The effects of teneligliptin on DNA damages in multiple metabolic organs of HFD-induced diabetic obese mice

Abstract

Both diabetes mellitus (DM) and obesity are characterized by hyperinsulinemia and higher incidence of microvascular complication, cardiovascular disease, and many kinds of cancer. Obesity and constant hyperglycemia increase oxidative stress and inflammation, resulting in loss of balance between DNA double strand break (DSB) and DNA damage response (DDR), and various clinical diseases such as diabetic complication, cardiovascular disease and cancer can occur. When cells are exposed to harmful stimuli, DSB occurs and DDR begins. Mammalian eukaryotic cells repair DSBs primarily by two mechanisms of DDR; non-homologous end-joining (NHEJ) and homologous recombination (HR). NHEJ, which appears at the time of metabolic damage, use many proteins such as Ku, DNA-dependent protein kinase catalytic subunit, XRCC4, DNA ligase IV, and XRCC4-like factor. Glucagon-like peptide-1 (GLP-1) not only shows anti-diabetic effect, but also shows multiple organ protective effects such as neuroprotection in brain and kidney protection in recent studies. Dipeptidyl peptidase-IV (DPP-IV) inhibitor, which inhibits DPP-IV and prolongs GLP-1 effect, is more widely used around the world than GLP-1 receptor agonist, but the study on DPP-IV inhibitor’s organ protective effects has not conducted yet. In this study, we aimed to investigate not only glycemic control effect but also organ protective effects of DPP-IV inhibitor, using teneligliptin to high fat diet (HFD)- induced diabetic obese mice. Mice were classified into five groups according to HFD and dose of teneligliptin administration. Teneligliptin showed improvement of glucose regulation capacity, and this is assumed to be because of attenuated hepatic gluconeogenesis increase and protected insulin secretion capacity. HFD-induced obese mice showed higher levels of NHEJ proteins in multiple metabolic organs, indicating more DNA damage occurred in diabetic obese condition compared to normal control group. Furthermore, we showed decreased DNA damage in multiple metabolic organs and kidney which is an important target organ after teneligliptin administration, and proved teneligliptin’s organ protective effects.