title: CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion.
abstract: Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. yujinaka@a5.keio.jp
authors: Yuji
authors: Y
authors: Nakamura
authors: Takanori
authors: T
authors: Kanai
authors: Keita
authors: K
authors: Saeki
authors: Miho
authors: M
authors: Takabe
authors: Junichiro
authors: J
authors: Irie
authors: Jun
authors: J
authors: Miyoshi
authors: Yohei
authors: Y
authors: Mikami
authors: Toshiaki
authors: T
authors: Teratani
authors: Takahiro
authors: T
authors: Suzuki
authors: Naoteru
authors: N
authors: Miyata
authors: Tadakazu
authors: T
authors: Hisamatsu
authors: Nobuhiro
authors: N
authors: Nakamoto
authors: Yoshiyuki
authors: Y
authors: Yamagishi
authors: Hajime
authors: H
authors: Higuchi
authors: Hirotoshi
authors: H
authors: Ebinuma
authors: Shigenari
authors: S
authors: Hozawa
authors: Hidetsugu
authors: H
authors: Saito
authors: Hiroshi
authors: H
authors: Itoh
authors: Toshifumi
authors: T
authors: Hibi
mesh_terms: D000208:Acute Disease; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002108:Ceruletide / Q000633:toxicity; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D054390:Receptors, CCR2; D018027:Receptors, Glucagon; D002108:Ceruletide