Portrait of author

Anne Færch Jørgensen:
In vivo genetic screening for therapeutic targets for type 2 diabetes

Date: 15-10-2020    Supervisor: Kim Rewitz

Diabetes afflicts 1 in 11 adults globally and causes enormous human and economic losses. Between a fifth and half of the cost related to diabetes treatment is spent on diabetes complications, caused by suboptimal blood glucose management, suggesting that the current treatment is not adequate. In this thesis I argue that in vivo forward genetic screening in the model organism Drosophila melanogaster, may contribute to the search for new therapeutic targets for type 2 diabetes.

I review commonalities between the highly conserved insulin signaling pathway and the responses to hypercaloric diets, which can cause insulin resistance through induction of intracellular stress responses and the innate immune response in both mammals and flies. In addition, I attach two manuscripts which identify two possibly conserved mechanisms of attenuation of insulin signaling, through in vivo forward genetic screening.

In Manuscript I, hypoxia is found to be a key regulatory inhibitor of systemic growth. Specifically, hypoxia in the adipose tissue inhibits Drosophila insulin-like peptide (Dilp) secretion in a Hypoxia Inducible Factor a dependent manner.

In Manuscript II, gut-derived Bursicon signaling is found to inhibit high sugar diet (HSD)-induced lipid accumulation, and attenuate HSD-induced Dilp expression and release via Rk in the insulin producing cells. Interestingly, while HSD-induced Bursicon inhibits Dilp expression, Bursicon signaling is necessary for expression of Dilp3.

I conclude that modeling insulin signaling in Drosophila, may further our understanding of the conserved mechanisms underlying diet-induced insulin resistance, and thus may prove helpful in the search for new therapeutic targets for type 2 diabetes.