Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Chua, Streamson C.; Liu, S Mei; Li, Q; Yang, Lucy M.; Thassanapaff, V T; Fisher, Peter

doi:10.1007/s00125-002-0880-z

Cited by 65 publications

(52 citation statements)

References 48 publications

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“…There are numerous examples where background strain has affected lipid and carbohydrate metabolism in mice. The Lep-ob and Lepr-db mutations both produce identical phenotypes on the same background strain and yet a pronounced tendency to diabetes on different backgrounds (5). Genetic background has a profound effect on many aspects of the A-ZIP/F-1 lipoatrophic mouse phenotype, including opposite effects on muscle and liver insulin resistance and triglyceride clearance (6).…”

Section: Discussionmentioning

confidence: 99%

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Gregorio

Hensley²,

Lu³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

150

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Obesity-related insulin resistance may be caused by adipokines such as IL-6, which is known to be elevated with the insulin resistance syndrome. A previous study reported that IL-6 knockout mice (IL-6−/−) developed maturity onset obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin levels. Because IL-6 is associated with insulin resistance, one might have expected IL-6−/− mice to be more insulin sensitive. We examined body weights of growing and older IL-6−/− mice and found them to be similar to wild-type (IL-6+/+) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed no differences in body composition. There were no differences in fasting blood insulin and glucose or in triglycerides. To further characterize these mice, we fed 11-mo-old IL-6−/− and IL-6+/+ mice a high- (HF)- or low-fat diet for 14 wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed insulin resistance in the HF animals but no difference due to genotype. In the GTT, IL-6−/− mice demonstrated elevated postinjection glucose levels by 60% compared with IL-6+/+ but only in the HF group. Although IL-6−/− mice gained weight and white adipose tissue (WAT) with the HF diet, they gained less weight than the IL-6+/+ mice. Total lipoprotein lipase activity in WAT, muscle, and postheparin plasma was unchanged in the IL-6 −/− mice compared with IL-6+/+ mice. There were no differences in plasma leptin or TNF-α due to genotype. Plasma adiponectin was ∼53% higher (71.7 ± 14.1 μg/ml) in IL-6−/− mice than in IL-6+/+ mice but only in the HF group. Thus these data show that IL-6−/− mice do not demonstrate obesity, fasting hyperglycemia, or abnormal lipid metabolism, although HF IL-6−/− mice demonstrate elevated glucose after a GTT.

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Section: Discussionmentioning

confidence: 99%

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Gregorio

Hensley²,

Lu³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

150

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“…2b, 6c), demonstrating the persistence of beta cell compensation with age and indicating that the onset of hyperglycaemia in MKR mice is not due to a low potential of the FVB/NJ strain for beta cell compensation. Similarly, although transfer of the Lepr db mutation to the FVB/NJ background results in hyperglycaemia, these mice nonetheless maintain insulin secretion and exhibit an enormous increase in beta cell number [30].…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

et al. 2005

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Aims/hypothesis: Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes. Materials and methods: Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function. Results: Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice. Conclusions/interpretation: Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction.

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“…These animals (3-4 months of age) were sacrificed between 8 and 12 a.m., and liver tissues were collected for use in TG hydrolase activity assays. Congenic ob/ob mice of the FVB background were derived as described previously (27). Experiments were performed using both male and female mice ranging from 3 to 5 months of age.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we determined the role of HSL and ATGL in hepatic lipolysis, and we evaluated the potential of adenoviral overexpression of these enzymes as a means to ameliorate hepatic steatosis in ob/ob mice (27) and mice with diet-induced insulin resistance and obesity.…”

mentioning

confidence: 99%

Hepatic Overexpression of Hormone-sensitive Lipase and Adipose Triglyceride Lipase Promotes Fatty Acid Oxidation, Stimulates Direct Release of Free Fatty Acids, and Ameliorates Steatosis

Reid

Ables

Otlivanchik

et al. 2008

Journal of Biological Chemistry

262

213

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Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40 -60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-␤-hydroxybutyrate levels were increased 3-5 days after infection in both HSL-and ATGL-overexpressing male mice, suggesting an increase in ␤-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be attributed to increases in ␤-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity. Nonalcoholic fatty liver disease (NAFLD)4 is often associated with obesity, insulin resistance, and metabolic syndrome (1, 2). Nonalcoholic steatohepatitis (NASH), the more virulent form of NAFLD, can lead to cirrhosis. Current treatments for subjects with NAFLD are usually directed at alleviating the associated metabolic symptoms of the patients (3). Insulin sensitizers such as thiazolidinediones or metformin improve insulin sensitivity with concomitant reduction of liver fat contents in human and mouse models (3-5). The amelioration of hepatic steatosis by these agents is likely secondary to improved insulin sensitivity. Imbalances between the input, oxidation, synthesis, and output of fatty acids (FA) all could contribute to hepatic steatosis, and dysregulation of each pathway has been documented in animal models (6). For example, leptin-deficient ob/ob mice are insulin-resistant, dyslipidemic, and have fatty livers despite the up-regulation of FA oxidation genes (7, 8) and increases in mitochondrial and peroxisomal ␤-oxidation (9). Hepatic steatosis in these animals is attributed to the up-regulation of sterol-responsive element-binding protein (SREBP) 1c, a master regulator of lipogenesis (10), and the consequent increase in de novo lipogenesis (11,12). FA uptake in the liver is also likely increased as genes involved in FA uptake and transport (e.g. CD36) are up-regulated in these animals (13). NAF...

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Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB-Lepr db ) and obese (DBA-Lep ob ) mice

Cited by 65 publications

References 48 publications

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

Hepatic Overexpression of Hormone-sensitive Lipase and Adipose Triglyceride Lipase Promotes Fatty Acid Oxidation, Stimulates Direct Release of Free Fatty Acids, and Ameliorates Steatosis

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