hymecromone and Hyperglycemia

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.

Topics: Animals; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Extracellular Matrix; Forkhead Transcription Factors; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hymecromone; Hyperglycemia; Immune Tolerance; Insulin; Insulin-Secreting Cells; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Transgenic; Prediabetic State; Receptors, Leptin; T-Lymphocytes, Regulatory

This study was conducted to evaluate the effects of umbelliferone (UF) and 4-methylumbelliferone (mUF) on high-fat diet-induced hypertriglyceridemia and hyperglycemia in mice. The mice were assigned to normal control, high-fat control, and high-fat with UF or mUF groups. For UF or mUF groups, the high-fat diet was supplemented with UF or mUF at 0.02% (wt/wt) for 12weeks. Both UF and mUF significantly decreased plasma triglyceride, free fatty acid and glucose levels, adipocyte size, white adipose tissue weights, and hepatic phosphatidate phosphohydrolase activity and significantly increased plasma adiponectin levels and hepatic fatty acid β-oxidation activity compared with the high-fat control group. UF and mUF improved glucose intolerance and hepatic steatosis in the high-fat fed mice. Long-term high-fat diet intake induced an increase in hepatic CYP2E1 activity and lipid peroxide and cytosolic hydrogen peroxide contents and suppressed superoxide dismutase and glutathione peroxidase activities, which were reversed by UF and mUF supplementation. These results indicate that UF and mUF similarly ameliorate hypertriglyceridemia and hyperglycemia partly by modulating hepatic lipid metabolism and the antioxidant defense system along with increasing adiponectin levels.

Topics: Animals; Blood Glucose; Body Weight; Cytochrome P-450 CYP2E1; Dietary Fats; Dietary Supplements; Energy Intake; Gene Expression Regulation; Hymecromone; Hyperglycemia; Hypertriglyceridemia; Lipid Peroxidation; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Umbelliferones

Changes in the extracellular matrix organization within vascular walls are critical events in the process of atherosclerosis including diabetic macroangiopathy. Here, we examined whether glucose can directly modulate connective tissue reorganization by human vascular smooth muscle cells (VSMCs). Using a collagen gel contraction (CGC) assay, we demonstrated that in comparison with normal glucose concentration (5 mM), high glucose concentration (25 mM) inhibits the efficacy of VSMCs to contract collagen gels. With human genome microarrays, we showed a significant increase in the expression of hyaluronan synthase 2 (HAS2) by VSMCs in hyperglycemic conditions. The finding was verified with quantitative real-time polymerase chain reaction, which also revealed that the expression of the other hyaluronan synthesizing enzymes, HAS1 and HAS3, was stimulated concomitantly. A corresponding increase was observed in hyaluronan (HA) production. Treatment of VSMCs either with hyaluronidase or with 4-methylumbelliferone, an inhibitor of HA synthesis, partially restored the diminished CGC efficacy of VSMCs in hyperglycemic conditions. In conclusion, high glucose concentration stimulated HA synthesis by VSMCs and modulated their ability to reorganize collagen-rich matrix. Because HA is known to enhance the development of atherosclerosis and restenosis after percutaneous coronary interventions, our study provides a new potential mechanism whereby hyperglycemia leads to disturbed vascular remodeling in diabetic patients through stimulation of HA synthesis.

Topics: Cells, Cultured; Connective Tissue; Dose-Response Relationship, Drug; Extracellular Matrix; Gene Expression Profiling; Glucose; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Hymecromone; Hyperglycemia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle