The Link between Obesity and Diabetes

Type-2 diabetes is a chronic condition of hyperglycemia, which is now found in 400 million people around the world, and is estimated by 2040 to affect 600 million people around the world. It is strongly linked to the level of obesity. One explanation for the rising prevalence of the condition around the world is the secular trends that we see in obesity in virtually every population around the world. We know that if people at risk of diabetes lose weight, they have a strongly reduced risk of diabetes. Indeed, people, who have drastic weight reduction through surgical interventions, like bariatric surgery, they have an immediate effect on diabetes, and actually in some instances it leads to reversal condition entirely. So, obesity and diabetes are strongly linked.

Treatment of diabetes critically involves avoidance of weight gain and indeed treatment to encourage weight loss. One of the intriguing questions is what is the pathophysiological basis of that link between obesity and diabetes. Now epidemiological studies have traditionally looked at the association between overall levels of obesity, characterized by the body mass index, which is a ratio of weight by height squared. When that is in excess of 30, people have a very high risk of progressing to diabetes.

Now in addition to that other studies have looked at the regional distribution of fat. This has been characterized in large epidemiological studies by a ratio of the waist circumference to the hip circumference. People who have a high ratio, in other words have more of the fat deposited centrally, tend to be a much greater risk of diabetes. It appears that that effect is independent of the overall level of obesity. There is something about where the fat is deposited that’s critical. This gave rise to many years of study focusing on that central adiposity, the fat that’s deposited either around the organs, or in the organs, particularly in the central part of the body. It was thought that that was where the problem lay.

Some clues to alternative hypothesis came from extreme mutations and extreme genetic forms of fat storage, which are also associated with diabetes. There’s a condition called lipodystrophy, where patients have an inability to store fat peripherally. By peripherally I mean predominantly in the legs. If they can’t store fat in the legs -these patients have very thin legs – when they have excess energy intake, that fat has to go somewhere. So, the fat then goes into the central part of the body and patients with lipodystrophy have hepatic steatosis, that livers are full of fat and these people are very resistant to insulin, very difficult to treat.

Now that condition is interesting because the primary defect lies not in having the fat deposited centrally, but the inability to store the fact in a safe-deposit peripherally. This is an underlying pathophysiological mechanism that could explain the link between obesity and diabetes. Recently advances in genetics and the ability to study very large populations have suggested that that same mechanism, which we see at play in people with extreme mutations, is also present in a more subtle form in other people, who don’t have mutations, but who have common variations.

A group from Cambridge led by Robert Scott have recently published papers showing that genetic variants that are associated with inability to store fat peripherally, are associated with insulin resistance and higher risk of diabetes and heart disease. They are also associated, in the presence of energy excess, with storage of the fat centrally. This gives rise to some very intriguing new hypotheses as to why people, who have an inability to store fat peripherally in a safe-deposit, get more fat centrally, and eventually insulin resistance and diabetes.

There is a range of different treatments for diabetes. We have tended in the past to use them in all individuals without consideration to whether they have a certain subtype of diabetes or not. I think the future lies in stratification, in be able to identify subgroups of the populations, who might respond better to particular types of therapy than others.

One of the problems with many therapies for diabetes is that they actually also give rise to weight gain, so we might be controlling the hyperglycemia, but sometimes at the cost of greater weight gain. I’m thinking of the sulfonylurea agents, in particular – insulin itself. If you give insulin to patients they tend to be more hungry, tend to put weight on and you get into a bit of a vicious cycle of controlling the hyperglycemia, but not controlling the weight.

The cornerstone of diabetes therapy should be to find therapies that both address the obesity, the weight loss and the hyperglycemia. That’s starts with lifestyle to mention. This is not an adjunctive therapy , this is really the cornerstone. We should be much more aggressive, particularly in early phase diabetes of encouraging patients to lose weight and be more physically active and equal. Without that our therapy are really trying to push a stone up a hill.

In the past we talked about diabetes gradually getting worse over time. That gives rise to a state in the patients that somehow the condition is going to get away from them, they can’t control it. It’s actually very empowering to patients to say that when the diabetes first comes on, that if they can lose maybe ten percent of their body weight, it is possible to put their diabetes into remission. I think it’d be wrong to talk about a cure, but drastic weight loss at the time of diagnosis and early on in the trajectory of someone’s diabetes can give rise to remission of the diabetes and avoidance of the complications.

Ray Taylor in Newcastle has demonstrated in patients, who’s undergone very low calorie diets, that diabetes can be reversed, and he’s currently engaged in a trial to demonstrate the benefits of that. The one would suspect that those benefits will be sizeable. After that, in conjunction with that aggressive lifestyle matted modification, there are other therapies, the first of which is metformin.

Metformin is a drug that impacts on glucose levels, but importantly also impacts on obesity level, unlike some other therapies for diabetes, is also incredibly cheap and safe. It really is the first drug of choice or for all people with type-2 diabetes. A critical question is should we be giving it to people at risk of the condition.

Studies in the United States have shamed in people at risk that it can reduce the risk of progression from pre-diabetes to diabetes. A critical question is whether giving metformin before the diagnosis of diabetes is associated with avoidance of the complications of diabetes. Now, these are primarily heart disease, but also cancer, because obesity and hyperglycemia are strongly related to a set of cancers. It is possible that metformin therapy given before the onset of diabetes could result in reduction both of heart disease and cancer. That has never been shown in a clinical trial. In the United Kingdom we are currently completing a feasibility study for a trial called GLINT which will involve a randomized control trial of metformin given to people at risk of diabetes with the outcome being progression to heart disease.

One obvious question is whether there’s a genetic basis to obesity. It is known that obesity is highly heritable and we’ve identified through Genome-Wide Association Study some hundred genes that the impact on obesity. The question is what pathway do they impact on obesity. It appears that most of those genetic variants impact on central pathways that control appetite. Currently there is no evidence of those genetic variants being associated with a reduction of energy, expenditure or reduction of physical activity. It appears, if anything, that all the genetic evidence lies on the pathway of the having excess energy intake rather than reduced energy expenditure.

For many years it was thought that people who were obese might have slower metabolism or might have lower energy expenditure. In fact the reverse is true. Energy expenditure is highly related to body mass, so people, who tend to be bigger, tend to have higher energy expenditure. Whether there are subtle differences in energy expenditure between people who go on to get obesity, and whether those have a genetic basis is largely unknown, predominantly because we haven’t studied it and large enough population. In the face of the strong link between obesity and diabetes and the evident epidemics of both conditions around the world, it’s paramount that science gives its attention to this issue predominantly.

The first priority should be to try and understand population approaches to reducing the prevalence of obesity and thereby reducing type-2 diabetes prevalence. This will probably not occur through individual action, but will require scientifically based prevention strategies that are addressed that the obesity epidemic of the population level. However that needs to be coupled with individually targeted approaches to prevention that are based on randomized controlled trials, and evidence-based interventions in people who’ve already got diabetes to reduce obesity either by surgical interventions, such as bariatric surgery, but preferably by cheap and readily available oral therapies. We may need to investigate more therapies that can be developed to help people who have excess energy, store that in an efficient and safe way.