doi:10.1016/j.mad.2007.12.009 
Copyright © 2008 Elsevier Ireland Ltd All rights reserved.
Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet
aDepartment of Comparative Medicine, University of Washington, Seattle, WA 98195, United States
bDepartment of Pathology, University of Washington, Seattle, WA 98195, United States
Received 7 September 2006;
revised 23 November 2007;
accepted 19 December 2007.
Available online 17 January 2008.
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Abstract
Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.
Keywords: Progeriod syndrome; Werner's syndrome; High fat and sugar diet; Type 2 diabetes; Obesity
Fig. 1. Body weights of mice fed a diabetogenic diet high in fat and sugar (HFS) or a standard rodent chow (CHOW) from 4 through 10 months of age. Values are presented as means ± S.E.M. for five to eight mice per cohort. Significance for each time point is shown by P-values less than *0.0001. Wrn(−/−) mice are represented as closed triangles and squares. Wild type (WT) mice are represented as open triangles and squares.
Fig. 2. Fasting serum leptin levels were determined at 6, 8 and 10 months of age in mice fed HFS or CHOW. Values are presented as means ± S.E.M. for five to eight mice per cohort (HFS WT, open stipled bars; HFS Wrn(−/−), closed stipled bars; CHOW WT, open bars; CHOW Wrn(−/−), closed bars). P-value denotes significant difference (*<0.03) between WT and Wrn(−/−) mice fed HFS or CHOW for each time point.
Fig. 3. Blood glucose levels in mice fed HFS diet starting at 4 months of age and continuing to 10 months of age. Values are presented as medians ± S.E.M. for five to eight mice per set with significant difference (*P = 0.022) between the WT and Wrn(−/−) mice. Wrn(−/−) mice are represented as closed triangles and squares and WT mice are represented as open triangles and squares.
Fig. 4. Fasting serum insulin levels in mice fed HFS at 6, 8 and 10 months of age. Mice were introduced to the diet at 4 months of age. Values are presented as means ± S.E.M. for five to eight mice per cohort (HFS WT, open stipled bars; HFS Wrn(−/−), closed stipled bars; CHOW WT, open bars; CHOW Wrn(−/−), closed bars). P-value (*<0.001) denotes significant difference between the WT mice and the Wrn(−/−) fed HFS at 6 and 8 months of age, respectively. Serum insulin levels at 10 months of age were similar to that observed in mice fed CHOW.
Fig. 5. (A) Intraperitoneal glucose tolerance test (IPGTT) for WT (open triangles) and Wrn(−/−) (closed triangles) mice fed HFS. Values are presented as means ± S.E.M. for five to eight mice per cohort. At 5 months of age and after 1 month on the diet, mice were fasted overnight before the IPGTT was performed. P-value (*<0.01) denotes significant difference between WT and Wrn(−/−) mice fed HFS 60 min after injection of glucose. (B) Insulin-mediated glucose disposal for Wrn(−/−) mice fed HFS diet. Values are presented as means ± S.E.M. for five to eight mice per cohort. At 10 months of age and after 6 months on the diet, mice fed HFS or CHOW were subjected to the assay. P-value denotes significant difference between WT and Wrn(−/−) mice fed HFS (**<0.004).
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