Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice

Abstract

It has been shown that all-trans retinoid acid (ATRA) hinders the development of autoimmune diabetes by inducing immune tolerance status. Meanwhile, exendin-4 increases beta-cell function and mass. Thus, we hypothesized that ATRA and exendin-4 combination therapy would prevent and reverse autoimmune diabetes. NOD/scid mice were intravenously transferred with splenocytes isolated from 12-week-old female NOD mice. After adoptive transfer, mice were treated with vehicle, ATRA (0.5 mg/mouse intraperitoneally every other day), exendin-4 (3 μg/kg subcutaneously twice daily), or combination for 6 weeks. Compared with vehicle, ATRA (P = 0.022) and ATRA plus exendin-4 (P = 0.013) treatment delayed the onset of diabetes. The pancreatic insulin content in mice treated with ATRA (P = 0.013) and exendin-4 (P < 0.02) was significantly higher than that of control mice. All but one spontaneous diabetic NOD mouse treated with ATRA and/or exendin-4 remained persistent hyperglycemic. ATRA and/or exendin-4 treatment did not alter their blood glucose levels and survival. Our results indicate that, before the onset of autoimmune diabetes, ATRA and exendin-4 treatment alone preserves pancreatic beta cells; ATRA and ATRA plus exendin-4 treatment delays the onset of autoimmune diabetes. However, after the onset of autoimmune diabetes, ATRA and/or exendin-4 treatment is unable to reverse hyperglycemia or improve survival.

All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

“…These findings indicated that ATRA protects against glomerular and tubule-epithelial hypertrophy in initial changes of DN without affecting elevation of blood glucose levels. These results are consistent with previous evidences of nephroprotective role of ATRA [13,14,15,16,17,18,35].…”

“…Previous studies have suggested that ATRA might protect against the development of renal pathological changes including DN [13,14,15,16,17]. Nevertheless, whether ATRA might attenuate renal fibrogenesis has not been studied in DN.…”

“…ATRA has a beneficial role on the progression of renal diseases. Its use is often associated with the reduction in proteinuria and improved glomerular and tubular lesions [14,15]. We previously reported that ATRA is a nephroprotective agent in a model of acute renal failure [16], and its administration exerts antioxidant effects that prevented the loss of renal tight junction proteins, claudins 5 and 2 in DN [17].…”

Retinoic Acid, Leaky Gut, and Autoimmune Diseases

“…Subsequently, RA treatment was able to lessen pancreatic destruction through counteracting with the inflammatory niche-induced damage. However, after the initiation of T1D, RA treatment might not be sufficient to reverse hyperglycemia nor improve the survival rates even when combined with exendin-4, a glucagon-like peptide-1 receptor agonist that enhances pancreatic β-cell function [ 90 ]. These findings indicate that disease stage-specific modulation of the immune system with RA and RA therapies could be promising preventions but not cures for T1D.…”

Vitamin A: a missing link in diabetes?

“…Pharmacological administration of RA to non-obese diabetic (NOD) mice, which like BB rats spontaneously develop a T1D phenotype with autoimmune destruction of β cells, delayed the onset and severity of T1D and protected from the loss of β-cell mass[50]. Two studies convincingly demonstrated that RA prevented the immunodestruction of β cells in NOD mice by increasing the numbers of tolerogenic immunosuppressive Treg cells, which suppressed CD4 + and CD8 + T-effector cells[51,52].…”