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 -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.

DOC2B promotes insulin sensitivity in mice via a novel KLC1-dependent mechanism in skeletal muscle

“…While it is generally agreed that DOC2B is vital to insulinstimulated GLUT4 vesicle translocation [13], the precise mechanism(s) involving DOC2B remain unresolved. GLUT4 translocation starts with the binding of extracellular insulin to the insulin receptors (INSRs) on the skeletal muscle PM, which activates a phosphorylation-dependent intracellular signalling cascade.…”

“…GLUT4 translocation starts with the binding of extracellular insulin to the insulin receptors (INSRs) on the skeletal muscle PM, which activates a phosphorylation-dependent intracellular signalling cascade. This cascade triggers the intracellular GLUT4containing vesicles to translocate to the PM, where the vesicles are docked and fused via soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) proteins [13,14], including two target-associated (t)-SNARE proteins, syntaxin 4 (STX4) and synaptosome-associated protein 23 (SNAP23), as well as one vesicle-associated (v)-SNARE protein, VAMP2 [15][16][17]. Vesicle fusion promotes the integration of GLUT4 into the PM, which facilitates glucose uptake.…”

WNK1 kinase is essential for insulin‐stimulated GLUT4 trafficking in skeletal muscle

“…WNK1 regulates both endocytosis and exocytosis of various transmembrane transporter proteins . WNK1 promotes SNARE‐associated vesicle delivery and fusion to plasma membrane . Insulin activates PI3K/Akt kinase to promote the translocation of SNARE‐associated GLUT4 vesicle .…”

“…The functional relationship between individual TBC1D4 phosphorylation site and WNK1 regulation of GLUT4 awaits further future studies. Translocation of GLUT4-containing vesicles upon insulin stimulation is mediated via SNARE protein complex [8]. Defects of SNARE protein complex and GLUT4 trafficking in skeletal muscle are strongly correlated with insulin resistance and diabetes [8,13,21].…”

Regulation of Insulin Secretion and Mechanism of Production-Secretion

“…7,8,12 Bu çalışmalarda, Ca 2+ sinyalinden bağımsız olarak işlev gören bir K ATP -kanal bağımsız yolağının, insülin sekresyonunun uyarılmasına aktif olarak katıldığı ileri sürülmektedir; 8,12 bu yola ise amplifiye yol adı verilmektedir. 8,13 Bu K ATP bağımsız yolunun önemi, kanalın iki alt biriminden herhangi birinin işlevsiz olduğu ve işlevsel K ATP 'den yoksun KO fare modellerinde gösterilmiştir. 14,15 Bu deneklerde β-hücreleri, Ca 2+ düzeylerinde spontan artışlar sergilemekte ve glukoz, sınırlı insülin sekresyonuna neden olabilmektedir.…”