Loss of pancreatic β-cells or their proper function is characteristic of type 1 and type 2 diabetes, so restoring functional β-cell mass has been a major therapeutic goal in the field. A team led by Bridget Wagner at the Broad Institute's Center for the Science of Therapeutics, working with Broad associate member Rohit Kulkarni’s lab at Joslin Diabetes Center, showed that this may be achievable in humans. They found that the kinase-inhibiting enzyme 5-IT, which is known to promote β-cell mass in rodents, can also spark β-cell proliferation in humans by inhibiting the protein DYRK1A. The research, published in Diabetes, suggests a possible regenerative medicine approach to diabetes.

The human body is governed by complex biochemical circuits. Chemical inputs spur chain reactions that generate new outputs.  Understanding how these circuits work—how their components interact to enable life—is critical both to advancing basic biology and to identifying new treatments to disease, which arises when these circuits misfire. But getting to that understanding is no trivial task.

Histone deacetylase inhibitors (HDACi) hold therapeutic potential for many diverse diseases, including psychiatric disease and diabetes. But so far, most HDACi were found to inhibit more than one histone deacetylase, a characteristic that can decrease efficacy and contribute to side effects. In work published in ACS Chemical Biology, researchers Edward Holson and Florence Wagner of the Broad’s Stanley Center for Psychiatric Research, and colleagues present a toolkit of highly potent and differentially selective HDACi, which they developed to understand the role of histone deacetylases in cognition. The paper also reports the results of a collaboration with Bridget Wagner of Broad’s Center for the Science of Therapeutics, who used the toolkit to reveal that the isoform selective inhibition of HDAC3 by BRD3308 protects pancreatic beta cells from the effects of diabetes.

Studies have shown that obese mice and humans have increased serum levels of the fatty acid binding protein aP2, and that elevated aP2 levels correlate with metabolic complications. Since genetic loss of aP2 in mouse models and in humans results in lowered risk of cardiometabolic disease, the molecule offers an exciting opportunity for new intervention strategies.

Now, in a proof-of-principle study led by Broad associate member Gökhan S. Hotamisligil of the Harvard T.H. Chan School of Public Health's Sabri Ülker Center, researchers have shown that the protein may be a viable therapeutic target for type 2 diabetes. In the study, the authors identified a monoclonal antibody to aP2 that lowered fasting blood glucose, increased insulin sensitivity, and lowered both fat mass and incidence of fatty liver in obese mouse models. Their paper is published online in Science Translational Medicine.

Type 2 diabetes (T2D) affects more than 463 million people worldwide and is a leading cause of morbidity and mortality across the globe.

Variation in human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D), but scientists have found it challenging to pinpoint the specific variants that account for this risk. This week, a team led by Soumya Raychaudhuri and Xinli Hu of Broad Institute and Brigham and Women’s Hospital published a study that used new genotype imputation methods to identify independent amino acid positions, as well as interactions within the HLA region, that account for T1D risk. Taking this approach, they found that three key amino acid positions in HLA-DQ and HLA-DR molecules drive the vast majority of T1D risk. To learn more, read their paper online in Nature Genetics.

In one of the largest longitudinal studies of the microbiome to date, researchers from the Broad Institute of MIT and HarvardMassachusetts General Hospital (MGH), and the DIABIMMUNE Study Group have identified a connection between changes in gut microbiota and the onset of type 1 diabetes (T1D). The study, which followed infants who were genetically predisposed to the condition, found that onset for those who developed the disease was preceded by a drop in microbial diversity – including a disproportional decrease in the number of species known to promote health in the gut. These findings, published by Cell, Host & Microbe, could help pave the way for microbial-based diagnostic and therapeutic options for those with T1D.