title: Effect of hyperglycemia on hepatocellular carcinoma development in diabetes.
abstract: Compared with other cancers, diabetes mellitus is more closely associated with hepatocellular carcinoma (HCC). However, whether hyperglycemia is associated with hepatic carcinogenesis remains uncertain. In this study, we investigate the effect of hyperglycemia on HCC development. Mice pretreated with 7,12-dimethylbenz (a) anthracene were divided into three feeding groups: normal diet (Control), high-starch diet (Starch), and high-fat diet (HFD) groups. In addition, an STZ group containing mice that were fed a normal diet and injected with streptozotosin to induce hyperglycemia was included. The STZ group demonstrated severe hyperglycemia, whereas the Starch group demonstrated mild hyperglycemia and insulin resistance. The HFD group demonstrated mild hyperglycemia and severe insulin resistance. Multiple HCC were macroscopically and histologically observed only in the HFD group. Hepatic steatosis was observed in the Starch and HFD groups, but levels of inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor-α, and IL-1β, were elevated only in the HFD group. The composition of gut microbiota was similar between the Control and STZ groups. A significantly higher number of Clostridium cluster XI was detected in the feces of the HFD group than that of all other groups; it was not detectable in the Starch group. These data suggested that hyperglycemia had no effect on hepatic carcinogenesis. Different incidences of HCC between the Starch and HFD groups may be attributable to degree of insulin resistance, but diet-induced changes in gut microbiota including Clostridium cluster XI may have influenced hepatic carcinogenesis. In conclusion, in addition to the normalization of blood glucose levels, diabetics may need to control insulin resistance and diet contents to prevent HCC development.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Niwa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Achiwa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Izumoto
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Ryuya
authors.initials: R
authors.lastname: Maekawa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hosokawa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: tsune87@med.nagoya-u.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Tsunekawa
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D003013:Clostridium / Q000302:isolation & purification; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000382:microbiology; D004032:Diet / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000382:microbiology / Q000473:pathology; D041981:Gastrointestinal Tract / Q000382:microbiology; D006943:Hyperglycemia / Q000150:complications* / Q000382:microbiology / Q000473:pathology; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL
keywords: 7,12-Dimethylbenz (a) anthracene; Gut microbiota; Hepatocellular carcinoma; High-starch diet; Hyperglycemia; Insulin resistance