Quantifying Artificial Pancreas-related Changes in Diabetic Neuropathy

A complication of diabetes mellitus is damage to nerves called neuropathy which can lead to foot ulcers, infections and amputations. Patients with neuropathy may also experience pain, which can be difficult to control and the medications are limited by side effects. Neuropathy also affect the nerve supplying the heart and lungs (cardiac autonomic neuropathy (CAN)) which can be associated with premature death. Despite this there are no approved treatments to reverse the progression of neuropathy and management is focused on controlling blood glucose and other metabolic factors to prevent neuropathy and its symptoms from getting worse.

Patients with type 1 diabetes are prescribed multiple daily injections (MDI) of insulin to manage their glucose control. However, insulin pump therapy and, more recently, automated insulin delivery (AID) or the Artificial Pancreas can be used as the insulin delivery method for patients with type 1 diabetes mellitus. Manchester Diabetes, Endocrinology and Metabolism Centre is the first adult diabetes centre in Europe to pioneer and use a commercially-approved artificial pancreas in clinical practice. Insulin pump therapy and the automatic pancreas have the advantage of being able to provide insulin at variable
doses, which is closer to the natural process occurring within an individual without diabetes. Both are currently considered to be the most physiological method of insulin delivery and have been shown to improve glycaemic control, quality of life (QOL) and reduce the risk of hypoglycaemia (low blood glucose level). We have previously shown in a small group of people that use of an insulin pump therapy may improve symptoms of painful neuropathy via a more stable glucose profile. The peaks and drops in insulin may make neuropathy worse.

In the observational study we aim to investigate the use of the artificial pancreas and insulin pump therapy in their effect on neuropathy. We will use a variety of assessments and symptom questionnaires to assess structural and functional neuropathy status. We hypothesise that those patients receiving the newer technologies will demonstrate an improvement in symptoms and nerve regeneration.

I will analyse data from a randomised control trial comparing the artificial pancreas to a sensor-augmented closed loop system. The purpose of this is to evaluate the impact of these on cardiac autonomic neuropathy where I believe that the artificial pancreas will be able to offer a better delivery of glucose and thus have a positive impact on CAN.

This finding would have a significant impact for patients by providing evidence that patients with neuropathy would benefit from these devices. As these are devices that are already available on the NHS to patients satisfying specific criteria this study aims to show benefit in a wider cohort of patients which can be implemented immediately in clinical practice.

There are currently no approved disease modifying therapies to prevent, slow or repair nerve damage in diabetic peripheral neuropathy (DPN) or autonomic neuropathy. We have shown an improvement in painful DPN treated with continuous subcutaneous insulin infusion (CSII) which resulted in lower mean blood glucose levels, M-values and HbA1c. We have pioneered the use of corneal confocal microscopy (CCM) as a non-invasive surrogate marker for DPN, Furthermore we have also shown an improvement in corneal nerve morphology in patients with type 1 diabetes on CSII compared to multiple daily insulin injections (MDI) over 24 months.

Conventional CSII therapy is currently considered to be the most physiological method of insulin delivery and has been shown to improve glycaemic control, quality of life (QOL) and reduce the risk of hypoglycaemia. Recently the Artificial Pancreas (AP) has been shown to improve the time-in-target glucose range, HbA1c and reduce the occurrence of hypoglycaemia. Manchester Diabetes Centre is the first adult diabetes centre in Europe to pioneer and use a commercially-approved AP in clinical practice. We propose to build on our initial studies to assess the benefits of the AP and insulin pump therapy on DPN and CAN in people with type 1 diabetes over 12 months. A secondary arm will be a sub analysis of data from a NIH funded pilot study which is a randomised, cross-over design trial comparing AP vs. conventional sensor-augmented pump therapy in older T1D patients (>60 years old). Holter data which has already been collected from these patients at 4 months in each arm will be analysed for CAN. Our hypothesis is that AP will show an improvement DPN and CAN through improved glycaemic variability, reduced hypoglycaemia and overall improved glycaemic control.