Exocytosis proteins as novel targets for diabetes prevention and/or remediation?

Abstract

Diabetes remains one of the leading causes of morbidity and mortality worldwide, affecting an estimated 422 million adults. In the US, it is predicted that one in every three children born as of 2000 will suffer from diabetes in their lifetime. Type 2 diabetes results from combinatorial defects in pancreatic β-cell glucose-stimulated insulin secretion and in peripheral glucose uptake. Both processes, insulin secretion and glucose uptake, are mediated by exocytosis proteins, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, Sec1/Munc18 (SM), and double C2-domain protein B (DOC2B). Increasing evidence links deficiencies in these exocytosis proteins to diabetes in rodents and humans. Given this, emerging studies aimed at restoring and/or enhancing cellular levels of certain exocytosis proteins point to promising outcomes in maintaining functional β-cell mass and enhancing insulin sensitivity. In doing so, new evidence also shows that enhancing exocytosis protein levels may promote health span and longevity and may also harbor anti-cancer and anti-Alzheimer's disease capabilities. Herein, we present a comprehensive review of the described capabilities of certain exocytosis proteins and how these might be targeted for improving metabolic dysregulation.

Keywords: SNARE proteins; diabetes; double C2-domain protein B; glucose homeostasis; glucose-stimulated insulin secretion; insulin resistance; syntaxin 4.

Fig. 1.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) and SNARE accessory protein isoforms utilized by islet β-cells and skeletal muscle cells for vesicle exocytosis: a common subset of factors. Factors listed in the β-cell (blue circle) are known to facilitate glucose-stimulated insulin secretion, and those listed in the skeletal muscle cell (red circle) are required for insulin-stimulated glucose uptake. Those isoforms utilized by both β-cells and muscle cells are shown in the center overlap of the blue and red circle. VAMP2, -3, -7, and -8, vesicle-associated membrane proteins 2, 3, 7, and 8, respectively; STX1A, -2, -3, and -4, syntaxin 1A, 2, 3, and 4, respectively; t-SNARE, target membrane SNARE; v-SNARE, vesicle-associated SNARE; DOC2B, double C2-domain protein B.

Fig. 2.

Differential requirement of SNARE and SNARE accessory protein isoforms during each phase of glucose-stimulated insulin secretion from islet β-cells. Whereas the first phase of insulin release uses both STX1- and STX4-based complexes, the second phase of insulin release relies upon STX4-based SNARE complexes. Accessory factors shown to be affiliated with these complexes are also grouped with the corresponding t- and v-SNARE core complexes. Note: SNAP25/23 denotes that SNAP25 and SNAP23 both suffice in the affiliated complex.

Fig. 3.

Proposed mechanisms underlying the benefits of DOC2B overexpression. Overexpression of DOC2B has shown positive effects on whole body glucose homeostasis. The mechanism by which DOC2B overexpression exerts its positive effects in β-cells/muscle cells is still yet to be elucidated. A: DOC2B proposed to function as a scaffold for Munc18-1 and Munc18c binding and subsequent activation of STX4. B: DOC2B proposed to bind directly to STX4, allowing for STX4 activation and promotion of SNARE formation. C: DOC2B proposed to bind the light chain (Tctex-1) of the motor protein dynein, which functions along microtubules. DOC2B may act direct/indirectly on actin remodeling, subsequently allowing for translocation of vesicles to the plasma membrane.

Fig. 4.

Exocytosis proteins implicated in human neurological and metabolic diseases. SNARE protein abundances (STX4, STX1A, SNAP25, and VAMP2) are decreased and genetic polymorphisms implicated in a variety of neurodegenerative, autoimmune, and metabolic diseases. Therapies are proposed based on present studies that aim to replenish/preserve abundance of exocytosis proteins. STZ, streptozotocin.

Fig. 5.

Translational implications for SNARE/accessory proteins? Based on preliminary animal studies and in vitro analysis, targeting exocytosis proteins such as STX4 and DOC2B for enrichment appears to be beneficial in treatment strategies to deter aging/diminished healthspan, diabetes, and cancer.