Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes

Abstract

Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of β-cell mass and an early biomarker of T1D.

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

“…STX4, among other SNARE proteins such as STX1A, SNAP25, and VAMP2, have all been shown to be deficient in T2D human islets (Table 2). Notably, the regulatory factors of these SNARE proteins, such as multiple Munc18 isoforms, DOC2B, Munc13-1, multiple synaptotagmin isoforms, and synaptophysin, are also deficient (3,6,9,30,72,78,83,100). Modeling this in spontaneous rodent models of prediabetes and T2D, such as the obese and diabetic Zucker rats and the nonobese diabetic GK rat, revealed that many of these same exocytosis factor deficits are conserved (Table 2).…”

Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2

“…Granules purified from cells following a 72 hr treatment with palmitate (delivered as a BSA complex and used to model elevated free fatty acid [FFA] observed during T2D Rorsman and Ashcroft, 2018 ) exhibited a monophasic high-affinity calcium response (K 1/2 = 12 ± 2 µM, Figure 1B , blue). In contrast, granules purified from cells following a 20 hr treatment with cytokines TNF-α, INF-γ, and IL-1β that model the inflammation associated with the onset of T1D ( Aslamy et al, 2018a ; Aslamy et al, 2018b ) showed a shift to a low-affinity monophasic response (K 1/2 = 41 ± 4 µM, Figure 1B , red). Overexpression of Doc2B prior to cytokine treatment, which had previously been shown to reverse cytokine effects on β-cells ( Aslamy et al, 2018b ), prevented the shift of the calcium dose-response ( Figure 1C , purple).…”

“…CAPS2 was found to be enriched on syt-9 granules, while Doc2B was enriched on syt7 granules ( Figure 5B), indicating that the fusion regulatory machinery differs in part between the granule subpopulations. Moreover, there is a striking correlation between the loss of syt7 granules and the loss of Doc2B with the cytokine-induced type 1 diabetic phenotype ( Figure 1B and (Aslamy et al, 2018a, Aslamy et al, 2018b. The preservation of the syt7 granules by overexpression of Doc2B suggests a role for Doc2B in granule formation or in protecting these granules during cytokine treatment.…”

“…Treatments that mimic these defects have been identified and used to model diabetes in healthy human cells, rodent islets, and immortalized cell lines ( Aslamy et al, 2018a ; Aslamy et al, 2018b ; Gandasi and Barg, 2014 ; Hoppa et al, 2009 ; Olofsson et al, 2007 ). Onset of T1D is modeled by treatment of insulin-secreting cells with proinflammatory cytokines TNF-α, INF-γ, and IL-1β, which leads to decreased insulin release and a loss of Doc2B, an established biomarker for the disease ( Aslamy et al, 2018a ; Aslamy et al, 2018b ). T2D is associated with extended exposure to elevated free fatty acids (FFA) caused by high fat diets ( Grill and Qvigstad, 2000 ).…”

“…Stimulated secretion of insulin normally occurs in two sequential phases, an acute first phase and a sustained second phase, which are differently affected in the T1D and T2D models. Modeling the inflammation of T1D by cytokine treatment causes a defect in insulin secretion attributed to the loss of Doc2B ( Aslamy et al, 2018a ; Aslamy et al, 2018b ), which primarily suppresses the second phase of secretion ( Ramalingam et al, 2012 ). Conversely, modeling T2D by palmitate treatment strongly decreases the first phase ( Rorsman and Ashcroft, 2018 ).…”