Molecular and Cellular Biochemistry

, Volume 423, Issue 1–2, pp 93–104 | Cite as

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

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


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.


ER stress Insulin resistance High-fat High-fructose Gluconeogenesis Apoptosis 



Glucose-regulated protein-78


PKR-like ER kinase


Inositol-requiring enzyme-1α


X box-binding protein1


CCAAT/enhancer-binding homologous protein


Insulin-induced gene1


Sterol regulatory element-binding protein


Pancreatic and duodenal homeobox 1


Forkhead box protein O1


Phosphoenolpyruvate carboxykinase


c-Jun N-terminal kinases



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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Supplementary material

11010_2016_2828_MOESM1_ESM.docx (24 kb)
Supplementary material 1 (DOCX 23 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • M. Balakumar
    • 1
  • L. Raji
    • 1
  • D. Prabhu
    • 1
  • C. Sathishkumar
    • 1
  • P. Prabu
    • 1
  • V. Mohan
    • 1
  • M. Balasubramanyam
    • 1
  1. 1.Department of Cell and Molecular Biology and Dr. Rema Mohan High-Throughput Screening (HTS) LabMadras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialties Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention & ControlChennaiIndia

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