Our type 2 diabetes research

‘Pre-diabetes is common in overweight and obese people and, as with diabetes, it is a risk factor for cardiovascular disease, kidney disease, blindness and cancer,’ said Dr Dorit Samocha-Bonet. ‘Currently, individuals with pre-diabetes are advised to lose weight and exercise, but the long-term uptake of lifestyle modifications is poor and if they remain untreated, these people are at increased risk of developing T2D and its complications.

‘Our studies show that as they age, the majority of individuals with obesity will become insulin-resistant, and the results suggest that early effective interventions will protect most obese individuals from developing T2D. Our current biggest limitation is the inability to treat these people effectively, because we lack accessible tools to predict what would be the best treatment for an individual’.

Research by Professor Jerry Greenfield and Dr Dorit Samocha-Bonet, in collaboration with Professor Mark Febbraio, aims to provide tools to diagnose the different subtypes of pre-diabetes and predict treatment success for pre-diabetes and T2D.

‘In collaboration with Professors Elinav and Segal from Israel’s Weizmann Institute, we are conducting a series of studies over five years to distinguish between the different types of pre-diabetes.

‘By measuring body fat content, liver fat, blood markers, genome and signatures of microorganisms in the stool, we are looking to predict treatment success. Together, these measurements will form ‘signatures’ of the various pre-diabetes types that will allow us to more effectively treat pre-diabetes by individually tailoring treatment, avoiding exposure of the patient to medications that will not be effective and may cause unwanted side-effects.’

Professor Mark Febbraio, Head of Garvan’s Diabetes and Metabolism Division and Head of the Cellular and Molecular Metabolism Laboratory, is working with collaborators around the world to understand the cellular and molecular mechanisms associated with obesity and T2D and the role of exercise and exercise-induced cellular changes in combating chronic disease and some cancers.

Professor Febbraio and his group have recently demonstrated a new potential therapeutic target for obesity-induced insulin resistance. ‘Our research has shown that cytokines from the IL-6 family can be used to prevent obesity and insulin resistance and we have successfully patented a novel peptide called IC7 that activates IL-6 receptors. IC7 can prevent fatty liver and normalise blood glucose levels in T2D and we shortly hope to commence the first human studies.

‘Specifically, IC7 significantly improves glucose tolerance and blood glucose levels and prevents weight gain and fatty liver in obese mice. IC7 is safe in laboratory mice and shows no signs of provoking an immune response that would reduce its effectiveness. Before we go to human trials though, we need to demonstrate that IC7 works as a treatment for T2D in two more pre-clinical trials.’

T2D is a complex and progressive disease and while some of the newer therapies showed great promise, over time patients developed an immune response which then blocked the therapeutic effects of the drug. Because IC7 is something that already circulates freely in the body, it is far less likely to induce an immune response. Indeed, so far Professor Febbraio’s studies demonstrate that IC7 shows no signs of immunogenicity.

‘IC7 is a potent treatment for T2D that acts to reduce obesity, improve glucose tolerance, reduce fasting glucose and decrease fatty liver. Most importantly, we have been unable to detect any serious adverse events associated with IC7, and this gives us a great deal of confidence that IC7 can be a viable next generation treatment for obesity and T2D.’

In a productive collaboration, Professor Jerry Greenfield, Lab Head, Clinical Diabetes, Appetite and Metabolism, and Dr Dorit Samocha-Bonet, Leader Clinical Insulin Resistance Group, and their colleagues, are taking the first steps towards a personalised and targeted approach to the treatment of obesity and type 2 diabetes.

‘Not all people who carry excess weight are at the same risk of developing diabetes. We recruited a cohort of overweight and obese individuals to determine which volunteers have a resistance to the hormone insulin, which regulates the level of sugar in the blood after a meal,’ said Professor Greenfield.

‘We consider obese individuals who are not insulin-resistant, but instead remain sensitive to insulin, to be metabolically healthy.’

In studies so far, the researchers found that some participants were sensitive to insulin at muscle, but were resistant at liver, whilst others had the opposite profile – sensitive to insulin at liver, but resistant at muscle. They also found that obese individuals who are sensitive to insulin in muscle only, or liver only, are metabolically healthier in many respects than the group that is insulin-resistant at both sites.

‘Not only do they have lower blood pressure, but they also have less deep abdominal fat and less fat within the liver. In fact, judging by these criteria, the metabolic health of these people is similar to that of individuals who are insulin sensitive at both muscle and liver.’

Their work shows the complexity of human insulin resistance, suggesting that there are different drivers of insulin action at liver and muscle that may be determined by specific genetic pathways.

‘The demonstration that insulin sensitivity in the liver and muscle may occur independently in humans, potentially paves the way for earlier detection and individualised treatment of people at risk of developing metabolic disease,’ said Professor Greenfield.

‘Diabetes therapies may predominantly target muscle or liver insulin resistance, or the pancreas to stimulate the secretion of insulin and some medications will cause weight loss. However, as we don’t have the tools to decide what would be the most efficacious treatment in an individual, this often leads to treatment failure and unnecessary exposure to side effects.’

Professor Lesley Campbell is Lab Co-Head of Garvan’s Clinical Diabetes, Appetite and Metabolism Laboratory. Her work has not only shown strong heritability for overall and abdominal fat deposits, but has also revealed the gene for a new lipodystrophy – problems with the way the body produces, uses and stores fat, or ‘fat redistribution’ – and another diabetes syndrome.

‘The rising tide of diabetes in the world is predominantly due to the increase in T2D,’ said Professor Campbell, ‘but the number of people who have the disease and don’t know it, is equal to those already diagnosed. It is the commonest cause of new blindness, kidney disease and amputation.

‘The disorder is a heritable disorder and a family history of T2D is a major risk factor for both body weight problems and later diabetes and cardiovascular disease.

‘We need to diagnose this disorder early and help people with both lifestyle change and with novel medications which have been shown to extend life and lower the rate of complications. Treatment early in the disease process can offer significantly better outcomes.’

For many years Professor Campbell and her team have studied the healthy relatives of people with T2D and compared them with other people who are also healthy but have no known diabetic relatives, to find any physiological markers that show that they may be susceptible to getting T2D. Those who carry diabetes susceptibility genes show subtle physiological differences, even at the time when they are still non-diabetic by standard blood sugar tests.

‘Our research has shown several detectable physiological differences in the healthy relatives of people with T2D, and in response to a voluntary over-feeding study, these people gained more weight than those who didn’t have a relative with T2D.

‘We are now moving ahead to measure the indicators we have detected in healthy or pre-diabetic relatives and assess the effect of varied treatments to prevent progression to diabetes. This could be a major step to help reduce the prevalence of this disease and to detect it before harm is done.’