Insulin Resistance

Insulin resistance is one of the earliest detectable defects associated with a range of metabolic diseases including type 2 diabetes, cardiovascular disease, certain cancers as well as neurological disease. Major factors that contribute to insulin resistance in mammals include over nutrition, physical inactivity, ageing and pregnancy. A number of extracellular and intracellular factors have been implicated in insulin resistance including hyperinsulinemia, steroids, growth hormone, inflammation, oxidative stress, lipotoxicity and mitochondrial defects. How these factors contribute to insulin resistance, how they interact with one another and whether induce insulin resistance by separate mechanisms remains unclear.

 

Overview image_Figure 1.jpg

Studies in our lab indicate that a number of these factors may induce insulin resistance via a common mechanism. We have found that different modes of insulin resistance are often associated with mitochondrial oxidative stress, yet precisely how this impairs insulin action is not known. Intriguingly, our work has also highlighted that insulin resistance is not a generalised defect in the insulin signalling pathway, but is rather specific to insulin-regulated glucose transport (FIG. 2). How this specificity is achieved and the implications of this selectivity for long term health in the context of hyperinsulinaemia are questions we are trying to address in the laboratory.

Figure 1. The contribution of insulin resistance to the development of T2D. Under fasting conditions blood glucose levels are maintained via gluconeogenesis. Following a meal, increased circulating glucose is detected by the pancreas which responds by secreting insulin. Insulin acts to suppress gluconeogenesis and hepatic glucose output and to promote glucose uptake and storage in muscle and adipose tissue. In insulin resistance, the liver, muscle and adipose tissue are less sensitive to insulin, so blood glucose remains elevated. The pancreas can compensate by secreting greater amounts of insulin to regain control of blood glucose levels.


Figure 2.jpg

In a separate series of studies, we have been studying the dynamic progression of metabolic disease in mice fed high fat / high sucrose diet for different periods of time. These studies have revealed an unexpected pervasiveness of the detrimental effects of this diet on a multitude of systems including bone and brain. Surprisingly, we have also unveiled an unexpected adaptation to this diet involving beta cell expansion and hyperinsulinaemia leading to complete resolution of glucose tolerance in long term fed animals. This is a useful model for studying the link between diet, insulin resistance and whole body health.

 

Figure 2. Insulin resistant is selective for insulin-regulated glucose transport. Insulin activates the PI3K-Akt signalling cascade. Akt mediates a multitude of cellular processes via distinct substrates. Only insulin-stimulated glucose transport is sensitive to insulin resistance (dotted line).


Ongoing projects:


Mitochondria and insulin resistance
We recently identified that loss of coenzyme Q from mitochondria leads to insulin resistance through increased mitochondrial oxidants. Changes in other mitochondrial processes such as oxidative phosphorylation and mitochondrial dynamics are also implicated in insulin resistance. We aim to understand how these aspects mitochondrial biology interact to confer insulin resistance.  

Role of cellular metabolism in insulin resistance
We are using a range of -omics technologies to interrogate how cellular metabolism is altered in insulin resistance and how, in turn, this may influence insulin sensitivity.

Role of macronutrient ratios in driving insulin resistance and hyperinsulinaemia
We are interrogating how dietary fat and carbohydrate interact to cause insulin resistance and drive hyperinsulinaemia in different mouse strains. We are also interested in how hyperinsulinaemia influences organismal health via the action of insulin on cellular pathways other than glucose transport and organ systems other than the key metabolic target tissues (fat, muscle, liver). 

GLUT4 trafficking in insulin resistance
We are using novel GLUT4 reporter constructs to identify how GLUT4 trafficking is perturbed in insulin resistant cells.