Regulating SNARE mechanisms to remediate glucose dyshomeostasis

Beckman Research Institute/City Of Hope, Duarte CA

Investigators

Abstract

PROJECT SUMMARY Type 2 diabetes (T2D) impacts ~38 million people in the US, and a shocking >98 million have prediabetes. The transformational anti-obesity drugs address a substantial facet of the obese population with insulin resistance (IR) and type 2 diabetes (T2D). However, their use is limited with certain comorbidities, especially in the T2D- susceptible aging population. Insulin secretion by islet β-cells and peripheral insulin action in skeletal muscle (skm) depend upon exocytosis proteins, and failure of exocytosis is a key cause of susceptibility to (pre)T2D. Thus, there is an unmet need for additional safe/effective (pre)T2D therapies that coordinately improve insulin secretion and insulin action. To diminish these complications and halt progression to T2D, our long-term goal is to understand the signaling and exocytosis mechanisms that can be modulated to prevent or reverse prediabetes. Over the past funding cycle, we identified that the plasma membrane (PM)-localized Syntaxin 4 (STX4) is also a pivotal mitochondrial regulator, culminating as a master regulator of insulin secretion and peripheral insulin action. Provocative preliminary data show that: (i) STX4 is localized to β-cell and skm mitochondria; (ii) skm-specific STX4 enrichment in high-fat-diet (HFD)-obese mice fully restores peripheral insulin sensitivity by preventing mitochondrial dysregulation; (iii) STX4 activation promotes functional capacity in human T2D and prediabetic islet β-cells, as well as in skeletal myotubes; and (iv) STX4 depletion in skm or β- cells impedes mitochondrial turnover by mitophagy. Thus, our central hypothesis is that STX4 is essential for mitochondrial function in skm and β-cells, and that STX4 activation can prevent and/or reverse the damaging effects of diabetogenic stress. The rationale for the proposed research is that once new mechanisms of STX4 are elucidated, and the role of STX4 in glucose homeostasis is understood, STX4-regulated signaling can be modulated to prevent or reverse disease in the face of diabetogenic stimuli. Two Specific Aims (SA) will test our central hypothesis: SA1, we will determine the role of STX4 in skm mitochondrial function, mitochondrial turnover by mitophagy, and reversal of insulin resistance; in SA2, we will determine the role for STX4 in islet β-cell mitochondrial structure and function. We will use innovative inducible skm- and β-cell-specific STX4 transgenic mice, and our novel hit small molecule to evaluate the therapeutic potential of activating STX4 in human islets in vivo/ex vivo, as well as human pancreatic slices, in a translation-focused institutional environment at City of Hope. This work will demonstrate how STX4 subverts diabetogenic stress in skm and islets, providing new insights into how STX4 targeting might be used for prediabetes treatment/prevention of T2D. These results will also positively impact efforts to ameliorate prediabetes because the identified mechanisms are highly likely to provide new therapeutic targeting strategies.