(+)-Catechin mitigates impairment in insulin secretion and beta cell damage in methylglyoxal-induced pancreatic beta cells.

BACKGROUND: The formation of advanced glycation end products (AGEs) is the central process contributing to diabetic complications in diabetic individuals with sustained and inconsistent hyperglycemia. Methylglyoxal, a reactive carbonyl species, is found to be a major precursor of AGEs, and its levels are elevated in diabetic conditions. Dysfunction of pancreatic beta cells and impairment in insulin secretion are the hallmarks of diabetic progression. Exposure to methylglyoxal-induced AGEs alters the function and maintenance of pancreatic beta cells. Hence, trapping methylglyoxal could be an ideal approach to alleviate AGE formation and its influence on beta cell proliferation and insulin secretion, thereby curbing the progression of diabetes to its complications. METHODS AND RESULTS: In the present study, we have explored the mechanism of action of (+)-Catechin against methylglyoxal-induced disruption in pancreatic beta cells via molecular biology techniques, mainly western blot. Methylglyoxal treatment decreased insulin synthesis (41.5%) via downregulating the glucose-stimulated insulin secretion pathway (GSIS). This was restored upon co-treatment with (+)-Catechin (29.9%) in methylglyoxal-induced Beta-TC-6 cells. Also, methylglyoxal treatment affected the autocrine function of insulin by disrupting the IRS1/PI3k/Akt pathway. Methylglyoxal treatment suppresses Pdx-1 and Maf A levels, which are responsible for beta cell maintenance and cell proliferation. (+)-Catechin could significantly augment the levels of these transcription factors. CONCLUSION: This is the first study to examine the impact of a natural compound on methylglyoxal with the insulin-mediated autocrine and paracrine activities of pancreatic beta cells. The results indicate that (+)-Catechin exerts a protective effect against methylglyoxal exposure in pancreatic beta cells and can be considered a potential anti-glycation agent in further investigations on ameliorating diabetic complications.

Advanced glycation end-products (AGE) trapping agents: Design and synthesis of nature inspired indeno[2,1-c]pyridinones.

Advanced glycation end products (AGEs) are implicated to be the key players in most of the diabetic complications. The AGE's interfere with the proteins heterogeneously, thereby rendering denaturation and the consequent loss of function and accumulation. Thus, a novel natural product inspired indeno[2,1-c]pyridinone (4a-4ad) molecular templates with AGE's trapping potential was designed through scaffold hopping approach and synthesized via facile two-step synthetic route. Amongst the tested indeno[2,1-c]pyridinone hybrids, 4i, 4x and 4aa exhibited excellent efficiency in trapping the AGE's. The percentage of antiglycation is measured by the analytical model system, i.e. via MG trapping capacity; here the compounds 4i, 4x and 4aa with 50.03%, 69.58%, and 93.37% respectively has displayed promising efficiency. In particular, 4aa demonstrated better activity than the positive control aminoguanidine (79.82%). The in-vitro toxicity of compounds was tested on L6 rat skeletal muscle cell lines revealed that none of the compounds showed any significant toxicity at concentrations up to 1000 µM.