"In our model, stress conditions, such as a genetic variant or insulin resistance or a high-fat diet, lead to increased availability of the tribbles protein by as yet poorly understood mechanisms," says Dr. Kulkarni, who is also an Assistant Professor of Medicine at Harvard Medical School. "That in turns blocks the function of the ATF4 transcription factor, which ultimately leads to reduced insulin secretion."

In addition to revealing details on how the tribbles protein may hamper insulin secretion, the study suggested ways in which it may increase beta cell death and decrease beta cell proliferation. Tribbles normally binds and blocks the action of AKT, an insulin signaling protein directly involved in cell death and proliferation ”and the tribbles genetic variants bound more strongly to AKT, thereby blocking proliferation and promoting cell death.

"While our research started out looking at one particular genetic variant of tribbles, our findings may have a broader impact on patients with type 2 diabetes, because they highlight ways in which elevated levels of tribbles have an effect on the beta cell," Dr. Kulkarni adds. "The higher the protein, the greater the defect. Yes, the more the tribbles, the more the trouble for beta cells."

Source: Joslin Diabetes Center