Increased hepatic glucose production and decreased hepatic glucose uptake at the prediabetic phase in the Otsuka Long-Evans Tokushima Fatty rar model

Shiba, Yuici; Yamasaki, Yoshimitsu; Kubota, Minoru; Matsuhisa, Munehide; Tomita, Tadahiro; Nakahara, Itsuro; Morishima, Toyohiko; Kawamori, Ryuzo; Hori, Masatsugu

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Volume 47, Issue 8 , Pages 908-914, August 1998

Increased hepatic glucose production and decreased hepatic glucose uptake at the prediabetic phase in the Otsuka Long-Evans Tokushima Fatty rar model

Yuici Shiba
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Yoshimitsu Yamasaki
- Address reprint requests to Yoshimitsu Yamasaki, MD, First Department of Medicine, Osaka University School of Medicine, Yamadaoka 2-2, Suita, Osaka 565, Japan.
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Minoru Kubota
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Munehide Matsuhisa
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Tadahiro Tomita
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Itsuro Nakahara
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Toyohiko Morishima
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Ryuzo Kawamori
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
Masatsugu Hori
- First Department of Medicine, Osaka University School of Medicine, Osaka, Japan
- Department of Sociology, Kwansei Gakuin University, Nishinomiya, Japan
- Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan

Received 7 April 1997; accepted 4 February 1998.

Abstract

To investigate the time course of the hepatic glucose metabolism in non—insulin-dependent diabetes (NIDDM), we measured hepatic glucose production (HGP) and first-pass uptake of portal glucose infusion by the liver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans Tokushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, respectively). The fasting plasma glucose level in OLETF rats was significantly higher than in LETO rats at 28 weeks of age (8.9 ± 1.7 v 6.3 ± 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at ≥8 weeks of age. Basal HGP was significantly higher in OLETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 ± 1.7 v 9.4 ± 1.8 mg · kg⁻¹ · min⁻¹, P < .05; 28 weeks, 10.9 ± 1.6 v 7.1 ± 1.3 mg · kg⁻¹ · min⁻¹, P < .01). At 14 weeks, basal HGP was not sinificantly different between OLETF and LETO rats. However, at all study points, HGU during a portal glucose infusion was significantly lower in OLETF than in LETO rats (8 weeks, 0.9 ± 0.2 v 2.3 ± 0.5, P < .01; 14 weeks, 0.8 ± 0.3 v 1.4 ± 0.3, P < .05; 28 weeks, 0.7 ± 0.2 v 1.4 ± 0.3 mg · kg⁻¹ · min⁻¹, P < .01). Fasting plamsa free fatty acid (FFA) levels were not significantly different between OLETF and LETO, except at 8 weeks. Suppression of plasma FFA levels by endogenous insulin during a portal glucose infusion was impaired in OLETF rats compared with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal HGP and decreased HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these derangements may be accompanied by impaired lipid metabolism.