N^ε-(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells

Abstract

Lo MC, Chen MH, Lee WS, Lu CI, Chang CR, Kao SH, Lee HM. N ε -(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from ␤-cells. Am J Physiol Endocrinol Metab 309: E829 -E839, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00151.2015 ε -(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic ␤-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of ␣-lipoic acid (ALA) on mitochondria in AGEdamaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with wellorganized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSAinduced mitophage formation. Our study demonstrated that CML-BSA induced mitochondrial dysfunction and mitophagy in pancreatic ␤-cells. The findings from this study suggest that increased concentration of AGEs may damage ␤-cells and reduce insulin secretion. advanced glycated end products; mitochondrial dynamics; mitophagy; diabetes DIABETES MELLITUS IS CHARACTERIZED BY HYPERGLYCEMIA and long-term irreversible change of vascular and connective tissue. Advanced glycated end products (AGEs) have been directly implicated in the development of chronic complications of diabetes such as nephropathy, arteriosclerosis, retinopathy, neuropathy, and cataracts (30). AGEs can be formed via either the nonenzymatic "Maillard reaction" or increased polyol pathway flux (14). In particular, the reactive carbonyl group of methylglyoxal reacts with the amino group of lysine to produce protein conjugates with 3-deoxyglucosone-imidazolone, pyrraline, pentosidine, and N ε -(carboxymethyl) lysine (14). AGEs may impair insulin secretion and lead to the development of diabetes (7). A previous report showed that serum levels of N ε -(carboxymethyl) lysine-conjugated AGEs, a major constituent of AGEs, were elevated up to 42-44 U/ml in 7-mo-ol...

Gene coexpression network analysis identified potential biomarkers in gestational diabetes mellitus progression

“…In addition, lysine acetylation was also previously reported to affect both immunological and metabolic pathways, which could then induce type II diabetes and cardiovascular disease (Iyer & Fairlie, ; Kosanam et al, ). Nε‐(carboxymethyl) lysine‐conjugated bovine serum albumin is an essential component of advanced glycation end products which could damage mitochondrial functions and result in reducing insulin secretion followed by the incidence of diabetes (Lo et al, ). Diabetes could control many aspects of endocrine, including steroidogenesis, whose perturbation could in turn induce the initiation of diabetes (Hwang, ; Jangir, ).…”

High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report

“…Another study suggested that AGE injections can initiate β -cell dysfunction in vivo [25]. A recent in vitro study also indicated that CML caused mitochondrial dysfunction and mitophagy in β -cells and that high levels of AGEs may induce β -cell dysfunction and impair insulin secretion ability [26]. A recent epidemiological study also showed that increased fasting CML levels may be predictive of type 2 diabetes development [27].…”

Autophagy and its link to type II diabetes mellitus

“…The insulin resistant mice (beta-cell-specific Atg7 knockout mice) model has been shown that autophagy plays a crucial role in the development of diabetes and in preserving the structure and function of pancreatic beta cells. Accumulation of autophagosomes in the pancreatic beta cell has been demonstrated in db/db mouse model [134–136]. Fujitani et al showed that reduced insulin secretion was associated with pancreatic beta cell degeneration and impaired glucose in autophagy-deficient mice [136–138].…”