Resolvin D1 Decreases Severity of Streptozotocin-Induced Type 1 Diabetes Mellitus by Enhancing BDNF Levels, Reducing Oxidative Stress, and Suppressing Inflammation.

Siresha Bathina,Undurti N Das

doi:10.3390/ijms22041516

Siresha Bathina, Undurti N Das

Open Access

https://doi.org/10.3390/ijms22041516

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Abstract

Type 1 diabetes mellitus is an autoimmune disease characterized by increased production of pro-inflammatory cytokines secreted by infiltrating macrophages and T cells that destroy pancreatic β cells in a free radical-dependent manner that causes decrease or absence of insulin secretion and consequent hyperglycemia. Hence, suppression of pro-inflammatory cytokines and oxidative stress may ameliorate or decrease the severity of diabetes mellitus. To investigate the effect and mechanism(s) of action of RVD1, an anti-inflammatory metabolite derived from docosahexaenoic acid (DHA), on STZ-induced type 1 DM in male Wistar rats, type 1 diabetes was induced by single intraperitoneal (i.p) streptozotocin (STZ-65 mg/kg) injection. RVD1 (60 ng/mL, given intraperitoneally) was administered from day 1 along with STZ for five consecutive days. Plasma glucose, IL-6, TNF-α, BDNF (brain-derived neurotrophic factor that has anti-diabetic actions), LXA4 (lipoxin A4), and RVD1 levels and BDNF concentrations in the pancreas, liver, and brain tissues were measured. Apoptotic (Bcl2/Bax), inflammatory (COX-1/COX-2/Nf-κb/iNOS/PPAR-γ) genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) were measured in the pancreatic tissue along with concentrations of various antioxidants and lipid peroxides. RVD1 decreased severity of STZ-induced type 1 DM by restoring altered plasma levels of TNF-α, IL-6, and BDNF (p < 0.001); expression of pancreatic COX-1/COX-2/PPAR-γ genes and downstream insulin signaling proteins (Gsk-3β/Foxo1) and the concentrations of antioxidants and lipid peroxides to near normal. RVD1 treatment restored expression of Bcl2/Pdx genes, plasma LXA4 (p < 0.001) and RVD1 levels and increased brain, pancreatic, intestine, and liver BDNF levels to near normal. The results of the present study suggest that RVD1 can prevent STZ-induced type 1 diabetes by its anti-apoptotic, anti-inflammatory, and antioxidant actions and by activating the Pdx gene that is needed for pancreatic β cell proliferation.

Highlights

Clues as to the involvement of bioactive lipids such as GLA, DGLA, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), lipoxin A4 (LXA4), resolvins, protectins, and maresins in the pathobiology of T1DM are derived from the observation that (i) breast fed children have low incidence of T1DM [28,29,30]; (ii) cod liver oil supplementation during pregnancy reduces the risk of T1DM in the offspring [31]; (iii) human breast milk is rich in several bioactive lipids [25,26,27,31,32]; (iv) our previous studies which showed that BALs can prevent the development of T1DM in experimental animals [16,17,18,34,35,36,37,38,39]; and plasma concentrations of GLA, DGLA, AA, EPA, DHA, and LXA4 are low chemical-induced T1DM and patients with T1DM [35,36,37,38,39,46,47,48]
A gradual and sustained decrease in plasma glucose levels was noted in STZ +Resolvin D1 (RVD1)-treated animals from the end of the 2nd week to the end of the study (4th week), suggesting that there is a gradual regeneration of pancreatic β cells
This is supported by the observation that the expression of the Pdx gene and plasma insulin levels were increased in STZ + RVD1-treated animals in contrast to the suppressive action of STZ on these two indices (Figure 2C,D)

Summary

Introduction

Type 1 diabetes (T1DM) is an autoimmune disease in which a subclass of T lymphocytes induces apoptosis of pancreatic β cells [1,2]. These patients need life-long insulin replacement therapy. STZ-induced T1DM is a suitable model for studying β cell diabetic glucotoxicity as it partially destructs pancreas and reduces β cell mass [6]. STZ acute toxicity is of short duration These animals show continued deterioration of β cell function due to hyperglycemia established by acute STZ toxicity resulting in further β cell dysfunction [6,9,10]. Employing low dose (45 mg/kg) instead of high dose (100 mg/kg)

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