Chronological Appearance of Endocrine and Metabolic Dysfunctions Induced by an Unhealthy Diet in Rats

Abstract

Background and Objectives: The work was aimed to determine the chronological sequence of events triggered by a fructose-rich diet (FRD) (10% w/v in the drinking water) in normal rats. Material and Methods: Serum parameters, liver and islet markers of metabolism, inflammation and oxidative stress were determined weekly for 21 days. Results: At the end of the first week, rats fed with a FRD showed an early increase in circulating triglycerides, fat liver deposit, and enzymatic activity of liver glucokinase and glucose-6-phosphate dehydrogenase (G6P-DH). After two weeks of such a diet, liver glucose-6-phosphatase (G6Pase) activity and liver oxidative stress markers were significantly increased. Liver sterol regulatory element-binding protein 1c (SREBP1c) mRNA also increased in the second week while their target genes fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPAT) enhanced their expression at the third week. Liver and pancreatic inflammation markers also enhanced their gene expression in the last week of treatment. Whereas both control and FRD rats remained normoglycemic throughout the entire period of treatment, blood insulin levels were significantly higher in FRD animals at the third week, thereby evidencing an insulin-resistant state (higher HOMA-IR, HOMA-B and HIS indexes). Pancreatic islets isolated from rats fed with a FRD for 3 weeks also increased glucose-induced insulin secretion (8.3 and 16.7 mM). Conclusions: FRD induces asynchronous changes involving early hypertriglyceridemia together with intrahepatic lipid deposit and metabolic disturbances from week one, followed by enhanced liver oxidative stress, liver and pancreas inflammation, pancreatic β-cell dysfunction, and peripheral insulin-resistance registered at the third week. Knowledge of time-course adaptation mechanisms involved in our rat model could be helpful in developing appropriate strategies to prevent the progression from prediabetes to Type 2 diabetes (T2D) triggered by unhealthy diets.

Protective Effect of Monoterpene Isoespintanol in a Rat Model of Prediabetes Induced by Fructose

“…In previous studies employing the rat prediabetes model induced by administration of a fructose-rich diet, we demonstrated enhanced liver oxidative stress and inflammation, together with endocrine–metabolic dysfunction including insulin resistance [ 8 ], constituting a triad that self-perpetuates in a vicious pathogenic circle which can be effectively disrupted by antioxidant co-administration [ 9 ]. In this sense, isoespintanol has been shown to intervene pharmacologically through different pathways, including oxidative stress and inflammation regulation.…”

“…Fructose-fed rats showed significantly lower levels of p-Akt (phosphorylated at Serine473) together with an increase in hepatic markers of lipogenesis [ 8 ]. It is known that Akt can be activated by phosphorylation at Serine473 by mTORC2 [ 40 ].…”

“…Therefore, high consumption of free fructose (present in HFCS) is considered a major contributor to the current epidemic of diabetes, obesity, and other metabolic disorders [ 4 , 5 , 6 , 7 ]. In our laboratory, we have previously demonstrated that administration of a fructose-rich diet (10% w / v in the drinking water) to normal rats for three weeks, induced several endocrine–metabolic changes, including dyslipidemia, altered glucose tolerance, insulin resistance, liver steatosis, and endocrine pancreas dysfunction [ 8 , 9 , 10 , 11 , 12 ]. These abnormalities are like those described in the metabolic syndrome in humans and, in consequence, fructose-fed rats model constitute a good and validated model for studying possible pharmacological interventions at early stages of diabetes development.…”

Diabetes and diabesity in the view of proteomics, drug, and plant-derived remedies

“…[ 62 ] Fructose leads to several metabolic derangements, most importantly insulin resistance. [ 63 ] Fructose reduces the expression of GLUT4 gene, significantly increases hepatic triglyceride synthesis, impairs insulin signaling, and subsequently reduces insulin sensitivity. [ 59 , 64 ] Fructose reduces hepatic expression of IRS-2, increases plasma insulin levels, and causes an abnormal glucose tolerance test indicating disturbed hepatic insulin signaling.…”

Efecto de la ovariectomía prepuberal sobre la función del tejido adiposo blanco abdominal y subcutáneo

“…El consumo de fructosa está asociado al desarrollo de obesidad y sus comorbilidades, como dislipidemia, insulino-resistencia, hipertensión arterial y aparición de hígado graso [257][258][259] . Si bien la duración del tratamiento no permitió a los animales desarrollar grandes complicaciones, inició una respuesta que podría dirigirse hacia ese camino, tal como se encuentra descripto en sentido cronológico en otros estudios 260,261 . Los efectos provocados por la fructosa son amplios y complejos, influyendo sobre varios tejidos como el corazón 262,263 , hígado 264,265 y otros 266,267 , no obstante hemos dedicado nuestros esfuerzos a estudiar lo sucedido dentro del TAB y su asociación con el metabolismo general.…”