Skeletal muscle insulin resistance is the main cause of type 2 diabetes, and mitochondria play a key role. Ginsenoside CK is main active compound of ginseng with a variety of...

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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 Ca 2+ 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.

(1) Background: Skeletal muscle insulin resistance is the main cause of type 2 diabetes, in which mitochondrial homeostasis plays a key role. Ginsenoside CK is the main active compound of Panax ginseng C.A. Meyer with a variety of therapeutic effects, but there are few studies on its effect and mechanism on skeletal muscle insulin resistance; (2) Methods: qRT-PCR, Western blotting and Seahorse XFp cellular metabolism were used to detect the effects of CK on mitochondrial quality and function in skeletal muscle tissue and C2C12 cells. The insulin sensitivity was examined by immunofluorescence, 2-NBDG uptake and glycogen content detection. Mitochondrial morphology was observed by MitoTracker staining and transmission electron microscopy, and mitochondrial membrane potential (ΔΨm) was measured by JC-1. Finally, co-localization and siRNA targeting were used to illustrate the mechanisms of CK-induced mitophagy. (3) Results: We found that CK alleviates skeletal muscle insulin resistance by improving mitochondrial fusion/fission dynamic balance and mitochondrial fatty acid oxidation capacity in db/db mice. In fatty acid (FA)-induced insulin resistant C2C12 cell, CK promoted the translocation of GLUT4 to the cell membrane to improve glucose uptake and glycogen synthesis, and also improved the mitochondrial quality of C2C12 cells. CK improved the damaged ΔΨm, which was based on mitophagy activation. After knockdown of mitophagy-related receptors, the results revealed that DRP1/PINK1 was the key pathway of CK-induced mitophagy. (4) Conclusions: Ginsenoside CK activates skeletal muscle mitophagy via DRP1/PINK1 pathway to maintain mitochondria quality and function, and thereby alleviating insulin resistance in diabetic mice. These results indicate that ginsenoside CK is a promising lead compound against diabetes.