue (Guzman, 2020; Al Hayek, 2018). Less than 1% of insulin-dependent diabetes patients use insulin pumps, which are necessitated by the continued use of external devices, with associated maintenance and tolerance issues (Schade, 2006; Walsh, 2015; Bonfanti, 2016).

[0006] Insulin therapy is necessary for people with type 1 diabetes for the rest of their lives. Approximately 30 million people with type 1 diabetes worldwide require insulin (Garg, Rewers, & Akturk, 2018). The average individual with type 1 diabetes experiences approximately two episodes of symptomatic hypoglycemia per week. Severe hypoglycemia has an annual prevalence of 30-40% and an annual incidence rate of 1.0-1.7 episodes per patient (McCrimmon & Sherwin).

[0007] With an increasing number of people suffering from type 2 diabetes mellitus (T2DM), hypoglycemia has become an issue in this diabetic segment. Insulin therapy for T2DM is primarily prescribed in the later stages of the disease (HbA1c approximately 9% or higher). This segment of the T2DM population is large and growing with a total of 80 million patients worldwide (Garg et al., 2018). A study by Henderson et al. reported that 73% of insulin-dependent T2DM subjects experience hypoglycemic episodes annually, with 15% having severe episodes (Henderson, Allen, Deary, & Frier, 2003).

[0008] Treatment typically involves ingestion of fast-acting carbohydrates, injection of glucagon, or nasal inhalation of glucagon powder. However, these treatments are not ideal, especially for severe hypoglycemic episodes, and new therapeutic options are needed. Thus, new systems and methods for the treatment of hypoglycemia are needed.

[0009] Vagus nerve modulation for the treatment of hypoglycemic conditions In some aspects, the present disclosure provides systems and methods for hypoglycemic vagus nerve stimulation (HVNS). In certain embodiments, the HVNS system includes a continuous glucose monitor (CGM), a stimulation electrode / lead cranially attachable to the celiac branch of the posterior vagus nerve (PVN), and an implantable pulse generator (IPG) in a closed loop with a programmer to change settings for therapy customization.

[0010] In some aspects, the present disclosure also provides a minimally invasive electrode implantation method. In certain embodiments, the method includes implanting an electrode in a subject to be treated using a minimally invasive laparoscopic technique with enhanced visualization of the posterior vagus nerve and the celiac branch for optimal electrode placement. This can be accomplished by ensuring laparoscopic location of the celiac branch for correct electrode placement over the PVN.

[0011] In some aspects, the disclosure provides various operating parameters for HVNS. In certain embodiments, implementations of the method using selected operating parameters are effective to increase plasma glucose by at least about 20 mg / dL from a controlled clamp glucose level of 50 mg / dL within about 30 minutes after treatment in a subject.

[0012] In some aspects, the present disclosure provides for safe stimulation of the vagus nerve and end organs: little or no adverse behavior or organ damage is observed as a result of stimulation or gross necropsy from the animal studies presented in the examples of the present disclosure.

[0013] In some aspects, a system for treating hypoglycemia in a subject includes: (1) at least one electrode adapted to be positioned on the posterior vagus nerve (PVN) of the subject or on a celiac vagal branch of the PVN and to deliver an electrical signal to the posterior vagus nerve (PVN) of the subject or on a celiac vagal branch of the PVN; (2) an implantable pulse generator operably connected to the at least one electrode, the implantable pulse generator comprising a power module and a programmable therapy delivery module, the programmable therapy delivery module configured to deliver at least one therapy program, the at least one therapy program including at least one electrical signal therapy applied to the PVN via the at least one electrode; and (3) an external component comprising a communications system and a programmable storage and communications module, the programmable storage and communications module configured to store the at least one therapy program and to transmit the at least one therapy program to the implantable pulse generator. and (4) a glucose sensor operatively connected to the implantable pulse generator and the external component, the glucose sensor configured to continually monitor plasma glucose of the subject and to detect an increase or decrease in plasma glucose from a predetermined threshold level, wherein the implantable pulse generator is triggered to deliver the at least one electrical signal therapy when the subject's plasma glucose is equal to or less than a first predetermined threshold, and the implantable pulse generator stops delivering the at least one electrical signal therapy when the subject's plasma glucose is equal to or greater than a second predetermined threshold, the at least one electrical signal therapy comprising an electrical signal pattern having a frequency of about 1 Hz to about 200 Hz, a pulse width of about 0.1 milliseconds (ms) to about 10 ms in steps of about 0.1 ms, and a pulse amplitude of about 0.1 mA to about 12 mA in steps of about 0.1 mA, and the electrical signal therapy is configured to initiate neural stimulation to the subject's PVN.

[0014] In some embodiments, a method of treating hypoglycemia in a subject includes applying at least one electrical signal therapy to the subject's posterior vagus nerve (PVN) or the celiac vagus nerve branch of the subject's PVN using the system.

[0015] In another example, a system for treating hypoglycemia in a subject includes: (1) a first electrode adapted to be placed on a first nerve or organ and to deliver an electrical signal to the first nerve or organ; (2) optionally, a second electrode adapted to be placed on a second nerve or organ and to deliver an electrical signal to the second nerve or organ; and (3) an implantable pulse generator operably connected to the first and / or second electrodes, the implantable pulse generator comprising a power module and a programmable therapy delivery module, the programmable therapy delivery module configured to deliver at least one therapy program including a first therapy program and optionally a second therapy program, the first therapy program being a first therapy program and optionally a second therapy program. the first and / or second electrical signals are each configured to initiate activity on the first and / or second nerves or organs, respectively, the activity being nerve stimulation or nerve block; and (4) an external component comprising a communications system and a programmable storage and communications module, the programmable storage and communications module configured to store at least one therapy program and communicate the at least one therapy program to the implantable pulse generator.

[0016] In some embodiments, a method of treating hypoglycemia in a subject includes: (1) applying a first electrical signal to a first nerve or organ of the subject using a system as described herein, where the first electrical signal initiates nerve stimulation or a nerve block; and (2) optionally applying a second electrical signal to a second nerve or organ of the subject using the system, where the second electrical signal initiates nerve stimulation or a nerve block.

[0017] In some embodiments, the first and / or second electrical signals are each independently configured to upregulate or downregulate activity on the first and / or second target nerves or organs, respectively. In some embodiments, the first and second electrical signals are applied simultaneously, synchronously, intermittently, during substantially the same time, during substantially different times, or in a coordinated manner. In some embodiments, the first and / or second electrical signal treatments are each applied sequentially to the first target nerve or organ and / or the second target nerve or organ, respectively. In certain embodiments, the first electrical signal is an upregulation or stimulation signal.

[0018] In some embodiments, the method further comprises a glucose sensor configured to continuously monitor plasma glucose of the subject, the glucose sensor operatively connected to the implantable pulse generator and the external component. In some embodiments, the glucose sensor is configured to detect an increase or decrease in plasma glucose from a predetermined threshold level. In some embodiments, the implantable pulse generator is triggered to deliver the first and / or second electrical therapies when the subject's plasma glucose is equal to or less than a first predetermined threshold, and the implantable pulse generator stops delivering the first and / or second electrical therapies when the subject's plasma glucose is equal to or greater than a second predetermined threshold.

[0019] In some embodiments, the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, the anterior vagus nerve, the posterior vagus nerve, the hiatus of the posterior nerve, the hepatic branch of the vagus nerve, the celiac branch of the vagus nerve, the splanchnic nerve, the renal nerve, the renal artery, the sympathetic nerve, the baroreceptor, the glossopharyngeal nerve, the duodenum, the jejunum, the ileum, the small intestine, the colon, the stomach, the esophagus, the liver, the spleen, the pancreas, and combinations thereof. In certain embodiments, the first nerve or organ is the celiac branch of the posterior vagus nerve.

[0020] In some embodiments, the method further includes a glucose sensor configured to continuously monitor plasma glucose of the subject having type 1 or type 2 diabetes, the glucose sensor operatively connected to the implantable pulse generator and the external component. In at least these exemplary embodiments, the glucose sensor is configured to detect an increase or decrease in plasma glucose from a predetermined threshold level. In related embodiments, the implantable pulse generator is triggered to deliver the first and / or second electrical therapies when the subject's plasma glucose is at or below a first predetermined threshold, and the implantable pulse generator stops delivering the first and / or second electrical therapies when the subject's plasma glucose is at or above a second predetermined threshold.

[0021] Similar to the above-described embodiments, a subject having type 1 or type 2 diabetes can be treated, and the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, the anterior vagus nerve, the posterior vagus nerve, the hiatus of the posterior nerve, the hepatic branch of the vagus nerve, the celiac branch of the vagus nerve, the splanchnic nerve, the renal nerve, the renal artery, the sympathetic nerve, the baroreceptor, the glossopharyngeal nerve, the duodenum, the jejunum, the ileum, the small intestine, the colon, the stomach, the esophagus, the liver, the spleen, the pancreas, and combinations thereof. In certain embodiments, the first nerve or organ is the celiac branch of the posterior vagus nerve.

[0022] In some embodiments, the first nerve or organ and the second nerve or organ are different. In some embodiments, the first electrical signal is applied to a hepatic branch of the vagus nerve or anterior vagus nerve centered on a bifurcation of the hepatic nerve. In some embodiments, the first electrical signal is applied to a celiac branch of the vagus nerve or anterior vagus nerve centered on a bifurcation of the celiac nerve, liver, pancreas, or both.

[0023] In some embodiments, the first and / or second electrical signal each have an on-time and an off-time, and the off-time is selected to allow at least partial recovery of activity of the first and / or second nerve or organ. In some embodiments, the on-time is configured to initiate upon detection of a plasma glucose level of about 50 mg / dL or less, about 60 mg / dL or less, about 70 mg / dL or less, about 80 mg / dL or less. In some embodiments, the first and / or second electrical signal treatment is configured to increase the plasma glucose level by at least about 5 mg / dL in about 10 minutes. In some embodiments, the first and / or second electrical signal treatment is configured to increase the plasma glucose level by at least about 10 mg / dL in about 20 minutes. In some embodiments, the first and / or second electrical signal treatment is configured to increase the plasma glucose level by at least about 20 mg / dL in about 30 minutes.

[0024] In some embodiments, the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, about 0.1 Hz to about 100 Hz, or about 1 Hz to about 20 Hz, while in other embodiments, the first electrical signal has a frequency of about 200 Hz to about 10 kHz.

[0025] In some embodiments, the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz, about 0.1 Hz to about 100 Hz, or about 1 Hz to about 20 Hz, while in other embodiments, the second electrical signal has a frequency of about 200 Hz to about 10 kHz.

[0026] In some embodiments, the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz, and the second electrical signal has a frequency of about 200 Hz to about 10 kHz.

[0027] In some embodiments, the first electrical signal and / or the second electrical signal each independently include a signal pattern, each signal pattern including pulses having a pulse width between about 10 microseconds and about 10,000 microseconds.

[0028] In other related embodiments, the pulses of the first and / or second electrical signals are monophasic pulses, or biphasic pulses, or combinations thereof. In some embodiments, the first and / or second electrical signals each independently have an on-time of about 30 seconds to about 30 minutes. In some embodiments, the first and / or second electrical signals each independently have a current amplitude in the range of about 0.01 mAmps to about 20 mAmps. In some embodiments, the first and / or second electrical signals each independently include an abrupt onset of the pulse, or an increase in current / voltage amplitude, or an increase in frequency, or an increase in pulse width, or combinations thereof, at or near the onset of application of the first and / or second electrical signals.

[0029] In some embodiments, the first and / or second electrical signal therapies are configured to be applied intermittently multiple times per day and over multiple days, and the first and / or second electrical signals each have a frequency selected to upregulate activity on the first nerve or organ and have an on-time and an off-time, the off-time selected to allow at least partial recovery of activity of the first nerve or organ.

[0030] In some embodiments, the programmable storage and communication module is configured to store and communicate two or more therapy programs, each therapy program distinct from the others and configured to be selected for communication.

[0031] In some embodiments, the system further comprises a transmitter operably connected to the glucose sensor, the transmitter configured to communicate data generated by the glucose sensor to an external communication device.

[0032] In some embodiments, the communication system is selected from the group consisting of antenna, blue tooth technology, radio frequency, Wi-Fi, light, sound, and combinations thereof, and the communication system is configured to communicate at least one parameter of the therapy program to an external communication device.

[0033] In some embodiments, a method of making a system for treating hypoglycemia in a subject includes: (1) connecting a first electrode to an implantable pulse generator and placing the first electrode on a first nerve or organ; (2) optionally connecting a second electrode to the implantable pulse generator and placing the second electrode on a second nerve or organ; (3) configuring a programmable therapy delivery module of the implantable pulse generator to deliver at least one therapy program including a first electrical signal therapy and optionally a second electrical signal therapy, where the first electrical signal therapy is configured to be applied to the first nerve or organ via the first electrode and the second electrical signal therapy is configured to be applied to the second nerve or organ via the second electrode, where the first and / or second electrical signals initiate nerve stimulation or nerve block, respectively; and (4) configuring a programmable storage and communication module of an external component to store the at least one therapy program and communicate the at least one therapy program to the implantable pulse generator.

[0034] Definitions and Interpretations of Selected Terms The term "about" is not intended to broaden or limit the extent of equivalents that may otherwise be given a particular value. The term "about" in the context of the present disclosure means a value within 10% (±10%) of the value immediately following the term "about", including any numerical value within this range, a value equal to the upper limit (i.e., +10%) of this range, and a value equal to the lower limit (i.e., -10%) of this range. For example, the value "100" encompasses any numerical value between 90 and 110, inclusive (except for "100%" which always has an upper limit of 100%).

[0035] In some examples, one or more components may be referred to herein as being "configured to," "configurable to," "operable / operative to," "adaptable to," "capable of," "adapted to," etc. Those skilled in the art will recognize that such terms (e.g., "configured to") can generally encompass active components and / or inactive components and / or standby components, unless the context requires otherwise.

[0036] As used herein, a "cycle" means one repetition of a repeating pattern of an electrical signal.

[0037] A "stimulation cycle" specifically refers to a low frequency stimulation signal.

[0038] As used herein, "simultaneously" generally means that in the context of multiple electrical signals being applied, the multiple electrical signals are applied synchronously or at about the same time, at least during one period of time.

[0039] As used herein, "duty cycle" refers to the percentage of time charge delivered to a nerve in one cycle. In embodiments, the duty cycle can be modified by reducing the pulse width and / or by adding inactive phases between pulses, or both.

[0040] "Frequency" as used herein means the reciprocal of a period measured in Hertz.

[0041] As used herein, "high duty cycle" refers to an electrical signal pattern having a duty cycle of about 76% or greater.

[0042] As used herein, "low duty cycle" refers to a signal pattern having a duty cycle of about 75% or less.

[0043] As used herein, "high frequency" generally refers to a frequency of about 200 Hz or higher. As used herein, "high frequency signal" generally refers to HFAC or HFAV having a frequency of about 200 Hz or higher. High frequency signals are used, in particular, to downregulate or block neural activity.

[0044] As used herein, "low frequency" generally refers to frequencies below about 200 Hz.

[0045] As used herein, a "low frequency signal" or a "low frequency stimulation signal" generally refers to a stimulation signal having a frequency of 199 Hz or less. The stimulation signal is used, among other things, to upregulate or stimulate neural activity.

[0046] As used herein, "HFAC" refers to high frequency alternating current.

[0047] As used herein, "HFAV" refers to high frequency alternating voltage.

[0048] As used herein, "Hz" refers to Hertz.

[0049] As used herein, "off-time" refers to a period of time during which no charge is delivered to a nerve. In embodiments, the off-time is on the order of seconds and / or minutes.

[0050] "On-time" refers to the period during which multiple microsecond and / or millisecond cycles and / or stimulation cycles and / or stimulation activity phases are applied to a nerve. In embodiments, on-time is on the order of seconds and / or minutes.

[0051] "Period" refers to the length of time of one charging phase and one recharging phase, and may include one or more pulse delays. "Stimulation period" refers specifically to the length of time of one charging phase and one recharging phase in a low frequency stimulation signal. The stimulation period may also include one or more pulse delays.

[0052] "Pulse amplitude" is the amperage or voltage height of a pulse relative to a baseline.

[0053] As used herein, "pulse delay" refers to a period of time during which the impedance across the parallel electrical pathway to the nerve is at or near 0 ohms, with the intent of avoiding any unwanted electrical signals being delivered to the nerve.

[0054] As used herein, "pulse width" refers to the length of time of a pulse.

[0055] As used herein, "ramp down" refers to a period at the end of the application of an electrical signal or between different patterns of electrical signals to a patient's nerve during which the pulse amplitude of the signal is reduced.

[0056] As used herein, "ramp up" refers to increasing the pulse amplitude at the beginning of an applied electrical signal or between different patterns of electrical signals until the desired amplitude for therapy is reached. The starting amplitude of ramping may be below the current / voltage threshold of the block.

[0057] As used herein, a "therapy cycle" refers to a discrete period of time that includes one or more on-times and off-times. The pattern of on-times and off-times within a therapy cycle can be repetitive, non-fixed, or random throughout the therapy schedule.

[0058] As used herein, "therapy parameters" include, but are not limited to, frequency, pulse width, pulse amplitude, on-time, off-time, and pattern of the electrical signal.

[0059] As used herein, "therapy schedule" refers to the time at which therapy cycles are initiated, the number of therapy cycles, the timing of the therapy cycles, and the delivery duration of the therapy cycles for at least one day per week.

[0060] As used herein, "nerve" generally includes a nerve or any portion thereof, including but not limited to nerve branches, nerve fibers, trunks, and branching points.

[0061] The "anterior vagus nerve (AVN)" or "anterior vagus trunk" innervates the anterior surface of the esophagus and is composed primarily of fibers from the left vagus nerve. The "posterior vagus nerve (PVN)" or "posterior vagus trunk" innervates the posterior surface of the esophagus and is composed primarily of fibers from the right vagus nerve. The anterior and posterior vagus nerves are two separate and distinct nerves.

[0062] As used herein, "hepatic branch" refers to the nerve branch of the anterior vagus nerve below the diaphragm. The hepatic branch includes any area from the anterior vagus nerve cranial to the hepatic branch. In particular, the hepatic branch carries afferent information from the pancreas to the brain and efferent information from the brain to the pancreas.

[0063] As used herein, "celiac branch" generally refers to the nerve branch of the posterior vagus nerve below the diaphragm. The celiac branch includes any area from the posterior vagus nerve cranial to the celiac branch. In particular, the celiac branch carries afferent information from the pancreas to the brain and efferent information from the brain to the pancreas.

[0064] "Celiac fibers" as used herein refers to afferent or efferent axons that travel within the length of the vagus nerve between the pancreas and the brain. Afferent axons travel from the pancreas through the celiac branch of the vagus nerve, where they then travel to the posterior vagus nerve below the level of the diaphragm. Afferent axons then enter the thoracic cavity, primarily in the right cervical region. Afferent axons then enter the brainstem and form synaptic connections. Efferent fibers are part of the parasympathetic nervous system. The preganglionic cell bodies of the efferent fibers are in the brainstem and travel the length of the vagus nerve (like the afferent fibers) in close proximity to the pancreas to its postganglionic neurons.

[0065] "Liver fibers" as used herein refers to afferent or efferent axons that travel within the length of the vagus nerve between the liver and the brain. Afferent axons travel from the liver through the hepatic branch of the vagus nerve, where they then travel to the anterior vagus nerve below the level of the diaphragm. Afferent axons then enter the thoracic cavity, primarily in the left cervical region. Afferent axons then enter the brainstem and form synaptic connections. Efferent fibers are part of the parasympathetic nervous system. The preganglionic cell bodies of efferent fibers are in the brainstem and travel the length of the vagus nerve (similar to afferent fibers) close to the liver to its postganglionic neurons.

[0066] Where a range is provided, the range is inclusive of both endpoints and all real numbers therebetween, for example the range 200 Hz to 25 kHz includes, for example, 201 to 25 kHz, 202 to 25 kHz, as well as 24,999 Hz to 200 Hz, 24,998 Hz to 200 Hz, and 201 Hz to 24,999 Hz, 202 Hz to 24,998 Hz.

[0067] The subject matter of embodiments of the present disclosure will now be described with reference to the various drawing figures, in which like elements are numbered identically throughout. [Brief description of the drawings]

[0068] [Figure 1] FIG. 1 is a graphical representation of the change in blood glucose over time following stimulation of the celiac branch of the vagus nerve in type 2 diabetic Zucker rats. [Diagram 2]1 shows a schematic diagram of a system in which an implantable glucose sensor communicates with a pulse generator to initiate vagus nerve stimulation. [Diagram 3] A schematic diagram of a system is shown in which an implantable glucose sensor first communicates with an external device attached to the outside of the skin, and then communicates with a pulse generator to initiate vagus nerve stimulation. [Figure 4] Anatomy of the vagus nerve showing the branching point of interest and what is meant cranial to the branching point. [Diagram 5] Example of a small IPG positioned intraperitoneally on the vagus nerve cranial to the celiac branch. [Figure 6] Example of a small IPG positioned on the vagus nerve cranial to the celiac branch in the cervical cavity. [Figure 7] Example of a small IPG positioned intraperitoneally on the vagus nerve cranial to the celiac branch. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] Referring now to FIG. 1, data was obtained using a T2DM Zucker rat model, demonstrating that stimulation of the celiac branch of the vagus nerve alone (1 Hz 1 mA, 4 ms pulse width), or the posterior vagus trunk above the celiac branch, caused a significant increase in plasma glucose of 42 mg / dL over 15 minutes. In some embodiments, the stimulation is intended to release glucagon from the alpha cells of the pancreas to regulate blood glucose. Without wishing to be bound by a particular theory, the ability of a continuous or intermittent signal to initiate an increase in plasma glucose is contemplated. In at least these exemplary embodiments, the system may include parameters that provide stimulation only to the target nerve. In related embodiments, stimulation and blockage may be used in combination to allow consistent treatment of elevated and depressed blood glucose levels in a subject.

[0070] Referring to Figures 2-3, the HVNS system includes a pulse generator, a lead placed on the vagus nerve, and an implantable glucose sensor (for monitoring plasma glucose levels). The sensor sampling rate is approximately 1 second to 10 minutes. Figure 2 shows a schematic diagram of the system where the implantable glucose sensor communicates with the pulse generator to initiate vagus nerve stimulation. The implantable sensor detects low plasma glucose levels and sends a signal to turn on the pulse generator. Figure 3 shows a schematic diagram of the system where the implantable glucose sensor first communicates with an external device attached to the outside of the skin, and then communicates with the pulse generator to initiate vagus nerve stimulation.

[0071] The communication between the pulse generator and the glucose sensor can be via, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light, or sound. In some embodiments, the glucose sensor is under a layer of skin and communicates to a device outside the skin using a battery to power the wireless communication. The communication between the glucose sensor and a device outside the body can be via, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light, or sound. The device outside the skin then communicates with the pulse generator through, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light, or sound. The implantable glucose sensor, or an external device communicating with the implantable glucose sensor, can also communicate with a smart device (such as a phone running an app) to display the plasma glucose level and send an alarm when the plasma glucose reaches an unsafe low level. The communication to the smart device can be via, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light, or sound. Stimulation parameters include a frequency range of 0.01 Hz to 200 Hz, a current or voltage amplitude range of 0.1 mA to 12 mA or 0.1 to 12 volts, and a pulse width range of 0.1 ms to 10 ms. Stimulation can be continuous or bursts with burst intervals ranging from milliseconds, seconds to minutes.

[0072] Stimulation sites include any segment of the vagus nerve, including the anterior or posterior vagus trunk below the diaphragm, and branches of the anterior vagus trunk, such as the celiac branch from the posterior vagus trunk, the paraceliac branch from the anterior vagus trunk, or the hepatic branch from the anterior vagus trunk. Stimulation sites also include the anterior or posterior thoracic vagus nerve, or the left or right cervical vagus nerve. Any combination of vagus nerve stimulation sites is included.

[0073] In other embodiments, the HVNS system is fully closed loop with the primary cell RNR incorporating blue-tooth capability to communicate directly with the glucose transmitter. Low duty cycle on-demand stimulation can facilitate the use of small primary cell devices without the need for charging. The CGM transmitter can communicate with smart devices, allowing physicians to optimize therapy parameters during controlled type 2 diabetes trials.

[0074] In at least one exemplary embodiment, a system for treating hypoglycemia includes a pulse generator, a lead placed on the vagus nerve, and an implantable glucose sensor. The sensor sampling rate is about 1 second to 10 minutes. The implantable sensor detects low blood glucose levels and sends a signal to turn on the pulse generator (see FIG. 2). Communication between the pulse generator and the glucose sensor can be via, but is not limited to, Bluetooth technology, radio frequency, Wi-Fi, light, or sound. In some embodiments, the glucose sensor is under a layer of skin and communicates to a device outside the skin using a battery to power the wireless communication (FIG. 3). Communication between the glucose sensor and a device outside the body can be via, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light, or sound. The device outside the skin then communicates with the pulse generator through, but is not limited to, Bluetooth technology, radio frequency, Wi-Fi, light, or sound. The implantable glucose sensor, or an external device in communication with the implantable glucose sensor, can also communicate with the smart device to display blood glucose levels and send an alarm if stimulation is about to begin. Communication to the smart device can be via, but is not limited to, blue tooth technology, radio frequency, Wi-Fi, light or sound. Stimulation parameters include: frequency range of 0.01 Hz to 200 Hz; current or voltage amplitude range of 0.1 mA to 12 mA or 0.1 to 12 volts; pulse width range of 0.1 ms to 10 ms. Stimulation can be continuous or burst with burst intervals ranging from milliseconds, seconds to minutes.

[0075] In some embodiments, one or more or any combination of the stimulation parameters (frequency, current / voltage amplitude, pulse width, or burst pattern) may be changed at different glucose levels. An example may be having a lower frequency when blood glucose falls into a milder hypoglycemic state (such as 65 mg / dL). The stimulation frequency here may be, but is not limited to, a low frequency, such as 0.1-2 Hz. However, when glucose falls into a more severe level (such as 50 mg / dL), the output of the device will be at a higher frequency, such as, but not limited to, 2 Hz or higher (e.g., 3-60 Hz). An example of a combination of output parameters that changes between different glucose levels is applying a low frequency signal, such as 0.1-2 Hz, and a low current amplitude, such as 0.1-2 mA (or this range in volts), when the sensor detects a mild hypoglycemic event (such as, but not limited to, 65 mg / dL). However, if the sensor detects a more severe hypoglycemic episode (such as but not limited to 50 mg / dL), the frequency would be higher, such as but not limited to 3-60 Hz, combined with a combination of higher current amplitude outputs, such as but not limited to above 2 mA and below 12 mA (or this range in volts). Any combination of different stimulation parameters may be used depending on the reading from the glucose sensor level.

[0076] The stimulation parameters (frequency, current / voltage amplitude, pulse width, or burst pattern) may also change during the course of recovery from hypoglycemia. Such as a higher frequency output (e.g., 3-60 Hz) when glucose falls into a severe level (such as 50 mg / dL). The frequency would then gradually decrease during the course of recovery from hypoglycemia and signal cessation when glucose is restored to a safe level. The change in stimulation frequency during recovery may be a function based on the change in frequency over time, such as, but not limited to, a linear, exponential, or logarithmic function. For example, if the patient reaches a severe hypoglycemic state (such as 50 mg / dL), the frequency may be high (3-60 Hz) and then decreased in a linear (or nonlinear) manner over time until glucose is at a safe level (above 70 mg / dL). The change in frequency may also depend on the glucose level or rate of change of glucose level during recovery. For example, the frequency may decrease by 2 Hz for every 2 mg / dL increase in glucose. The change in signal output may be any combination of signal parameters during recovery from hypoglycemia.

[0077] In some embodiments, there may be periodic on-times and off-times during the episodic stimulation period, where the on-times may be from 1 second to 5 minutes and the off-times may be from 1 second to 5 minutes.

[0078] Reference is now made to FIG. 4, which shows that stimulation sites include any section of the vagus nerve. These sites include the celiac branch arising from the posterior vagus trunk, the paraceliac branch arising from the anterior vagus trunk, or the hepatic branch arising from the anterior vagus trunk. Stimulation sites may also include any section from the vagus nerve cranial to the bifurcation of the celiac or paraceliac nerve. Also, there may be multiple stimulation sites on the vagus nerve.

[0079] Stimulation for hypoglycemia treatment can be infrequent (e.g., 2 stimulation episodes / week, 1 stimulation episode / week, 1 stimulation episode / 2 weeks, 1 stimulation episode / month, 2 stimulation episodes / year, or 1 stimulation episode / year), with short stimulation episode durations (e.g., 1 minute, 5 minutes, and 30 minutes), at low frequencies (e.g., 1 Hz, 5 Hz, and 10 Hz), with pulse widths of 0.1 ms to 10 ms, and current or voltage amplitude ranges: 0.1 mA to 12 mA or 0.1 to 12 volts. This consumes little if any energy on the order of a week, month, or year, allowing for small batteries and small implantable pulse generators (IPGs or microneuromodulators).

[0080] Now, referring to Figures 5-6, a small IPG (505, 605) can be positioned directly on the nerve, without the need for leads and requiring less complex implantation procedures. A conductive electrode (610) (Figure 6) delivers stimulation pulses to the nerve and is positioned directly on the IPG. The implanted pulse generator (505, 605) can be placed on the celiac branch of the vagus nerve, the paraceliac branch, or any area of ​​the vagus nerve cranial to the bifurcation of the celiac or paraceliac nerve. This may include the right and / or left cervical aspects of the vagus nerve. In some embodiments, the IPG positioned on the nerve will be anchored to an adjacent anatomical feature, such as the esophagus, with the intention of reducing movement of the IPG (505, 605) on the nerve.

[0081] Referring now to FIG. 7, the micro-neuroregulator / IPG (705) is connected by wires (720) to a micro-subcutaneous wireless charger (715) below the skin layer. A signal from outside the body, such as a radio frequency signal, light, or sound, is used to periodically charge the device. The IPG (705) positioned on the nerve via the electrode(s) (710) can be a non-rechargeable primary cell device or a rechargeable device. The charging method can be the delivery of a radio frequency (RF) signal using a coil positioned above the skin layer and transmitting energy to the micro-subcutaneous wireless charger.

[0082] Hypoglycemia is not only observed in diabetic patients, but also results from other diseases such as renal failure, certain tumors, liver disease, hypothyroidism, inborn errors of metabolism, severe infections, reactive hypoglycemia, and a number of drugs, including alcohol use. The proposed device could be useful in treating hypoglycemia in patients with these conditions.

[0083] References Garg,SK,Rewers,AH,& Akturk,HK2018.Ever-Increasing Insulin-Requiring Patients Globally.Diabetes Technol Ther,20(S2): S21-S24. Henderson, JN, Allen, KV, Deary, IJ, & Frier, BM2003. Hypoglycaemia in insulin-treated Type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med, 20(12): 1016-1021. McCrimmon, RJ, &Sherwin, RSHypoglycemia in type 1 diabetes.Diabetes,59(10): 2333-2339.

[0084] The above specification, examples, and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

[0085] The following numbered clauses define further exemplary aspects and features of the present disclosure. 1. A system for treating hypoglycemia in a subject, comprising: a first electrode adapted to be positioned on a first nerve or organ and to deliver an electrical signal to the first nerve or organ; Optionally, a second electrode adapted to be positioned on a second nerve or organ and to deliver an electrical signal to the second nerve or organ; an implantable pulse generator operably connected to the first and / or second electrodes, the implantable pulse generator comprising a power module and a programmable therapy delivery module, the programmable therapy delivery module configured to deliver at least one therapy program including a first therapy program and optionally a second therapy program, the first therapy program including a first electrical signal treatment applied via the first electrode to a first nerve or organ, the second therapy program including a second electrical signal treatment applied via the second electrode to a second nerve or organ, the first and / or second electrical signals each configured to initiate an activity on the first and / or second nerve or organ, respectively, the activity being nerve stimulation or nerve block; A system comprising: an external component comprising a communication system and a programmable storage and communications module, the programmable storage and communications module configured to store at least one therapy program and to communicate the at least one therapy program to an implantable pulse generator. 2. The system of clause 1, wherein the first and / or second electrical signals are each independently configured to upregulate or downregulate activity on the first and / or second target nerves or organs, respectively. 3. The system of clause 1 or 2, wherein the first and second electrical signals are applied simultaneously, synchronously, intermittently, during substantially the same time, during substantially different times, or in a coordinated manner. 4. The system of any one of clauses 1 to 3, wherein the first and / or second electrical signal treatments are applied sequentially, respectively, to a first target nerve or organ and / or a second target nerve or organ. 5. The system of any one of clauses 1 to 4, further comprising a glucose sensor configured to continuously monitor plasma glucose of the subject, the glucose sensor operably connected to the implantable pulse generator and the external component. 6. A system described in any one of clauses 1 to 5, wherein the glucose sensor is configured to detect an increase or decrease in plasma glucose from a predetermined threshold level. 7. The system of clause 6, wherein the implantable pulse generator is triggered to deliver the first and / or second electrical therapies when the subject's plasma glucose is below a first predetermined threshold, and the implantable pulse generator stops delivering the first and / or second electrical therapies when the subject's plasma glucose is above a second predetermined threshold. 8. The system of any one of clauses 1-7, wherein the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus of the posterior nerve, hepatic branch of the vagus nerve, celiac branch of the vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerve, baroreceptor, glossopharyngeal nerve, duodenum, jejunum, ileum, small intestine, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof. 9. The system of any one of clauses 1 to 8, wherein the first and / or second electrical signals each have an on-time and an off-time, the off-time being selected to allow at least partial recovery of activity of the first and / or second nerve or organ. 10. The system of clause 9, wherein the on-time is configured to initiate upon detection of a plasma glucose level of about 50 mg / dL or less, about 60 mg / dL or less, about 70 mg / dL or less, or about 80 mg / dL or less. 11. The system of any one of clauses 1-10, wherein the first and / or second electrical signal treatments are configured to increase plasma glucose levels by at least about 5 mg / dL in about 10 minutes. 12. The system of any one of clauses 1-11, wherein the first and / or second electrical signal treatments are configured to increase plasma glucose levels by at least about 10 mg / dL in about 20 minutes. 13. The system of any one of clauses 1-12, wherein the first and / or second electrical signal treatments are configured to increase plasma glucose levels by at least about 20 mg / dL in about 30 minutes. 14. The system of any one of clauses 1 to 13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz. 15. A system described in any one of clauses 1 to 13, wherein the first electrical signal has a frequency of about 200 Hz to about 10 kHz. 16. The system of any one of clauses 1 to 15, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz. 17. The system of any one of clauses 1 to 15, wherein the second electrical signal has a frequency of about 200 Hz to about 10 kHz. 18. A system described in any one of clauses 1 to 13, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz and the second electrical signal has a frequency of about 200 Hz to about 10 kHz. 19. The system of any one of clauses 1-18, wherein the first electrical signal and / or the second electrical signal each independently include a signal pattern, each signal pattern including a pulse having a pulse width of about 0.1 microseconds to about 10,000 microseconds. 20. A system according to any one of clauses 1 to 19, wherein the pulses of the first and / or second electrical signals are monophasic pulses, or biphasic pulses, or a combination thereof. 21. The system of any one of clauses 1-20, wherein the first and / or second electrical signals each independently have an on-time of from about 30 seconds to about 30 minutes. 22. The system of any one of clauses 1-21, wherein the first and / or second electrical signals each independently have a current amplitude in the range of about 0.01 mAmps to about 20 mAmps. 23. The system of any one of clauses 1-22, wherein the first and / or second electrical signal each independently comprises a sudden onset of a pulse, or an increase in current / voltage amplitude, or an increase in frequency, or an increase in pulse width, or a combination thereof, at or near the start of application of the first and / or second electrical signal. 24. The system of any one of clauses 1-23, wherein the first and / or second electrical signal treatments are configured to be applied intermittently multiple times per day and over multiple days, and the first and / or second electrical signals each have a frequency selected to upregulate activity on the first nerve or organ and have an on-time and an off-time, the off-time selected to allow at least partial recovery of activity of the first nerve or organ. 25. A system described in any one of clauses 1 to 24, wherein the programmable storage and communication module is configured to store and communicate two or more therapy programs, each therapy program being different from the others and configured to be selected for communication. 26. The system of any one of clauses 1 to 25, further comprising a transmitter operably connected to the glucose sensor, the transmitter configured to communicate data generated by the glucose sensor to an external communication device. 27. A system described in any one of clauses 1 to 26, wherein the communication system is selected from the group consisting of antenna, blue tooth technology, radio frequency, Wi-Fi, light, sound, and combinations thereof, and the communication system is configured to communicate parameters of at least one therapy program to an external communication device. 28. A method of treating hypoglycemia in a subject, comprising: applying a first electrical signal to a first nerve or organ of a subject using the system of clause 1, the first electrical signal initiating nerve stimulation or a nerve block; Optionally, the method includes applying a second electrical signal to a second nerve or organ of the subject using the system described in clause 1, where the second electrical signal initiates nerve stimulation or nerve block. 29. The method of clause 28, wherein the first and second electrical signals are applied simultaneously, synchronously, intermittently, during substantially the same time, during substantially different times, or in a coordinated manner. 30. The method of clause 28 or 29, wherein the first and / or second electrical signal is configured to increase plasma glucose in the subject by at least about 5 mg / dL in about 10 minutes. 31. The method of any one of clauses 28-30, wherein the first and / or second electrical signal treatments are configured to increase plasma glucose levels by at least about 10 mg / dL in about 20 minutes. 32. The system of any one of clauses 28-31, wherein the first and / or second electrical signal treatments are configured to increase plasma glucose levels by at least about 20 mg / dL in about 30 minutes. 33. A method according to any one of clauses 28 to 32, wherein the first and / or second electrical signals are each applied continuously during an on-time followed by an off-time during which no signal is applied to the nerve or organ. 34. The method of any one of clauses 28-33, wherein the on-time is applied multiple times per day when the plasma glucose level is about 50 mg / dL or less, about 60 mg / dL or less, about 70 mg / dL or less, or about 80 mg / dL or less. 35. The method of any one of clauses 28-34, wherein the off-time is applied multiple times per day when the plasma glucose level is greater than about 80 mg / dL, greater than about 90 mg / dL, greater than about 100 mg / dL, or greater than about 110 mg / dL. 36. The method of any one of clauses 28 to 35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz. 37. The method of any one of clauses 28 to 35, wherein the first electrical signal has a frequency of about 200 Hz to about 10 kHz. 38. The method of any one of clauses 28 to 37, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz. 39. The method of any one of clauses 28 to 37, wherein the second electrical signal has a frequency of about 200 Hz to about 10 kHz. 40. The method of any one of clauses 28 to 35, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz and the second electrical signal has a frequency of about 200 Hz to about 10 kHz. 41. The method of any one of clauses 28-40, wherein the first nerve or organ and the second nerve or organ are independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus of the posterior nerve, hepatic branch of the vagus nerve, celiac branch of the vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerve, baroreceptor, glossopharyngeal nerve, duodenum, jejunum, ileum, small intestine, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof. 42. The method of any one of clauses 28 to 41, wherein the first nerve or organ and the second nerve or organ are different. 43. The method of any one of clauses 28 to 42, wherein the first electrical signal is applied to a hepatic branch of the vagus nerve or anterior vagus nerve centered at the bifurcation of the hepatic nerve. 44. The method of any one of clauses 28 to 42, wherein the first electrical signal is applied to the celiac branch of the vagus nerve or anterior vagus nerve, centered at the bifurcation of the celiac nerve. 45. The method of any one of clauses 28-42, wherein the first electrical signal is applied to the liver, the pancreas, or both. 46. ​​The method of any one of clauses 28 to 45, wherein the second electrical signal is applied to a splanchnic nerve, or the celiac branch of the vagus nerve, or the pancreas. 47. The method of any one of clauses 28 to 45, wherein the second electrical signal is not involved in the method. 48. The method of any one of clauses 28-47, further comprising administering an agent that improves glucose control. 49. The method of clause 48, wherein the agent reduces the amount of insulin and / or reduces the sensitivity of the cells to insulin. 50. A method of making a system for treating hypoglycemia in a subject, comprising: connecting a first electrode to an implantable pulse generator and positioning the first electrode on a first nerve or organ; Optionally, connecting a second electrode to the implantable pulse generator and placing the second electrode on a second nerve or organ; configuring a programmable therapy delivery module of the implantable pulse generator to deliver at least one therapy program including a first electrical signal therapy and optionally a second electrical signal therapy, the first electrical signal therapy being configured to be applied to a first nerve or organ via a first electrode and the second electrical signal therapy being configured to be applied to a second nerve or organ via a second electrode, the first and / or second electrical signals initiating nerve stimulation or nerve block, respectively; and configuring a programmable storage and communications module of an external component to store at least one therapy program and to communicate the at least one therapy program to an implantable pulse generator. 51. The method of clause 50, wherein the first and / or second electrical signals each have a frequency selected to initiate activity on a first and / or second target nerve or organ, respectively, and the activity is upregulation or downregulation of neural activity. 52. The method of clause 50 or 51, further comprising connecting a glucose sensor to the implantable pulse generator and using the glucose sensor to monitor or detect plasma glucose levels in the subject. 53. The method of any one of clauses 50-52, further comprising configuring a communication system of the external component to communicate at least one parameter of the therapy program to an external communication device. 54. The method of any one of clauses 50-53, further comprising connecting a transmitter to the glucose sensor to communicate data generated by the glucose sensor to an external communication device. 55. The method of any one of clauses 50 to 54, wherein the first and / or second electrodes are positioned on the nerve or organ via a laparoscopic approach. 56. A system for treating hypoglycemia in a subject, comprising: at least one electrode positioned on a nerve or organ of the subject and adapted to deliver an electrical signal to the nerve or organ of the subject; an implantable pulse generator operably connected to at least one electrode, the implantable pulse generator comprising a power module and a programmable therapy delivery module, the programmable therapy delivery module configured to deliver at least one therapy program, the at least one therapy program including at least one electrical signal therapy applied to a nerve or organ via the at least one electrode; an external component comprising a communication system and a programmable storage and communication module, the programmable storage and communication module configured to store at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator; a glucose sensor operatively and communicatively connected to the implantable pulse generator and the external component, the glucose sensor configured to continuously monitor plasma glucose in the subject and to detect an increase or decrease in plasma glucose from a predetermined threshold level; the implantable pulse generator is triggered to deliver the at least one electrical signal therapy when the subject's plasma glucose is at or below a first predetermined threshold, and the implantable pulse generator stops delivering the at least one electrical signal therapy when the subject's plasma glucose is at or above a second predetermined threshold; The system, wherein at least one electrical signal therapy is configured to initiate neural stimulation to a target nerve or organ. 57. The system of clause 56, wherein the nerve or organ is selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus of the posterior nerve, hepatic branch of the vagus nerve, celiac branch of the vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerve, baroreceptor, glossopharyngeal nerve, duodenum, jejunum, ileum, small intestine, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof. 58. The system of clause 56 or 57, wherein the nerve is the subject's posterior vagus nerve (PVN), or the celiac vagus branch of the PVN. 59. A system described in any one of clauses 56 to 58, wherein the electrical signal has an on-time and an off-time, the off-time being selected to allow at least partial recovery of nerve or organ activity. 60. The system of clause 59, wherein the on-time is configured to initiate upon detection of a plasma glucose level in the subject of about 50 mg / dL or less, about 60 mg / dL or less, about 70 mg / dL or less, or about 80 mg / dL or less. 61. The system described in clause 59 or 60, wherein the on-time is from about 30 seconds to about 30 minutes. 62. The system of any one of clauses 56 to 61, wherein at least one electrical signal treatment includes an electrical signal pattern having a frequency of about 1 Hz to about 200 Hz, or about 1 Hz to about 50 Hz, or about 1 Hz to about 20 Hz, or about 1 Hz to about 10 Hz, or about 1 Hz to about 5 Hz, or about 1 Hz to about 2 Hz. 63. A system described in any one of clauses 56 to 62, wherein the electrical signal pattern has pulse widths from about 0.1 microseconds to about 10 microseconds in steps of about 0.1 microseconds. 64. A system described in any one of clauses 56 to 63, wherein the electrical signal pattern has a pulse amplitude of about 0.1 mA to about 12 mA, in steps of about 0.1 mA. 65. A system described in any one of clauses 56 to 64, wherein the pulse of at least one electrical signal is a monophasic pulse, or a biphasic pulse, or a combination thereof. 66. The system of any one of clauses 56-65, wherein at least one electrical signal further comprises a sudden onset of a pulse, or an increase in current / voltage amplitude, or an increase in frequency, or an increase in pulse width, or a combination thereof, at or near the start of application of the electrical signal. 67. A system described in any one of clauses 56 to 66, wherein at least one electrical signal treatment is configured to be applied multiple times per day and intermittently over multiple days. 68. The system of any one of clauses 56-67, wherein at least one electrical signal treatment is configured to increase the subject's plasma glucose by at least about 5 mg / dL in about 10 minutes, or at least about 10 mg / dL in about 20 minutes, at least about 20 mg / dL in about 30 minutes, or at least about 30 mg / dL in about 45 minutes, or at least about 40 mg / dL in about 60 minutes. 69. The system of any one of clauses 56 to 68, wherein at least one electrical signal treatment is configured to cause an increase in glucagon secretion in the subject. 70. The system of any one of clauses 56-69, wherein application of at least one electrical signal treatment is configured to cause a decrease in insulin secretion in the subject. 71. The system of any one of clauses 56 to 70, further comprising a transmitter operably connected to the glucose sensor, the transmitter configured to communicate data generated by the glucose sensor to an external communication device. 72. A system described in any one of clauses 56 to 71, wherein the communication system is selected from the group consisting of antenna, blue tooth technology, radio frequency, Wi-Fi, light, sound, and combinations thereof, and the communication system is configured to communicate parameters of at least one therapy program to an external communication device. 73. A method for treating hypoglycemia in a subject in need of treatment for hypertension, comprising: A method comprising applying at least one electrical signal treatment to a subject's posterior vagus nerve (PVN) or a celiac vagus branch of the subject's PVN using a system described in any one of clauses 56 to 72. 74. The method of claim 73, wherein the electrical signal pattern applied to the has a frequency of about 1 Hz to about 20 Hz, a pulse width of about 0.1 microseconds to about 10 microseconds in steps of about 0.1 microseconds, and a pulse amplitude of about 0.1 mA to about 12 mA in steps of about 0.1 mA. 75. The method of clause 73 or 74, wherein application of the at least one electrical signal therapy increases the subject's plasma glucose by at least about 5 mg / dL, at least about 10 mg / dL, at least about 20 mg / dL, at least about 30 mg / dL, at least about 40 mg / dL, at least about 50 mg / dL, at least about 60 mg / dL, at least about 70 mg / dL, at least about 80 mg / dL, at least about 90 mg / dL, or at least about 100 mg / dL in about 60 minutes. 76. The method of any one of clauses 73 to 75, wherein application of at least one electrical signal treatment causes an increase in glucagon secretion in the subject. 77. The method of any one of clauses 73-76, wherein application of at least one electrical signal treatment causes a decrease in insulin secretion in the subject. 78. The method of any one of clauses 73-77, further comprising placing at least one electrode on the nerve or organ via a laparoscopic approach.

Claims

1. 1. A system for treating hypoglycemia in a subject, comprising: a first electrode adapted to be positioned on a first nerve or organ and to deliver an electrical signal to the first nerve or organ; Optionally, a second electrode adapted to be positioned on a second nerve or organ and to deliver an electrical signal to the second nerve or organ; an implantable pulse generator operably connected to the first and / or second electrodes, the implantable pulse generator comprising a power module and a programmable therapy delivery module, the programmable therapy delivery module configured to deliver at least one therapy program including a first therapy program and optionally a second therapy program, the first therapy program including a first electrical signal therapy applied to the first nerve or organ via the first electrode and the second therapy program including a second electrical signal therapy applied to the second nerve or organ via the second electrode, the first and / or second electrical signals each configured to initiate activity on the first and / or second nerve or organ, respectively, the activity being nerve stimulation or nerve block; an external component comprising a communication system and a programmable storage and communication module configured to store the at least one therapy program and to communicate the at least one therapy program to the implantable pulse generator.

2. 2. The system of claim 1, wherein the first and / or second electrical signals are each independently configured to upregulate or downregulate activity on the first and / or second target nerves or organs, respectively.

3. 10. The system of claim 1, wherein the first and second electrical signals are applied simultaneously, synchronously, intermittently, during substantially the same time, during substantially different times, or in a coordinated manner.

4. 10. The system of claim 1, wherein the first and / or second electrical signal therapies are each applied sequentially to the first target nerve or organ and / or the second target nerve or organ, respectively.

5. 10. The system of claim 1, further comprising a glucose sensor configured to continuously monitor plasma glucose of the subject, the glucose sensor operably connected to the implantable pulse generator and the external component.

6. The system of claim 1 , wherein the glucose sensor is configured to detect an increase or decrease in plasma glucose from a predetermined threshold level.

7. 7. The system of claim 6, wherein the implantable pulse generator is triggered to deliver the first and / or second electrical therapies when the subject's plasma glucose is below a first predetermined threshold, and wherein the implantable pulse generator stops delivering the first and / or second electrical therapies when the subject's plasma glucose is above a second predetermined threshold.

8. 2. The system of claim 1, wherein the first nerve or organ and the second nerve or organ are each independently selected from the group consisting of the vagus nerve, anterior vagus nerve, posterior vagus nerve, hiatus of the posterior nerve, hepatic branch of the vagus nerve, celiac branch of the vagus nerve, splanchnic nerve, renal nerve, renal artery, sympathetic nerve, baroreceptor, glossopharyngeal nerve, duodenum, jejunum, ileum, small intestine, colon, stomach, esophagus, liver, spleen, pancreas, and combinations thereof.

9. 1. A method of treating hypoglycemia in a subject, comprising: applying a first electrical signal to a first nerve or organ of the subject using the system of claim 1, the first electrical signal initiating nerve stimulation or a nerve block; Optionally, the method includes applying a second electrical signal to a second nerve or organ of the subject using the system of claim 1, the second electrical signal initiating nerve stimulation or a nerve block.

10. 10. The method of claim 9, wherein the first and second electrical signals are applied simultaneously, synchronously, intermittently, during substantially the same time, during substantially different times, or in a coordinated manner.

11. 10. The method of claim 9, wherein the first and / or second electrical signals are configured to increase plasma glucose in the subject by at least about 5 mg / dL in about 10 minutes.

12. 10. The method of claim 9, wherein the first and / or second electrical signal therapies are configured to increase the plasma glucose level by at least about 10 mg / dL in about 20 minutes.

13. 10. The system of claim 9, wherein the first and / or second electrical signal therapies are configured to increase the plasma glucose level by at least about 20 mg / dL in about 30 minutes.

14. 10. The method of claim 9, wherein the first and / or second electrical signals are each applied continuously for an on time followed by an off time during which no signal is applied to the nerve or organ.

15. 10. The method of claim 9, wherein the on-time is applied multiple times per day when the plasma glucose level is about 50 mg / dL or less, about 60 mg / dL or less, about 70 mg / dL or less, or about 80 mg / dL or less.

16. 10. The method of claim 9, wherein the off-time is applied multiple times per day when plasma glucose levels are greater than or equal to about 80 mg / dL, greater than or equal to about 90 mg / dL, greater than or equal to about 100 mg / dL, or greater than or equal to about 110 mg / dL.

17. 10. The method of claim 9, wherein the first electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

18. 10. The method of claim 9, wherein the first electrical signal has a frequency of about 200 Hz to about 10 kHz.

19. 10. The method of claim 9, wherein the second electrical signal has a frequency of about 0.01 Hz to about 200 Hz.

20. 10. The method of claim 9, wherein the second electrical signal has a frequency of about 200 Hz to about 10 kHz.

Images