Diabetes – Malfunctioning brown fat and pancreatic beta cells

Supported by EU funding, the BETABAT (Development of novel treatment strategies based on knowledge of cellular dysfunction in diabetes) project is searching for novel avenues to address cell dysfunction in diabetes. This four-year project is testing the hypothesis that deleterious metabolic crosstalk between beta cells and BAT aggravates cellular dysfunction in diabetes.

Scientists are screening for small molecule probes, and testing novel modifications of known drugs, viral vectors and transgenic animals to genetically validate targets.

BETABAT has achieved considerable progress in several directions. The project showed that the markers of endoplasmic reticulum (ER) stress are present in islets from patients with type 1 and type 2 diabetes mellitus. It characterised in detail the crosstalk between ER stress and inflammation-induced apoptosis in models of diabetes.

Research established that immune and metabolic stress causes death of pancreatic beta cells via activation of the mitochondrial or intrinsic pathway of apoptosis. They also developed models to study apoptosis in brown adipocytes using mitochondrial toxins and ER stressors.

Developing the concept that BAT activation protects against diabetes, the project identified two new adipokines, secreted by adipose tissue. Increasing BAT activity in mice with impaired insulin secretion improved their metabolic profile.

Scientists have translated obtained information on organelle dysfunction into novel therapeutic approaches to restore normal beta cell and BAT function in diabetics. A pilot clinical trial set up by BETABAT is the first of its kind that tests individualised strategies for type 2 diabetes.

BETABAT demonstrated that chemical chaperones (modulators of ER stress) protect mouse models of type 1 diabetes against hyperglycaemia. This may lead to clinical trials in the coming years. Importantly, BETABAT has also obtained novel data indicating that candidate genes for type 1 diabetes regulate beta cell responses to viral infections, pointing to novel avenues to protect these cells in early disease.

After 3 years of research, BETABAT has produced 107 peer-reviewed publications in high-impact journals. The mechanisms leading to cellular dysfunction of beta cells and BAT in the context of diabetes are defined by the cellular vulnerability imposed by diabetogenic genes. This novel and global view to a complex disease has important therapeutic implications.