Glucolipotoxicity and GLP-1 secretion

Abstract

IntroductionThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels.Research design and methodsTo investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function.ResultsChronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats.ConclusionThese results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.

RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine

“…Deletion of Scd1 reduces the synthesis of oleic and palmitoleic acids and thus prevents the accumulation of lipids in cells [ 51 ]. A recent study has shown that glucolipotoxic conditions can reduce GLP-1 secretion [ 52 ]; therefore, increased levels of intracellular lipids may be detrimental to GLP-1 secretion. In support of this, whole-body knockout of Scd1 results in the accumulation of lipids in the liver, causing hepatic steatosis and hyperlipidaemia [ 41 ].…”

The Impact of Incretin-Based Medications on Lipid Metabolism

“…Wang and colleagues in 2018 found that diabetic patients with dyslipidemia have impaired GLP-1 secretion that directly correlated with lipotoxicity [ 88 ]. Moreover, GLP-1 secretion may be increased in response to lipotoxicity and dyslipidemia in an effort to mitigate them [ 89 ]. In summary, incretin-based medications have pharmacological properties that enable them to inhibit lipotoxicity and thereby help to prevent lipotoxicity-dependent disorders, especially renal and cardiovascular complications [ 90 ].…”

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

“…T2DM is characterized by pancreatic β-cell dysfunction and insulin resistance. It has been shown that chronic hyperglycemia leads to the decrease of insulin biosynthesis and secretion due to β-cell glucose toxicity [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and that the reduction of insulin mRNA expression is accompanied by decreased nuclear expression of insulin transcription factors such as MafA and PDX-1 [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Such phenomena are known as β-cell glucose toxicity.…”