Figure 7.

Inhibition of Cell Surface Mistargeted VDAC1 Restores GSIS in Prediabetic db/db Mice and in Human T2D Islets

(A–C) One-hour exposure to VDAC1 antibody (10 nM) or metformin (20 μM) restores impaired glucose-stimulated ATP generation in islets of diabetic db/db mice in parallel with suppression of ATP release (B) and augments GSIS (C). Mean ± SEM (n = 4).

(D) Insulin secretion in human ND islets cultured at 5 or 20 mM glucose (72 hr) in the presence and absence of VDAC1 antibody or metformin, followed by 1 hr incubation at 1G or 16.7G.

(E) Acute addition of VDAC1 inhibitors (1 hr) improves glucose-stimulated ATP generation in islets from T2D donors.

(F) Improved GSIS in the T2D islets shown in (E). Mean ± SEM (3–6 donors).

(G) The VDAC1 inhibitor VBIT-4 prevents hyperglycemia in prediabetic db/db mice injected at 6 weeks (25 mg/kg daily intraperitoneally [i.p.]) compared with vehicle-treated db/db mice (n = 12). C57/bl6 mice receiving either VBIT-4 (n = 5) or vehicle (n = 6) are also depicted. Six db/db mice from each group were followed for another 3–4 weeks for reversibility of the treatment. All C57/bl6 mice were monitored throughout. Note the gradual increase and long duration before reaching full hyperglycemia after VBIT-4 cessation.

(H) Plasma glucose concentrations during intraperitoneal glucose tolerance test (2 g/kg) in db/db or C57/bl6 mice after VBIT-4 treatment as in (G). Mean ± SEM of 12 mice (12 db/db and 5–6 C57/bl6 in each group).

(I) AUC for plasma glucose.

(J) AUC for plasma insulin (for plasma insulin values, see Figure S7J).