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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

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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.

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Abbreviations

GRP-78:

Glucose-regulated protein-78

PERK:

PKR-like ER kinase

IRE-1α :

Inositol-requiring enzyme-1α

XBP1:

X box-binding protein1

CHOP:

CCAAT/enhancer-binding homologous protein

INSIG1:

Insulin-induced gene1

SREBP1c:

Sterol regulatory element-binding protein

PDX1:

Pancreatic and duodenal homeobox 1

FOXO1:

Forkhead box protein O1

PEPCK:

Phosphoenolpyruvate carboxykinase

JNK:

c-Jun N-terminal kinases

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Acknowledgments

Authors acknowledge grant support from the Department of Biotechnology (DBT) & Indian Council of Medical Research (ICMR), New Delhi, Govt. of India. Authors also acknowledge financial assistance (Senior Research Fellowship) from the Council of Scientific & Industrial Research (CSIR), New Delhi, India.

Author Contributions

M. B. conceived and designed the study, provided critical research materials, assisted with analysis of the results, composed, drafted, and edited the manuscript. V. M. reviewed and edited the manuscript. B. M., L. R., D. P., C. S., and P. P. performed the experiments, acquired and analyzed the data, interpreted the results, and contributed to discussion. Both B. M and L. R. equally contributed to the molecular investigations on ER stress markers.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) Lab, Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialties Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention & Control, Gopalapuram, Chennai, 600086, India

    M. Balakumar, L. Raji, D. Prabhu, C. Sathishkumar, P. Prabu, V. Mohan & M. Balasubramanyam

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  1. M. Balakumar
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  2. L. Raji
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  6. V. Mohan
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Balakumar, M., Raji, L., Prabhu, D. et al. 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. Mol Cell Biochem 423, 93–104 (2016). https://doi.org/10.1007/s11010-016-2828-5

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