Fatty acid receptor GPR120: its potential role in islet function and Type 2 diabetes mellitus

Abstract

Diabetes mellitus is a chronic disease that represents a major socioeconomic burden worldwide; approximately 90–95% of patients are diagnosed as Type 2 diabetes mellitus (T2DM) among the new cases of diabetes. Pancreatic islet β-cell failure is one of the key features of T2DM, which is resultant from chronic hyperglycemia and hyperlipidemia, thus eventually leading to β-cell insulin secretion deficiency and β-cell apoptosis. Specifically, compensatory β-cell insulin secretion becomes inadequate and T2DM risks increase when islet-cell failure develops as a result of various factors such as glucotoxicity and lipotoxicity [1]. Meanwhile, insulin resistance leads to hyperglycemia and lipid accumulation as islet β-cell compensatory responses to increased insulin resistance fall, concomitant with progressive reduction in islet β-cell function, leading to eventual islet failure and with decreased β-cell mass and insulin deficiency as seen in the later stages of T2DM [1]. Notwithstanding the existence of this evidence, the detailed mechanism(s) by which hyperglycemia and hyperlipidemia induce islet failure thus T2DM have yet to be elucidated. In this context, chronic hyperglycemia dramatically upregulates pancreatic islet lipid metabolism through substrate availability, leading to changes in glucose and lipid metabolic enzymes and alteration of critical transcription factors [2]. Increased lipid accumulation and prolonged hyper glycemia are the most likely main causes of islet apoptosis and islet failure. Hyperlipidemia and lipotoxicity in islets, which are concomitant with decreased glucose-stimulated insulin secretion, contribute to islet dysfunction and increased induction of islet β-cell apoptosis [3]. In view of this fact, identification of agents that can target intra-islet lipid accumulation and glucose stress is required. In addition, islet lipotoxicity and glucotoxicity also trigger islet endoplasmic reticulum (ER) stress, activating apoptotic pathways and increasing misfolded protein formation, thus contributing further to increased “GPR120 has critical roles in lipid metabolism and energy balance, providing crucial regulation of insulin metabolism and of normoglycemia.”