High-fructose diet is as detrimental as high-fat diet in the induction of insulin resistance and diabetes mediated by hepatic/pancreatic endoplasmic reticulum (ER) stress

Abstract

In the context of high human consumption of fructose diets, there is an imperative need to understand how dietary fructose intake influence cellular and molecular mechanisms and thereby affect β-cell dysfunction and insulin resistance. While evidence exists for a relationship between high-fat-induced insulin resistance and metabolic disorders, there is lack of studies in relation to high-fructose diet. Therefore, we attempted to study the effect of different diets viz., high-fat diet (HFD), high-fructose diet (HFS), and a combination (HFS + HFD) diet on glucose homeostasis and insulin sensitivity in male Wistar rats compared to control animals fed with normal pellet diet. Investigations include oral glucose tolerance test, insulin tolerance test, histopathology by H&E and Masson's trichrome staining, mRNA expression by real-time PCR, protein expression by Western blot, and caspase-3 activity by colorimetry. Rats subjected to high-fat/fructose diets became glucose intolerant, insulin-resistant, and dyslipidemic. Compared to control animals, rats subjected to different combination of fat/fructose diets showed increased mRNA and protein expression of a battery of ER stress markers both in pancreas and liver. Transcription factors of β-cell function (INSIG1, SREBP1c and PDX1) as well as hepatic gluconeogenesis (FOXO1 and PEPCK) were adversely affected in diet-induced insulin-resistant rats. The convergence of chronic ER stress towards apoptosis in pancreas/liver was also indicated by increased levels of CHOP mRNA & increased activity of both JNK and Caspase-3 in rats subjected to high-fat/fructose diets. Our study exposes the experimental support in that high-fructose diet is equally detrimental in causing metabolic disorders.

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

“…High fructose intake produces immediate change in hepatic and extrahepatic substrate metabolism, but the overall glucose production remains unchanged in some reports of human subjects [10] and rodents [11]. More frequently, fasting or postprandial glucose concentrations are increased after high fructose consumption in clinical trials [12] and animal experiments [13]. The elevated glucose output may cause an increase of insulin demand and trigger insulin over-release.…”

“…Impairment of β-cell mass and function inmales with high fructose diets result from dysregulation of leptin signaling and activation of protein kinase B (PKB/Akt)/Forkhead box protein (Fox) O1 in rat islets [15]. ER stress occurs in pancreatic β-cells under high fructose diet, as it is closely associated with insulin resistance, inflammation and abnormal lipid metabolism, possibly leading to glucose intolerance and insulin resistance [13]. …”

Fructose Consumption in the Development of Obesity and the Effects of Different Protocols of Physical Exercise on the Hepatic Metabolism

“…On the other hand, liver seems to be a key organ in the development of metabolic complications related to fructose-rich diets [21,22,23,24]. Wistar rats were fed diets containing 65% of the calories from fructose, and the accumulation of fat and collagen in the liver tissue was as evident as observed in animals fed a diet rich in saturated fat, promoting apoptosis in this tissue and activation of proteins related to endoplasmic reticulum stress and inflammatory process [21].…”

“…Wistar rats were fed diets containing 65% of the calories from fructose, and the accumulation of fat and collagen in the liver tissue was as evident as observed in animals fed a diet rich in saturated fat, promoting apoptosis in this tissue and activation of proteins related to endoplasmic reticulum stress and inflammatory process [21]. Recently, an important study with primates showed that diets rich in fructose were able to induce a hepatic steatosis stage, with lipid droplet size positively correlated to time of exposure to the diet [24].…”

Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome

“…In a study in rats, fructose induced the mRNA and protein expression of ER stress markers, including GRP-78, PERK, IRE1α, and CHOP in the liver [81]; which on one hand might contribute to the hepatic activation of SREBP-1c and lipid accumulation in fructose-induced NAFLD [38], and on the other hand the increased ER-stress is also suggested to cause hepatic insulin resistance by increasing de novo lipogenesis [10,82]. Another central role of the ER is to control the transport and metabolism of cholesterol, an essential component of cellular membranes, which is mainly regulated by transcription factors of the SREBP family [83].…”