The prevalence of type 2 diabetes mellitus (T2DM) has increased considerably in recent years, highlighting the importance of developing new therapeutic strategies. Insulin-resistance and gradual dysfunction of pancreatic islets are the mainstay in the progression of T2DM. Therefore, preserving the function of the pancreas may lead to new prospective approaches. Our previous studies suggested that grape seed procyanidin B2 (GSPB2), a natural polyphenol product, exhibited protective effects on diabetic vasculopathy. However, effects of GSPB2 on a diabetic pancreas remain unknown. In this study, we provided strong evidence that GSPB2 exerted protective effects on a diabetic pancreas. GSPB2 attenuated the elevated body weights, food intake and advanced glycation end-product (AGE) levels in db/db mice (p < 0.05), though it had no significant effect on glucose levels. The increased islet sizes, insulin levels, as well as HOMA-IR were also improved by GSPB2 treatment in db/db mice (p < 0.05). Milk fat globule epidermal growth factor-8 (MFG-E8), an estimated target of GSPB2 in our previous studies, was up-regulated in pancreatic tissues whereas GSPB2 treatment down-regulated the protein level (p < 0.05). Since MFG-E8 is highly involved in inflammation, we further investigate pro-inflammatory cytokines interleukin-1β (IL-1β) and NLRP3 levels. We found that levels of IL-1β and NLRP3 increased in a diabetic pancreas while GSPB2 treatment notably attenuated these alterations (p < 0.05). In conclusion, our results suggest that inflammation is involved in the damage of a diabetic pancreas and GSPB2 provides protective effects at least in part through anti-inflammation.

Hypertension Research, official publication of the Japanese Society of Hypertension, publishes papers reporting original clinical and experimental research in the field of hypertension and related cardiovascular diseases.

Low-grade inflammation is one of the characteristics of metabolic disorders induced by diabetes mellitus. The present study explores the underlying mechanism of milk fat globule epidermal growth factor 8 (MFG-E8) on necroptosis-induced intestinal inflammation and intestinal epithelial endocrine cell dysfunction in diabetes. Compared with the normal control group, pathological changes such as blunt and shortened villus and denuded villus tips were observed in ileum tissue of streptozotocin (STZ) induced senescence-resistant 1 (SAMR1) and senescence-accelerated prone 8 (SAMP8) diabetic mice under light microscope. Western blotting and immunohistochemistry (IHC) displayed significantly decreased protein expression of MFG-E8 in SAMR1 and SAMP8 diabetic mice, accompanied by an increased expression of phosphorylated mixed lineage kinase domain-like (p-MLKL) and HMGB1. In addition, advanced glycation end products (AGEs) significantly increased the pro-inflammatory mediators (TNF-α, IL-1β, IL-6) and HMGB1 by activating the receptor-interacting protein kinase 3 (RIPK3)/MLKL signaling pathway in enteroendocrine STC-1 cells. D-pinitol pretreatment markedly attenuated the release of pro-inflammatory mediators and increased the expression of MFG-E8. MFG-E8 small interfering RNA (siRNA) promoted, while MFG-E8 overexpression inhibited, the activation of receptor-interacting proteins (RIPs) pathway and pro-inflammatory factors. Our study demonstrated that downregulation of MFG-E8 is an important phenomenon in the pathogenesis of diabetes-related intestinal inflammatory damage. MFG-E8 overexpression and D-pinitol intervention could protect against necroptosis-induced intestinal inflammation and maintain the function of enteroendocrine STC-1 cells in diabetes.