Hypoglycaemia worsens atherosclerosis through inflammatory pathways.

People with diabetes have more heart attacks and strokes than people without diabetes. The risk of heart disease and stroke is worse if diabetic control is poor. In diabetes, the level of sugar (glucose) in the blood tends to go very high, and is brought back to normal by tablets or injections of insulin. We already know that inadequate control of glucose levels tends to cause inflammation in the blood vessels, which results in furring up of these vessels, and causes strokes and heart attacks.

Because of that clear link between poor control of diabetes and heart attacks, we've been focusing treatment on getting ever better control of sugar levels in the blood in our patients. However, we've started to realise that where the sugar level goes too low, this is also harmful. Acute drops in sugar levels are very unpleasant for patients, and are also associated with heart attacks and heart damage.

We are beginning to understand that low blood sugar may cause inflammation in a similar way to high blood sugar levels. I want to see if this is true and if I can do things to prevent the harmful effects of low blood sugar.

To do this, I'm going to set up an experiment in otherwise healthy people where we deliberately make their blood sugar low, then expose them to material purified from dead bacteria. This will test how low blood sugars affect the inflammatory response, and look at how the immune system handles stress and infection after episodes of low blood sugar.

I will also set up models where I can see the exact mechanism of inflammation. I will look in mice that are prone to furring up of the arteries, and see if low blood sugars makes this artery damage worse. I will see whether, as I suspect, the low blood sugars cause the immune system to become overactive. Finally, I will see if I can prevent this low blood sugar-associated damage and help to develop treatments that could be used in humans to reduce heart attack risks.

These studies together will work to show why and how low blood sugars are harmful to the heart and circulation. I hope that they will help us understand the very best levels of blood sugar to aim for in people with diabetes, and help us to understand how to minimise any harm that might occur when sugar levels go too low.

Background:

Patients with diabetes are at increased risk of atherosclerosis and associated cardiovascular morbidity. Considerable work has addressed how hyperglycaemia may be associated with these processes, but it is now becoming evident that hypoglycaemic episodes are also associated with cardiovascular risk. Whilst some of this risk is mediated by sympatho-adrenal pathways, it is becoming increasingly evident that episodes of hypoglycaemia drive inflammatory pathways.

Hypothesis:

My hypothesis is that hypoglycaemia primes the innate immune response and increases cardiovascular risk through monocyte mobilisation and activation. I have generated pilot data supporting this hypothesis, showing that hypoglycaemia in humans mobilises monocytes and is associated with prolonged rises in high sensitivity CRP.

Objectives and methodology:

To test my hypothesis in more detail I will:

1. Create a human model of in vivo hypoglycaemia followed by low dose in vivo endotoxin challenge to determine the extent to which hypoglycaemia mobilises monocytes, activates innate immunity, and primes monocytes to respond to inflammatory stimuli.

2. Create a model of acute hypoglycaemia in ApoE-/- mice, examining the extent to which episodes of hypoglycaemia mobilise monocytes from the marrow, cause the establishment of monocyte-producing haematopoietic colonies in the spleen, and accelerate atherosclerosis.

3. Determine whether blockade of monocyte trafficking by targeting the chemokine receptor CCR2 may reduce hypoglycaemia-associated accelerations in atherosclerosis pathology.

Scientific and medical opportunities:

These studies will create new human and mouse models that will combine to determine the extent to which acute episodes of hypoglycaemia accelerate atherosclerosis through monocyte mobilisation and monocyte activation, and show in proof of principle studies that these pro-inflammatory consequences of hypoglycaemia may be therapeutically targeted.

1. Impact on research professionals.

I will show how new human models of the interaction of diabetes and inflammation can be developed, and will share both data and human experimentation protocols widely. I will help to develop and participate in networks of investigators who study the human directly, to create a community of like-minded researchers developing translational research bridging effectively between the human and mouse. These benefits will be immediately apparent as I develop these networks. Personally, this project will allow me to gain the requisite breadth of knowledge and skills to develop into an academic physician.


2. Impact on patients.

Diabetes and its cardiovascular complications are amongst the leading causes of morbidity and mortality both nationally and globally. I will help to explain how hypoglycaemia may increase cardiovascular risk in diabetes, and how this risk may be mediated. I will show in proof of principle studies how this risk may be modified by therapeutic targeting of monocyte trafficking. I believe these studies will help to inform guidelines on the appropriate tightness of diabetic control management, as well as developing considerations of how to minimise cardiovascular risk in patients experiencing episodes of acute or recurrent hypoglycaemia. I am passionate about communicating the results of science to patient groups, and I hope that these studies will give inspiration and hope to patients with diabetes, and a continuing sense of the commitment of the academic clinical community to the addressing of their needs. If found to be beneficial, I envisage modulation of the inflammatory pathways I describe may start to have a therapeutic impact within the next 5-10 years.


3. Impact on UK research culture.

These studies will show that the UK is capable of generating new models of human/murine interface research. I hope and believe that developing such expertise in the UK will continue to attract high profile R&D investment in the UK. Creating these models will generate new test beds in which therapeutics can be studied early in clinical trials development. These developments should have benefit for the greater UK research community over the next 5 years following on from my Fellowship.