Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Protective effects of black bamboo leaves on the glucose-induced toxicity in Caenorhabditis elegans

Introduction: Previous studies have suggested that high glucose (HG) condition shortens the lifespan of worms by increasing glycolytic flux followed by accelerating reactive oxygen species (ROS) production, termed glucose toxicity. This study was designed to investigate the protective effects of the leaves of black bamboo (Phyllostachys nigra var. henosis) on the HG-induced toxicity using Caenorhabditis elegans model system. Methods: To determine the effect of black bamboo leaf extract (BLE) against HG-induced toxicity, lifespan assay was carried out with wild-type and daf-16 null mutant worms under 2% glucose condition. The involvement of DAF-16 was further confirmed by observing fluorescence signal of transgenic mutant carrying DAF-16::GFP transgene. ROS levels and glucose concentration of worms were analyzed using fluorescent probe H2DCF-DA and glucose meter, respectively. Nile-red staining was carried out to evaluate the lipid storage of worms. Intercellular lipid accumulation was measured using Oil-Red O staining method. Results: BLE strongly extended the lifespan of worms under not only normal culture condition but also HG condition. Our additional studies suggested that DAF-16 activation was responsible for BLE-mediated longevity and protective action against glucose toxicity. In addition, HG-fed worms showed increased ROS generation, and it was completely normalized by BLE treatment. Moreover, BLE reduced body glucose concentration and lipid accumulation in HG-fed worms. We further confirmed the inhibitory effect of BLE on lipid storage under HG condition using 3T3-L1 adipocytes. Conclusion: These therapeutic values of BLE on glucose toxicity raise the possibility that BLE might have beneficial effects on the pathogenesis of diabetes mellitus.

High Mobility Group Box 1 and Dickkopf-Related Protein 1 as New Biomarkers of Type 2 Diabetes Mellitus: Associations with Increased Glucose Toxicity and Atherogenicity and Lower β Cell Function

Background: Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to increased levels of high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). Objective: The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Methods: Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. Results: HMGB1 and DKK1 are significantly higher in T2DM irrespective of hypertension. T2DM was also accompanied by increased atherogenicity indices. HMGB1 and DKK1 are significantly correlated with HbA1c, glucose, indices of insulin resistance, β-cell function, and glucose toxicity, and different atherogenic indices. A large part of the variance in the β-cell index (30.5%) and glucose toxicity (34.8%) was explained by the combined effects of HMGB1 and DKK1 and hypertension. We found that 18.3% of the variance of the atherogenic index of plasma was explained by HMGB1 and DKK1 levels and that 31.2% was explained by glucose toxicity, HMGB1 and body weight. Conclusion: The higher serum HMGB1 and DKK1 levels in T2DM patients and the associations with atherogenicity indicate that low grade inflammation and disorders in the Wnt pathways are associated with T2DM and that both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are new drug targets in the treatment of T2DM.