Long-term hypertriglyceridemia and glucose intolerance in rats fed chronically an isocaloric sucrose-rich diet

doi:10.1016/0026-0495(87)90019-9

Metabolism

Volume 36, Issue 11, November 1987, Pages 1013-1020

https://doi.org/10.1016/0026-0495(87)90019-9 Get rights and content

Abstract

We have previously shown that short-term feeding [20 to 25 day induction period (IP)] normal rats a sucrose-rich diet (SRD) results in an increase of plasma (P), liver (L), and heart (H) triacylglycerol (TG) levels, accompanied by a drop in plasma postheparin total (T-TGL) and hepatic (H-TGL) triglyceride lipases activities, IV glucose intolerance (low Kg) and hyperinsulin responses both in vivo and in vitro, suggesting that a state of insulin resistance had developed. Since normalization of P-TG ensued in the medium term [40 to 55 day adaptation period (AP)] we decided to carry out a longitudinal, long-term (90 to 120 day) follow-up study to observe the dynamic behavior of the above metabolic and hormonal parameters as compared to the appropriate time course control rats were fed the standard chow (STD). Results obtained indicated that normalization of all parameters studied took place during the medium term (40 to 55 day) AP including P,L,H-TG,T-TGL, and H-TGL, IV glucose tolerance and insulin secretion both in vivo and in vitro. Results obtained during the long-term (90 to 120 day) period were as follows: P-TG, SRD: 1.80 ± 0.22 v 0.77 ± 0.06 in STD (P < .01); L-TG, SRD: 21.2 ± 2.6 v 9.7 ± 0.3 in STD (P < .001); H-TG, SRD: 6.99 ± 0.57 v 4.05 ± 0.20 in STD (P < .01); H-TGL, SRD: 5.81 ± 0.25 v 5.75 ± 0.64 in STD; T-TGL, SRD: 7.75 ± 0.34 v 7.84 ± 0.65 in STD; Kg. 10⁻², SRD: 0.98 ± 0.12 v 1.45 ± 0.16 in STD (P < .01); IRI in vivo, SRD: 95 ± 8 v 96 ± 11 in STD; IRI in vitro: 0 mmol/L glucose: 17 ± 6; 5.6 mmol/L glucose: 64 ± 8 (P < .01). Percentage of H-TGL of T-TGL was unchanged. Thus, normalization of metabolic and hormonal parameters recorded during the AP was followed by a recurrence of abnormal TG levels in plasma and tissues as well as an abnormal glucose tolerance in the long-term follow-up [recurrence period (RP)] in spite of normal levels of T-TGL and H-TGL, normal insulin response in vivo to IV glucose and only moderate increments of insulin release in vitro. Our results indicate that feeding chronically high sucrose to rats leads to major multiphasic abnormalities in carbohydrate and lipid metabolism, which are similar to those found in patients with lipid disorders associated with glucose intolerance or non-insulin-dependent diabetes mellitus. SRD fed rats may prove to be a valuable experimental animal model in which to carry out studies on the pathophysiologic mechanisms involved in the above human disorders.

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Obesity and particularly visceral adiposity are accompanied by increased oxidative stress (OS) due to an unfavorable critical balance between the generation of free radicals and antioxidant defenses that in turn affect insulin signaling and contribute to insulin resistance, all of them key factors of the metabolic syndrome. Recent investigations have shown that increases in the consumption of natural dietary sources with antioxidant bioactive compounds may support the prevention of OS. Salvia hispanica L. seed is a rich botanical source of α-linolenic acid 18:3 n–3 and is a promising source of antioxidants because it contains considerable amounts of chlorogenic and caffeic acids, myricetin, quercetin, and kaempferol, among others. This chapter analyzes the effect of dietary S. hispanica L. seeds upon the improvement and/or reversion of OS and its relationship with insulin insensitivity. It focuses on the adipose tissue of an experimental model of dyslipidemia, impaired glucose homeostasis, insulin resistance, and visceral adiposity.
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Notwithstanding, NAFLD onset also coincided with the triggering of peripheral insulin resistance. MetS development herein described is corroborated by previous studies, which reported similar development of central obesity, hypertriglyceridemia, glucose intolerance, hyperinsulinemia and insulin resistance, besides applying higher supplementary sucrose concentrations (35%–63%) for at least 12 weeks in rodents [43–46]. Interestingly, HSD mice gained more body weight despite having had a lower energy intake throughout the experimental time.
Childhood consumption of added sugars, such as sucrose, has been associated to increased risk of metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Although the mechanisms underlying NAFLD onset are incompletely defined, recent evidence has proposed a role for the endoplasmic reticulum (ER) stress. Thus, the present study sought to investigate the metabolic outcomes of high-sucrose intake on weaned Swiss mice fed a 25% sucrose diet for 30, 60 and 90 days in comparison to regular chow-fed controls. High-sucrose feeding promoted progressive metabolic and oxidative disturbances, starting from fasting and fed hyperglycemia, hyperinsulinemia, glucose intolerance and increased adiposity at 30-days; passing by insulin resistance, hypertriglyceridemia and NAFLD onset at 60 days; until late hepatic oxidative damage at 90 days. In parallel, assessment of transcriptional and/or translational levels of de novo lipogenesis (DNL) and ER stress markers showed up-regulation of both fatty acid synthesis (ChREBP and SCD1) and oxidation (PPARα and CPT-1α), as well as overexpression of unfolded protein response sensors (IRE1α, PERK and ATF6), chaperones (GRP78 and PDIA1) and antioxidant defense (NRF2) genes at 30 days. At 60 days, fatty acid oxidation genes were down-regulated, and ER stress switched over toward a proapoptotic pattern via up-regulation of BAK protein and CHOP gene levels. Finally, down-regulation of both NRF2 and CPT-1α protein levels led to late up-regulation of SREBP-1c and exponential raise of fatty acids synthesis. In conclusion, our study originally demonstrates a temporal relationship between DNL and ER stress pathways toward MetS and NAFLD development on weaned rats fed a high-sucrose diet.
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Long term excess sucrose feeding in rodents induces weight gain, hyperglycemia and glucose intolerance, with variable insulin responses (Hallfrisch, Lazar, Jorgensen, & Reiser, 1979; Lombardo, Drago, & Chicco, 1996). A high sucrose diet can also induce insulin resistance, hyperinsulinemia (Gutman, Basilico, Bernal, Chicco, & Lombardo, 1987) or hypertriglyceridemia and hypertension without obesity or changes in fasting plasma glucose and leptin (Chevalier, Wiley, & Leveille, 1972; Agheli, Kabir, & Berni-Canani, 1998; London, Lala, & Berger, 2007). Diabetes alters wound healing (Meyer, 1996; Nolan, Damm, & Prentki, 2011) and is associated with higher PD prevalence and increased severity in humans (Leite, Marlow, & Fernandes, 2013; Watanabe, Petro, Shlimon, & Unterman, 2008).
To characterize in rice rats: (a) periodontitis (PD) progress with feeding of standard laboratory rat chow (STD) during ages 4–80 weeks; and (b) PD progress with feeding of a high sucrose-casein (H-SC) diet during young adulthood.
One group (N = 12) was euthanized at age 4 weeks (Baseline). Four groups (N = 8-16) consumed a STD diet from baseline and were necropsied at ages 22, 30, 52, and 80 weeks. Three groups (N = 10-16) consumed an H-SC diet from baseline. Two were necropsied at ages 22 and 30 weeks, respectively. The third switched to the STD diet at age 22 weeks and was necropsied at age 30 weeks. All mandibles/maxillae were assessed by histometry for degree of periodontal inflammation (PD Score), alveolar crest height (ACH, mm), and horizontal alveolar bone height (hABH, mm²).
In STD diet rats aged ≥30 weeks, all endpoints were worse (P < 0.05) than at Baseline. In H-SC diet rats aged ≥22 weeks, all endpoints were worse than at Baseline (P < 0.05). At age 22 weeks, all endpoints were worse in the H-SC group than in the STD group (P < 0.05). By age 30 weeks, the STD and H-SC groups did not differ.
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Among the sugars, the monosaccharide, fructose, and the disaccharide, sucrose (fructose + glucose), seem to be of greater concern than glucose alone (as a monosaccharide, or as a polysaccharide in starch). The fructose-containing sugars seem to cause greater derangement when it comes to elevated insulin levels,56,65,66 reduced insulin sensitivity,67–71 increased fasting glucose concentrations,72,73 and increased glucose and insulin responses to a sucrose load.56,65 Providing liquid fructose supplementation to a western-type diet in mice increases lipid burden and atherosclerosis despite identical calorie consumption.74
Dietary guidelines continue to recommend restricting intake of saturated fats. This recommendation follows largely from the observation that saturated fats can raise levels of total serum cholesterol (TC), thereby putatively increasing the risk of atherosclerotic coronary heart disease (CHD). However, TC is only modestly associated with CHD, and more important than the total level of cholesterol in the blood may be the number and size of low-density lipoprotein (LDL) particles that contain it. As for saturated fats, these fats are a diverse class of compounds; different fats may have different effects on LDL and on broader CHD risk based on the specific saturated fatty acids (SFAs) they contain. Importantly, though, people eat foods, not isolated fatty acids. Some food sources of SFAs may pose no risk for CHD or possibly even be protective. Advice to reduce saturated fat in the diet without regard to nuances about LDL, SFAs, or dietary sources could actually increase people's risk of CHD. When saturated fats are replaced with refined carbohydrates, and specifically with added sugars (like sucrose or high fructose corn syrup), the end result is not favorable for heart health. Such replacement leads to changes in LDL, high-density lipoprotein (HDL), and triglycerides that may increase the risk of CHD. Additionally, diets high in sugar may induce many other abnormalities associated with elevated CHD risk, including elevated levels of glucose, insulin, and uric acid, impaired glucose tolerance, insulin and leptin resistance, non-alcoholic fatty liver disease, and altered platelet function. A diet high in added sugars has been found to cause a 3-fold increased risk of death due to cardiovascular disease, but sugars, like saturated fats, are a diverse class of compounds. The monosaccharide, fructose, and fructose-containing sweeteners (e.g., sucrose) produce greater degrees of metabolic abnormalities than does glucose (either isolated as a monomer, or in chains as starch) and may present greater risk of CHD. This paper reviews the evidence linking saturated fats and sugars to CHD, and concludes that the latter is more of a problem than the former. Dietary guidelines should shift focus away from reducing saturated fat, and from replacing saturated fat with carbohydrates, specifically when these carbohydrates are refined. To reduce the burden of CHD, guidelines should focus particularly on reducing intake of concentrated sugars, specifically the fructose-containing sugars like sucrose and high-fructose corn syrup in the form of ultra-processed foods and beverages.
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^☆: Supported by CONICET (Consejo Nacional de Investigaciones Cientificas y Tecnológicas), Argentina by Grant 0088/85, and with financial aid from A.J. Roemmers Foundation for Biochemistry Research, Argentina.

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Long-term hypertriglyceridemia and glucose intolerance in rats fed chronically an isocaloric sucrose-rich diet☆

Abstract

Atherosclerosis

Life Sci

Metabolism

Metabolism

J Nutr

J Lipid Res

Am J Clin Nutr

J Lipid Res

J Biol Chem

Clin Chim Acta

J Biol Chem

Biochim Biophys Acta

Metabolism

Metabolism

J Nutr

Am J Clin Nutr

Carbohydrate induced and fat lipemia

Trans Assoc Am Physicians

Diabetic hypertriglyceridemia in the rat: animal models stimulating the syndromes of impaired glucose tolerance non-insulin dependent diabetes, and insulin dependent diabetes

Effect of different levels of protein in sucrose and starch diets on lipid synthesis in the rat

Isr J Med Sci

Post-heparin plasma hepatic triglycerides lipase and monoglyceride hydrolase activities in hyperlipemia induced by a sucrose-rich diet

Biomed Pharmacother

Effect of sucrose diet on insulin secretion in vivo and in vitro and on triglyceride storage and mobilisation of the heart of rats

Horm Metab Res

Effect of sucrose and fructose on carbohydrate and lipid metabolism and the resulting consequences

Long-term effects of moderate fructose feeding on lipogenic parameters in Wistar rats

Nutr Rep Int