title: Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β-cell failure in type 2 diabetes.
abstract: Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in β-cells. We examined whether RAGE contributes to β-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive β-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher β-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.
authors: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
authors: Dong
authors: D
authors: Han
authors: Yasuhiko
authors: Y
authors: Yamamoto
authors: Seiichi
authors: S
authors: Munesue
authors: So
authors: S
authors: Motoyoshi
authors: Hidehito
authors: H
authors: Saito
authors: Myat Thu Thu
authors: MT
authors: Win
authors: Takuo
authors: T
authors: Watanabe
authors: Koichi
authors: K
authors: Tsuneyama
authors: Hiroshi
authors: H
authors: Yamamoto
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D002460:Cell Line; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression; D018149:Glucose Intolerance; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D017127:Glycation End Products, Advanced; D007328:Insulin; D020738:Leptin; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D054411:Receptors, Leptin