Correlation between lipid and glycogen contents in liver and insulin resistance in high-fat[ndash ]fed rats treated with the lipoprotein lipase activator NO-1886

Kusunoki, Masataka; Tsutsumi, Kazuhiko; Hara, Tsutomu; Ogawa, Hitoshi; Nakamura, Toshio; Miyata, Tetsuro; Sakakibara, Fumihiko; Fukuzawa, Yoshitaka; Suga, Takashi; Kakumu, Shinichi; Nakaya, Yutaka

doi:10.1053/meta.2002.32732

Cited by 44 publications

(35 citation statements)

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“…Liver insulin resistance is usually accompanied by increased deposition of triglycerides and/or other lipid metabolites in the liver (31,32). Indeed, liver triglycerides were significantly higher in both LID and LIDϩALSKO mice that showed liver insulin resistance compared with control and ALSKO mice with normal liver triglycerides and normal liver insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex

et al. 2003

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Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice with a gene deletion of the acid-labile subunit (ALSKO) demonstrate a 65% reduction in circulating IGF-1 levels, with normal GH levels and no signs of insulin resistance. To further clarify the relative roles of increased GH and decreased IGF-1 levels in the development of insulin resistance, we crossed the two mouse lines and created a double knockout mouse (LID؉ ALSKO). LID؉ALSKO mice demonstrate a further reduction in circulating IGF-1 levels (85%) and a concomitant 10-fold increase in GH levels. Insulin tolerance tests showed an improvement in insulin responsiveness in the LID؉ALSKO mice compared with controls; LID mice were very insulin insensitive. Surprisingly, insulin sensitivity, while improved in white adipose tissue and in muscle, was unchanged in the liver. The lack of improvement in liver insulin sensitivity may reflect the absence of IGF-1 receptors or increased triglyceride levels in the liver. The present study suggests that whereas GH plays a major role in inducing insulin resistance, IGF-1 may have a direct modulatory role.

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Section: Discussionmentioning

confidence: 99%

Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex

et al. 2003

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“…Cytosolic TG (the end product of the fatty acid esterification pathway) are a positive marker for hepatic insulin resistance (65). Previous studies have shown that hepatic insulin resistance is reversed when hepatic TG content is reduced by 1) administration of the fat-derived hormone "adiponectin" into lipoatrophic mice (lipoatrophic mice have elevated hepatic TG content and hepatic insulin resistance) (131), 2) fat transplantation into A-ZIP/F-1 fatless mice, which have elevated hepatic TG content and hepatic insulin resistance (60), and/or 3) administration of an AMP-activated protein kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide-1-B-D-ribofuranoside (AICAR), to high fat-fed rats (51).…”

Section: Lipid and Hepatic Insulin Resistancementioning

confidence: 99%

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Lam

Carpentier

Lewis

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

239

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nisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 284: E863-E873, 2003; 10.1152/ajpendo.00033.2003.-The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia.lipid; hepatic insulin resistance FREE FATTY ACIDS (FFA), which are often elevated in obese individuals (6, 15, 29,70), have been implicated as an important causative link in the associations between obesity, insulin resistance, and type 2 diabetes mellitus (11,48,56,73,82). Elevated plasma FFA clearly impair the ability of insulin to stimulate muscle glucose uptake (45,98). This effect is associated with a reduction in insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity, an important step in the insulin-signaling cascade that has been shown to be inhibited by FFA-induced PKC activation in muscle (42,53). In contrast, although a number of studies have indicated that elevated plasma FFA and high-fat diets can increase postabsorptive (referred to throughout this manuscript as "basal") hepatic glucose production (HGP) (7, 14,67,68,113) and induce hepatic insulin resistance (i.e., reduce the ability of insulin to suppress HGP) (9, 13,51,67,68,74,91,97,102,111,125), the magnitude of these effects and the mechanisms involved remain controversial.Because elevated HGP and hepatic insulin resistance have been well documented in individuals with type 2 diabetes (12, 40,85), studies that examine the effects of FFA on hepatic glucose metabolism are essential in understanding the pathogenesis of insulin resistance in type 2 diabetes. In this brief review, the physiological effects of FFA on hepatic glucose metabolism and the putative mechanisms of these effects will be discussed. FFA AND BASAL HGP FFA and GluconeogenesisGlucose is produced by glycogenolysis and gluconeogenesis in the liver. FFA increase hepatic gluconeogenesis both in vitro and in vivo (11, 20,127). FFA stimulation of gluconeogenesis has been attributed to the production of 1) acetyl-CoA derived from FFA oxidation, which allosterically activates pyruvate carboxylase, 2) NADH, which is used for the formation of glyceraldehyde 3-phosphate from 1,3-bisphosphoglycerate, and 3) ATP, which is used as an energy source. Additionally, increased levels of citrate (product of acetyl-CoA derived from FFA o...

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“…Clamp experiments in humans reveal an impaired suppression of HGO by insulin in patients with hepatic steatosis before the onset of impaired glucose tolerance or overt type 2 diabetes (32). Animal studies have similarly described negative correlations between perturbed hepatic insulin action and liver fat content (19).…”

mentioning

confidence: 96%

Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis

Buettner

Ottinger

Schölmerich

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Recent in vivo studies have demonstrated a strong negative correlation between liver triglyceride content and hepatic insulin sensitivity, but a causal relationship remains to be established. We therefore have examined parameters of direct hepatic insulin action on isolated steatotic livers from high-fat (HF)-fed rats compared with standard chow (SC)-fed controls. Direct hepatic action of insulin was assayed in Wistar rats after 6 wk of HF diet by measuring the insulin-induced suppression of epinephrine-induced hepatic glucose output in an isolated liver perfusion system. Insulin-induced activation of glycogen synthase was measured by quantifying the incorporation of radioactive UDP-glucose into glycogen in HF and SC liver lysates. HF diet induced visceral obesity, mild insulin resistance, and hepatic steatosis. Both suppression of epinephrine-induced glycogenolysis and activation of glycogen synthase by insulin were sustained in HF rats; no significant difference from SC controls could be detected. In conclusion, in our model, triglyceride accumulation into the liver was not sufficient to impair direct hepatic insulin action. The data argue for an important role of systemic factors in the regulation of hepatic glucose output and hepatic insulin sensitivity in vivo.

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Correlation between lipid and glycogen contents in liver and insulin resistance in high-fat[ndash ]fed rats treated with the lipoprotein lipase activator NO-1886

Cited by 44 publications

References 0 publications

Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex

Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex

Mechanisms of the free fatty acid-induced increase in hepatic glucose production

Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis

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