Clinical Diabetes, Appetite and Metabolism

Our Lab is focused on the challenge of modern times: that evolution has left many of us with good survival genes which make us prone to gain weight easily and develop type 2 diabetes in times of plenty.

Our recent discoveries have been that healthy relatives of people with type 2 diabetes probably carry genes for obesity (explaining why so many have weight problems). Possible pathophysiological precursors have been detected in otherwise healthy at risk subjects from our detailed studies.  Our lab has optimised human muscle biopsies through the addition of an ice-cold saline lavage. This minimises manipulation of the sample, washes off excess blood, and avoids excessive warming of the sample by exposure to room air. We also published our study showing that when asked to overeat for one month, within days the healthy relatives of people with type 2 diabetes had gained more weight than those who didn’t have diabetic relatives, although both groups were treated identically. 

On the flipside, we have identified a group of overweight and obese humans who appear to be at lower risk of diabetes and heart disease than other obese individuals. A major focus of our laboratory is to establish the factors that confer this metabolic protection and to devise a set of clinical criteria that will assist in their identification in clinical practice. The outcome of this research will expand our knowledge regarding the relative importance of metabolic abnormalities, such as abdominal and liver fat, on the development of insulin resistance and diabetes. We will find out what protects the overweight and obese people and whether they remain at lower risk of metabolic disease over long periods of time.

Another focus of our group is the identification of specific genetic defects that cause diabetes and obesity in humans. The conditions we are studying are monogenic or single-gene obesity disorders (including melanocortin 4 deficiency), lipodystrophies (partial and generalised) and monogenic diabetes (previously known as MODY – Maturity Onset Diabetes of the Young). Major improvement in insulin resistance after bariatric surgery in a lipodystrophy due to a novel gene has just been reported for the first time.

Along these lines, an important area we have looked at with the Neuroscience Division and the Prader Willi Syndrome (PWS) Clinic at Royal Prince Alfred Hospital has been the difficult paradox of PWS: a genetic cause of relentless appetite from early childhood in a child who is initially born as a floppy baby who feeds poorly. We have described some of the abnormalities and have tested a possible treatment to help the desperate families. This has now been put into randomised trial in USA. We are hoping to test a new diabetes drug to help in the search for effective treatments in the coming year to help families with this major challenge.

Other studies have established the effects of glutamine, an amino acid, on metabolism, both in isolation and in combination with a new diabetes medication. Glutamine appears to have a promising effect on glucose lowering in the post-meal state and may offer a simple, novel and effective treatment in type 2 diabetes. We are studying the effects on an alkaline diet on insulin sensitivity in humans, to determine whether there is any scientific evidence that this approach improves metabolic health.

We have undertaken collaborative studies with the Department of Clinical Pharmacology at St Vincent’s Hospital to study the effects of metformin, particularly in relation to specific genetic variations in humans.

Our work continues the careful clinical phenotyping of disease or pre-disease states with a search for biomarkers or genetic insights into causation. Collaboration with the University of Sydney’s Brain and Mind Institute and with our own Psychiatric services has extended the possible scope of the studies for the future.

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