Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake
Introduction
Diets enriched in fructose are known to induce features of metabolic syndrome in rats [1], [2]. However, these studies are frequently criticized for using excessive concentrations of fructose that are not physiological (eg, 60%) or for administering fructose alone (when most exposure to humans is as sucrose or high-fructose corn syrup) [3], [4]. Furthermore, there remains debate whether the effects of fructose to induce metabolic syndrome are simply a consequence of excessive energy intake [5]. Finally, whereas there are some data that added sugars may increase the risk for type 2 diabetes mellitus both experimentally [6] and in humans [7], [8], there is only minimal evidence that they have specific effects to induce islet cell dysfunction [9], [10], [11].
We therefore tested the hypothesis that a sucrose-based diet containing only 20% fructose might induce features of fatty liver and metabolic syndrome. To address whether the effects observed were specific to fructose, we administered an identical diet to control rats in which the sucrose was replaced with starch. Furthermore, all rats were pair fed so that each animal ate the exact same number of calories. To further ensure that intake was not excessive, all rats were fed approximately 90% of normal intake. The slight restriction in caloric intake is to simulate a dieting individual who still ingests a diet high in added sugars. Studies were performed in male Sprague-Dawley breeder rats, which are known to spontaneously develop features of metabolic syndrome as they age [12], [13]. Using this model system, we report that sucrose accelerated the development of metabolic syndrome and type 2 diabetes mellitus compared with starch-fed rats, in association with the development of mild inflammation in the pancreas.
Section snippets
Animals and diets
Eight-month-old male Sprague-Dawley breeder rats (Charles Rivers, Wilmington, MA) were housed in the animal facility at the University of Colorado. Rats were kept under temperature- and humidity-controlled specific pathogen-free conditions and maintained on a 12-hour light-dark cycle. The experimental protocols were approved by the University of Colorado Animal Care and Use Committee.
Rats were randomly divided into 2 groups, consisting of sucrose-fed (n = 10) or starch-fed (n = 10) rats. The
Results
Rats were pair fed isocaloric diets containing sucrose or starch for 4 months. Because all rats were pair fed, all rats received the identical energy intake.
Discussion
Although high concentrations of fructose are known to induce metabolic syndrome in male Sprague-Dawley rats, the studies have been criticized as being nonphysiologic. In addition, studies using pure fructose have been criticized because they do not mimic dietary habits in humans in which most fructose is from added sugars that also contain glucose either as a disaccharide (sucrose) or as a mixture of free monosaccharides (high-fructose corn syrup). Furthermore, there is significant debate over
Conflict of Interest
Dr R Johnson, Dr Nakagawa, and Dr Lanaspa have patent applications related to lowering uric acid or blocking fructose metabolism in the treatment of metabolic syndrome. Dr Johnson also has a book, The Sugar Fix (Rodale, 2008; and Simon and Schuster, 2009), which discusses the potential role of fructose in the obesity epidemic.
Acknowledgment
Supported by National Institutes of Health grant HL-68607 and startup funds at the University of Colorado (RJJ).
References (59)
No unique role for fructose sweeteners in obesity or cardiorenal disease
Am J Clin Nutr
(2008)Dietary sweeteners containing fructose: overview of a workshop on the state of the science
J Nutr
(2009)- et al.
Accelerated loss of islet beta cells in sucrose-fed Goto-Kakizaki rats, a genetic model of non-insulin-dependent diabetes mellitus
Am J Pathol
(1998) - et al.
Dietary regulation of fructose metabolism in the intestine and in the liver of the rat: time response and effect of cycloheximide
Int J Biochem
(1979) - et al.
Mechanisms for the acute effect of fructose on postprandial lipemia
Am J Clin Nutr
(2007) - et al.
Fatty acid metabolism and lipid secretion by perfused livers from rats fed laboratory stock and sucrose-rich diets
J Lipid Res
(1987) - et al.
Fructose consumption as a risk factor for non-alcoholic fatty liver disease
J Hepatol
(2008) - et al.
Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men
J Nutr
(1983) - et al.
Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose
Am J Clin Nutr
(1983) - et al.
Effect of fructose feeding on insulin secretion and insulin action in the rat
Metabolism
(1980)
Nocturnal hypertension in mice consuming a high fructose diet
Auton Neurosci
Fructose-induced hyperuricaemia
Lancet
Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents
J Pediatr
Effect of increased serum urate levels on virgin rats with no arteriosclerosis versus breeder rats with preexistent arteriosclerosis
Metabolism
The relation of sugar intake to beta cell function in overweight Latino children
Am J Clin Nutr
Effects of dietary fructose on plasma lipids in healthy subjects
Am J Clin Nutr
Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism
Nutr Rev
Adiponectin and adiponectin receptors
Endocr Rev
Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association
Circulation
Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid
Am J Physiol
Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women
Jama
Sugar sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis
Diabetes Care
Augmented beta cell loss and mitochondrial abnormalities in sucrose-fed GK rats
Virchows Arch
Islet adaptive changes to fructose-induced insulin resistance: beta-cell mass, glucokinase, glucose metabolism, and insulin secretion
J Endocrinol
Age-related pancreatic islet changes in Sprague-Dawley rats
Toxicol Pathol
Pathophysiological differences between paired and communal breeding of male and female Sprague-Dawley rats
Circ Res
Fructose induces the inflammatory molecule ICAM-1 in endothelial cells
J Am Soc Nephrol
The tight junction protein, MUPP1, is up-regulated by hypertonicity and is important in the osmotic stress response in kidney cells
Proc Natl Acad Sci U S A
Dietary regulation of fructose metabolism in the intestine and in the liver of the rat. Duration of the effects of a high fructose diet after the return to the standard diet
Arch Int Physiol Biochim Biophys
Cited by (137)
Accumulation and ecotoxicological effects induced by combined exposure of different sized polyethylene microplastics and oxytetracycline in zebrafish
2023, Environmental PollutionCitation Excerpt :The significantly increased ballooning rate in OTC and SNO treatments might be influenced by the enriched PPAR signaling pathway, which regulate the hepatic lipogenesis (Nguyen et al., 2008). Starch and sucrose are essential in energy metabolism regulation in livers (Roncal-Jimenez et al., 2011), the disturbances of glucose metabolism induced by microplastics has been reported in previous research (Sheng et al., 2021; Zhao et al., 2020). Similar to our results, microplastics and their combination with triclosan induced an enriched pathway of starch and sucrose metabolism (Sheng et al., 2021).
Bidirectional temporal relationships between uric acid and insulin and their joint impact on incident diabetes
2023, Nutrition, Metabolism and Cardiovascular DiseasesUric Acid and Chronic Kidney Disease: Still More to Do
2023, Kidney International ReportsNeuro-behavioral implications of a high-fructose diet
2023, Diet and Nutrition in Neurological Disorders
Author contributions: study design: CRJ, MAL, CJR, TN, LGS, DJ, RJJ; performance of study: CRJ, MAL, CJR, LGS, AAH ; data analysis; CRJ,MAL, CJR, AAH; KM; writing, reviewing, and editing of manuscript: CRJ, MAL, TN, LGS, DJ, KT, MM, YYS, RJJ.