Researchers have discovered a new mechanism by which obesity leads to type 2 diabetes, raising the possibility of new and more effective treatments.

Type 2 diabetes arises when the body is unable to produce sufficient insulin, an essential hormone which facilitates the absorption of glucose into the body. Prolonged exposure to high glucose levels can lead to complications including heart disease, kidney disease and cancer. The causes of type 2 diabetes are not as yet well understood, but lifestyle factors such as obesity are commonly thought to lead to the condition, which affects one in 12 people worldwide.

In research published today in the Journal of Clinical Investigation, scientists were able to establish a previously unknown link between high BMI and reduced insulin production. The researchers uncovered the connection by exposing donor samples to doses of peptides known as incretins, which in their natural state help to raise the body’s insulin levels after meals. The researchers found that in samples donated by patients with a normal BMI, this exposure led to an unexpected boost in insulin production dubbed the “incretin effect”. This effect was then found to break down altogether in samples taken from patients with higher BMI.

Dr David Hodson of the Section of Cell Biology in Imperial’s Department of Medicine, one of the lead authors on the paper, said: “The disruption of the incretin effect in patients with higher BMI may help explain the connection between obesity and type 2 diabetes. The hope is that with further research new treatments can be developed that specifically target this new mechanism to restore insulin levels within the body.”

The production of insulin within the body is governed by beta cells in parts of the pancreas known as the islets of Langerhans. Although insulin production is maximised when these beta cells coordinate their activity and work together, such coordination tends to be very weak in humans.

This research marks the first time that incretins have been observed to boost coordinated beta cell activity to improve insulin output, though this coordination is disrupted by high BMI. The researchers used calcium imaging technology to observe the beta cells’ behaviour.

Professor Guy Rutter, another of the lead authors from Imperial’s Department of Medicine, said “By applying sophisticated imaging techniques, we’ve been able to show that the 'cooperativity' between beta cells is a little like that between musicians in an orchestra: in this case, incretin acts like a conductor, improving insulin secretion by preventing players being out of time with each other. By showing here that high levels of fat target this dynamic, resulting in chaos, we hope to be able to improve existing diabetes therapies and eventually lower the burden of this disease.”

Reference

DJ Hodson et al. 'Lipotoxicity disrupts incretin-regulated human β cell connectivity' J Clin Invest. 2013 doi:10.1172/JCI68459