Type 1 diabetes mellitus (T1DM) lacks insulin secretion due to autoimmune deficiency of pancreatic β-cells. Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches. Mannogalactoglucan is the main type of polysaccharide from natural mushroom, which has potential medicinal prospects. Nevertheless, the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated. In this study, we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide (AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A. mellea and investigated the potential therapeutic value of AAMP-N in T1DM. We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice. AAMP-N activated unfolded protein response (UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo. Besides that, AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors, increased Ca²⁺ signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase II (CamkII) and cAMP/PKA signals, and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2 (VAMP2). Collectively, these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function, indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance. Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia. Ginsenoside is a natural active component in Panax ginseng C.A. Meyer, and some of them enhance thermogenesis. However, there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis. Using thermogenic protein uncoupling protein 1 (UCP1)-luciferase reporter assay, we identified ginsenoside F1 as a novel UCP1 activator in the ginsenosides library. Using pull down assay and inhibitor interference, we found F1 binds to β3-adrenergic receptors (β3-AR) to enhance UCP1 expression via cAMP/PKA/CREB pathway. We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice, including body weight, body composition and energy expenditure. The results of proteomics showed that F1 significantly up-regulated thermogenesis proteins and lipolytic proteins, but down-regulated fatty acid synthesis proteins. Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifically by promoting the browning of white adipose tissue in obese mice. Additionally, ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes, and shows a stronger mitochondria respiration ability than norepinephrine. These findings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.