Treatment of Type 1 Diabetes

Abstract

Modulation of neural signaling of a pancreas-related sympathetic nerve is capable of improving glycaemic control by inhibiting T cell activation or migration to the pancreas, and hence providing a way of treating or preventing type 1 diabetes.

1 . A device or system comprising at least one electrode, suitable for placement on or around a pancreas-related sympathetic nerve of a subject, and a signal generator for generating a signal to be applied to the pancreas-related sympathetic nerve via the at least one electrode such that the signal reversibly modulates the neural activity of the pancreas-related sympathetic nerve to produce a change in a physiological parameter in the subject, wherein the change in the physiological parameter is one or more of the group consisting of: an increase in blood insulin level, a reduction in (fasting) blood glucose level, a reduction in glycated haemoglobin (HbA1c) level, a reduction in inflammation systemically (e.g. indicated by the levels of circulating cytokines and/or C- reactive protein) or locally in the pancreas, such as insulitis (e.g. indicated by the levels of C-peptide, autoreactive T cells, and/or autoantibodies), an increase in catecholamine levels in the pancreas, an increase in GABA levels in the pancreas, and an increase in the number of pancreatic β cells in the pancreas. 
     
     
         2 . The device or system of  claim 1 , wherein the change in physiological parameter is one or more of the group consisting of: an increase in blood insulin level, a reduction in (fasting) blood glucose level, a reduction in glycated haemoglobin (HbA1c) level, a reduction in inflammation systemically (e.g. indicated by the levels of circulating cytokines and/or C-reactive protein) or locally in the pancreas, such as insulitis (e.g. indicated by the levels of C-peptide, autoreactive T cells, and/or autoantibodies), and an increase in catecholamine levels in the pancreas. 
     
     
         3 . The device or system of  claim 1 , wherein the pancreas- related sympathetic nerve is a pancreas- related sympathetic nerve supplying the lymphatic system of the pancreas. 
     
     
         4 . The device or system of  claim 1 , wherein the signal stimulates the neural activity of the pancreas- related sympathetic nerve. 
     
     
         5 . The device or system of  claim 1 , wherein the signal generator is a voltage or current source configured to generate an electrical signal to be applied to the pancreas-related sympathetic nerve via the at least one electrode. 
     
     
         6 . The device or system of  claim 5 , wherein the at least one electrode is in the form of an electrode array. 
     
     
         7 . The device or system of  claim 5 , wherein the signal selectively stimulates the neural activity of nerve fibers supplying the lymphatic system of the pancreas. 
     
     
         8 . The device or system of  claim 5 , wherein the electrical signal has a frequency between 0.1 Hz and 100 Hz. 
     
     
         9 . The device or system of  claim 5 , wherein the electrical signal has a current between 0.01 mA and 10 mA. 
     
     
         10 . The device or system of  claim 5 , wherein the electrical signal is a charge-balanced DC signal comprising a cathodic pulse and an anodic pulse. 
     
     
         11 . The device or system of  claim 1 , comprising a detector (e.g. physiological sensor subsystem) for detecting one or more signals indicative of one or more physiological parameters; determining from the one or more signals one or more physiological parameters; determining the one or more physiological parameters indicative of worsening of the physiological parameter; and causing the signal to be applied to the pancreas-related sympathetic nerve via the at least one electrode. 
     
     
         12 . The device or system of  claim 1 , wherein the signal generator is configured to apply the electric signal for a finite period of time. 
     
     
         13 . A method of reversibly modulating neural activity in a pancreas-related sympathetic nerve, comprising: (i) implanting in the subject a device or system of  claim 1 ; (ii) positioning the neural interfacing element in signaling contact with the pancreas-related sympathetic nerve; and optionally (iii) activating the device or system. 
     
     
         14 . The method of  claim 13 , wherein the method is for treating type 1 diabetes (T1D). 
     
     
         15 . The method of  claim 13 , further comprising administering GABA, a GABA analogue, or a GABA-enhancing agent to the subject. 
     
     
         16 . The method of  claim 15 , wherein the GABA-enhancing agent is selected from the group consisting of benzodiazepines such as diazepam, alprazolam, clonazepam, lorazepam, or chloradiazepozide; barbituates such as phenobarbital, pentobarbital, butobarbital, amobarbital, secobarbital or thiopental; baclofen; acamprosate; pregabalin; gabapentin; tiagabine; lamotrigine; topiramate; neuroactive steroids such as allopregnalone or ganaxolone; nabiximols such as sativex; and combinations thereof. 
     
     
         17 . A method of controlling a device or system comprising at least one electrode, suitable for placement on or around a pancreas-related sympathetic nerve of a subject, and a signal generator for generating a signal to be applied to the pancreas-related sympathetic nerve via the at least one electrode such that the signal reversibly modulates the neural activity of the pancreas-related sympathetic nerve to produce a change in a physiological parameter in the subject, the method comprising the steps of: sending control instructions to the device or system, and applying the signal to the pancreas-related sympathetic nerve in response to the control instructions.