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Understanding the long-term complications of diabetes mellitus: a major world-wide problem

Jaipaul Singh is Professor of Physiology in the Schools of Forensic & Investigative Sciences and Pharmacy & Biomedical Sciences.

Jai gained his BSc degree from the University Of Guyana in 1971. In 1974, he joined the University of St Andrews where he obtained his PhD. He joined Preston Polytechnic (now UCLan) in 1984 and became Professor in 1993, after working at St Andrews, the University of Dundee and Liverpool University. In 2011 Jai was awarded a DSc in recognition of his lifetime contribution to his work on diabetes.

In his lecture Jai explained what diabetes is all about and how it can affect us. He also presented experimental data explaining what we know so far on some of the diabetes-induced long term complications such as heart problems, indigestion, dry eyes and ageing and inflammation. Professor Mike Holmes, Head of Graduate Research School, and Alison Naylor, joined Jai in his office to find out more.

Jaipaul Singh

Can you tell me what your research is about?

My research is focussed mainly on diabetes mellitus (DM), investigating diabetes-induced cardiac fibrosis and dysfunction. Previously, we did a lot of research on diabetes-induced exocrine gland insufficiencies (indigestion and dry eyes), ageing, exercise and diabetes, and plant-based-diabetic treatment using bitter melon.

DM is a major global metabolic disorder currently affecting about 300 million people worldwide, including 3-4 million in the UK.

It costs world Governments almost £500 billion annually to diagnose, treat and care for diabetic patients. DM is classified as type 1 or insulin-dependent, and type 2 non-insulin-dependent. People with type 1 DM need insulin because their islet beta cells in the pancreas do not produce enough insulin. Type 2 DM arises from our modern life style and obesity; so called ‘diabesity’. Type 2 DM is more common affecting about 95% of all (285 million) diabetics. About 70% of them have insulin but the hormone is inactive or insensitive in stimulating glucose uptake into the cells of the body. The other 30% have low insulin and they require an insulin supplement or drugs, which can stimulate insulin synthesis and release. People with type 2 DM are treated mainly with some hypoglycaemic drugs (metformin is a typical example) and general changes in life style habits including diet and regular exercise.

DM arises from high blood glucose levels or hyperglycaemia since insulin is unable to stimulate cellular glucose uptake. Glucose is excreted into the urine leading to constant urination, thirst, hunger and fatigue. If left untreated, DM can lead to a number of long term complications including blindness, kidney failure, the inability to feel, indigestion, dry eyes, memory loss, foot ulcers, impotence and more importantly, heart failure (cardiomyopathy). The majority of diabetics will subsequently die from heart failure.

As such, it is important to investigate the relationship between DM and heart failure.

We are interested in DM itself from its start to the development of the cardiomyopathy and fibrosis over a period of 2 years. We have done work on both type 1 and type 2 diabetic hearts, investigating changes in the morphology and physiology of the hearts.

So far our results have shown that during both type 1 and type 2 DM, the muscle cells of the heart become weak and enlarged and many die. These pathological processes are believed to be due to the lack of glucose as food and the hyperglycaemia inducing oxidative stress due to the production of oxygen free radicals and carbonylation (damage to the amino acids of contractile and transporting calcium proteins) in the heart. The heart produces a number of endogenous signalling molecules including atrial natriuretic factor (ANP), brain natriuretic factor (BNP), transforming growth factor beta 1 (TGF-beta 1) and several kinases (Akt-tor:p70S6K). In response, the heart reacts or remodels by increasing the amount of collagens and other molecules resulting in fibrosis and muscle cell enlargement. The fibrotic heart becomes stiff and is unable to accommodate enough blood for its pumping action. This leads to a much weaker heart, failure and sudden death. We have shown that people who have border line DM or pre-diabetes can also suffer from the same cardiac consequence but is not as severe as the full blown uncontrolled DM.

Our studies show that the weak diabetic heart has a problem with relaxation and thus filling and subsequent contraction compared to a normal healthy heart. The diabetic heart takes a longer time to generate peak contraction, pumps less blood during each beat and it takes longer to relax. This pathophysiological effect of the heart is due to elevated diastolic free calcium (dysfunction). Results have shown that calcium-transporting proteins are somehow affected by DM leading to this deranged calcium signalling in the heart cells.

So is there a way to treat the fibrosis and general heart dysfunction during DM and improve the heart function?

The first job is to understand the DM-induced pathological process and then find out how we can prevent the cardiac myopathy, the development of the fibrosis and the dysfunction of cellular calcium. We are hoping that people from the pharmaceutical companies will read our research findings and develop new drugs to either prevent or treat these conditions. Just as for the control of the cholesterol level, where statin compounds inhibit the production of bad cholesterol, perhaps drugs can be developed to inhibit TGF-alpha 1, and reduce the fibrosis. Other drugs may be developed to either prevent or reduce the oxidative stress and carbonylation of the heart.

In addition to treatment, we should try to prevent the DM; prevention is better than cure. There are drugs like insulin to treat type 1 DM and a variety of hypoglycaemic drugs to treat type 2 DM, but why use drugs? The 285 million type 2 diabetics are an enormous burden for the health services globally. Only people between the ages of 30 and 40 years used to get type 2 DM, but now children as young as 12 years of age are getting it. Governments have to address this global problem at an early stage starting at school level. Parents also have to feed their children healthy diets and keep them within the weight limits for their age and height (body mass index of less than 25). There is a simple way to treat the disease, which is to be careful with what and how much you eat; eating more cereals, vegetables and fresh fruits, avoiding fats and the most important taking exercise of at least 30 minutes daily. Collaborative work is required to prevent this disease. Unfortunately, this is not happening in either the UK or worldwide.

I heard recently that the study had been made in the United States where a group of type 2 diabetics were put on a very strict dietary regime, almost a starvation diet, for a period of time, under the care of doctors. This resulted in type 2 diabetes subsiding and an effective cure for some of the participants – is this something that you heard about?

Yes. People are using different methods in tackling the problem. Some claim that when you exercise, you produce a novel compound which activates the insulin tyrosine kinase cellular receptors so that the insulin can now stimulate glucose uptake into the cells of the body thereby reducing the blood glucose level. Another explanation is that exercise can lead to cell starvation and as a result glucose is forced into the starved cells. For us to control this disorder, type 2 diabetics must take regular exercise and modify their diet, and possibly some starvation may help in controlling and stabilising type 2 DM, but it is better to start dietary changes and exercise at an early stage, especially with the pre-diabetic condition.

We have specialised cells inside our gastro-intestinal (GI) tract, called the L cells, which can produce a special hormone called GLP-1 (glucagon-like peptide-1). It is an endogenous substance, which can stimulate insulin production and release. In turn, the insulin helps to stimulate the glucose into cells. This is beneficial to those 30% of the type 2 diabetics who have reduced insulin levels. In relation to your question, I believe that what you are talking about is probably related to this GLP-1. It is now well known that starvation can help to modulate GLP-1 release which mediates physiological processes in the body to make more insulin to regulate blood glucose levels. In collaboration with Professor Ernest Adeghate from the United Arab Emirates University, we have investigated the physiological roles of both GLP-1 and its agonist, exenatide as a novel way to treat type 2 DM.

From what you say, you have done a huge amount of work, but is there a lot more still to do in solving the problem of diabetes?

Initially, we studied exocrine pancreatic and salivary gland insufficiency. People with DM cannot digest carbohydrates and as a result they suffer from indigestion, because they do not have enough amylase, the enzyme to digest the carbohydrates. We have shown that DM affects the production of amylase at molecular level. Since we had other tissues available, we looked at the lacrimal (tear) glands and we have again shown that people who have DM suffer from dry eyes. They do not produce enough anti-bacterial enzymes and fluid to moisten the eyes and to prevent infection. Likewise, our other studies on skeletal muscles show that they become very small and weak following DM. However, the main focus of my work has been on the heart. There are so many different experiments still to do. Currently, we are investigating the role of thyroid hormones in preventing diabetes-induced heart diseases. Some recent results have shown that hypothyroidism can enhance diabetes-induced heart problems. People with hyperthyroidism rarely suffer from diabetes-induced heart failure. The message is clear; if you have hypothyroidism make sure you have supplements of thyroid hormone in order to prevent heart failure later in life. Another interesting area is to investigate the role of regular exercise in type 2 DM in conjunction with psychological intervention in preventing the long term complications of DM including heart disease. It is very difficult to get people to take regular exercise but our previous studies have shown that if you combine regular exercise with psychological training, diabetic patients continue to exercise. Another interesting area is to investigate the effect of age on inflammatory mediators and markers during DM. Our previous studies have shown that age-related chronic type 2 DM produced higher levels of inflammatory blood borne markers indicating that these patients may be susceptible to a heart attack later in life.

So you probably need another life-time to do all this work?

Yes. I work with a colleague, Professor Keshore Bidasee in Omaha, Nebraska, USA and he has a theory about treating the cardiomyopathy problem. He believes that the calcium releasing mechanism from the internal store (sarcoplasmic reticulum) in the heart muscle cell is the problem. The store has numerous calcium channels called the ryanodine receptors. DM leads to carbonylation of the calcium channel ryanodine receptors allowing pulses of calcium to be asynchronously released into the cytoplasm leading to elevated diastolic calcium. We can develop drugs to reverse this effect.

What was really interesting at the April 2012 meeting of Experimental Biology in San Diego, USA was that there are so many new scientific papers coming out explaining novel methods to treat type 2 DM. These included regular exercise, diet changes and natural therapies using different plants that can be used to treat the disease. For example, I am interested in Momordica charantia or bitter melon, which can be used to treat diabetes. There are also 300 other plants that have potential beneficial anti-diabetic properties. The problem with DM is the quality of life for the patients. Probably by next year, there will be type 3 DM which is Alzheimer’s disease! ­If you become diabetic you could end up with Alzheimer’s disease and at this moment Dr Tony Ashton is investigating DM and its relationship with Alzheimer’s disease in the School of Pharmacy and Biomedical Sciences.

Finally, what’s next?

I am 65 years of age and I would love to go on working until I am 85! But you have to think about life itself, how much can you do. I do have other things in mind, but I would like to continue the research and supervise my students. In research, you do not want to stop because you have to keep the mind proactive. If you do not keep the mind active, you probably die faster! I have just been invited by a colleague to write a few reviews for some top heart journals on diabetes-induced heart failure (ryanodine receptors, fibrosis and remodelling) and another one on thyroid hormone and diabetes-induced heart failure. These are areas in which I would like to continue with our research. Then, there is this business of fibrosis, we want to understand the cellular and molecular mechanism(s) involved in the development of fibrosis and remodelling of the heart. These are the main areas in terms of my future research.